2021
|
Serhan, Nadine ; Cenac, Nicolas ; Basso, Lilian ; Gaudenzio, Nicolas Mas-related G protein-coupled receptors (Mrgprs) - Key regulators of neuroimmune interactions Article de journal Neuroscience Letters, 2021, ISSN: 03043940. Liens | BibTeX @article{Serhan2021,
title = {Mas-related G protein-coupled receptors (Mrgprs) - Key regulators of neuroimmune interactions},
author = {Serhan, Nadine and Cenac, Nicolas and Basso, Lilian and Gaudenzio, Nicolas},
doi = {10.1016/j.neulet.2021.135724},
issn = {03043940},
year = {2021},
date = {2021-01-01},
journal = {Neuroscience Letters},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
|
2020
|
Starkl, Philipp ; Watzenboeck, Martin L; Popov, Lauren M; Zahalka, Sophie ; Hladik, Anastasiya ; Lakovits, Karin ; Radhouani, Mariem ; Haschemi, Arvand ; Marichal, Thomas ; Reber, Laurent L; Gaudenzio, Nicolas ; Sibilano, Riccardo ; Stulik, Lukas ; Fontaine, Fr{é}d{é}ric ; Mueller, Andr{é} C; Amieva, Manuel R; Galli, Stephen J; Knapp, Sylvia IgE Effector Mechanisms, in Concert with Mast Cells, Contribute to Acquired Host Defense against Staphylococcusaureus. Article de journal Immunity, 53 (4), p. 793–804.e9, 2020, ISSN: 1097-4180 (Electronic). Résumé | Liens | BibTeX @article{Starkl2020,
title = {IgE Effector Mechanisms, in Concert with Mast Cells, Contribute to Acquired Host Defense against Staphylococcusaureus.},
author = {Starkl, Philipp and Watzenboeck, Martin L and Popov, Lauren M and Zahalka, Sophie and Hladik, Anastasiya and Lakovits, Karin and Radhouani, Mariem and Haschemi, Arvand and Marichal, Thomas and Reber, Laurent L and Gaudenzio, Nicolas and Sibilano, Riccardo and Stulik, Lukas and Fontaine, Fr{é}d{é}ric and Mueller, Andr{é} C and Amieva, Manuel R and Galli, Stephen J and Knapp, Sylvia},
doi = {10.1016/j.immuni.2020.08.002},
issn = {1097-4180 (Electronic)},
year = {2020},
date = {2020-10-01},
journal = {Immunity},
volume = {53},
number = {4},
pages = {793--804.e9},
abstract = {Allergies are considered to represent mal-directed type 2 immune responses against mostly innocuous exogenous compounds. Immunoglobulin E (IgE) antibodies are a characteristic feature of allergies and mediate hypersensitivity against allergens through activation of effector cells, particularly mast cells (MCs). Although the physiological functions of this dangerous branch of immunity have remained enigmatic, recent evidence shows that allergic immune reactions can help to protect against the toxicity of venoms. Because bacteria are a potent alternative source of toxins, we assessed the possible role of allergy-like type 2 immunity in antibacterial host defense. We discovered that the adaptive immune response against Staphylococcus aureus (SA) skin infection substantially improved systemic host defense against secondary SA infections in mice. Moreover, this acquired protection depended on IgE effector mechanisms and MCs. Importantly, our results reveal a previously unknown physiological function of allergic immune responses, IgE antibodies, and MCs in host defense against a pathogenic bacterium.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Allergies are considered to represent mal-directed type 2 immune responses against mostly innocuous exogenous compounds. Immunoglobulin E (IgE) antibodies are a characteristic feature of allergies and mediate hypersensitivity against allergens through activation of effector cells, particularly mast cells (MCs). Although the physiological functions of this dangerous branch of immunity have remained enigmatic, recent evidence shows that allergic immune reactions can help to protect against the toxicity of venoms. Because bacteria are a potent alternative source of toxins, we assessed the possible role of allergy-like type 2 immunity in antibacterial host defense. We discovered that the adaptive immune response against Staphylococcus aureus (SA) skin infection substantially improved systemic host defense against secondary SA infections in mice. Moreover, this acquired protection depended on IgE effector mechanisms and MCs. Importantly, our results reveal a previously unknown physiological function of allergic immune responses, IgE antibodies, and MCs in host defense against a pathogenic bacterium. |
Jendoubi, Fatma ; Gaudenzio, Nicolas ; Gallini, Adeline ; Negretto, Mathilde ; Paul, Carle ; {Bulai Livideanu}, Cristina Omalizumab in the treatment of adult patients with mastocytosis: A systematic review. Article de journal Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology, 50 (6), p. 654–661, 2020, ISSN: 1365-2222 (Electronic). Résumé | Liens | BibTeX @article{Jendoubi2020b,
title = {Omalizumab in the treatment of adult patients with mastocytosis: A systematic review.},
author = {Jendoubi, Fatma and Gaudenzio, Nicolas and Gallini, Adeline and Negretto, Mathilde and Paul, Carle and {Bulai Livideanu}, Cristina},
doi = {10.1111/cea.13592},
issn = {1365-2222 (Electronic)},
year = {2020},
date = {2020-06-01},
journal = {Clinical and experimental allergy : journal of the British Society for Allergy and Clinical Immunology},
volume = {50},
number = {6},
pages = {654--661},
abstract = {BACKGROUND: Mastocytosis is associated with mast cell (MC) mediator-related symptoms for which limited therapies are available. OBJECTIVE: Our aim was to assess the efficacy and safety of omalizumab in the treatment of MC mediator-related symptoms in adult patients with mastocytosis. RESULTS: We identified one multi-centre retrospective cohort study (39 patients), one retrospective cohort study (13 patients), 4 case series and 10 case reports. No published controlled randomized study was identified. We included 69 patients (13 patients with cutaneous mastocytosis and 56 with systemic mastocytosis). The mean age was 48 years. Omalizumab maintenance dose was 300 mg for the majority of patients. The mean duration of treatment was 17 months. Treatment led to a tolerability of venom immunotherapy and to a complete resolution of severe reactions in all patients with post-honeybee sting anaphylaxis. Complete resolution of idiopathic anaphylaxis episodes was noted in 84% of the patients. Complete resolution of palpitations, gastrointestinal, cutaneous, neuropsychiatric, respiratory and musculoskeletal symptoms was observed at a rate of 43%, 29%, 27%, 11%, 9% and 0%, respectively. Efficacy was maintained for the entire duration of the treatment in all but four responders. Adverse events were reported for 13 patients. CONCLUSIONS AND CLINICAL RELEVANCE: Omalizumab appears to prevent some life-threatening reactions associated with mastocytosis and may be a good option to treat the associated symptoms. However, the evidence relied upon is observational, uncontrolled and from a small number of patients. A randomized controlled trial is needed to better understand the place of omalizumab in mastocytosis treatment.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Mastocytosis is associated with mast cell (MC) mediator-related symptoms for which limited therapies are available. OBJECTIVE: Our aim was to assess the efficacy and safety of omalizumab in the treatment of MC mediator-related symptoms in adult patients with mastocytosis. RESULTS: We identified one multi-centre retrospective cohort study (39 patients), one retrospective cohort study (13 patients), 4 case series and 10 case reports. No published controlled randomized study was identified. We included 69 patients (13 patients with cutaneous mastocytosis and 56 with systemic mastocytosis). The mean age was 48 years. Omalizumab maintenance dose was 300 mg for the majority of patients. The mean duration of treatment was 17 months. Treatment led to a tolerability of venom immunotherapy and to a complete resolution of severe reactions in all patients with post-honeybee sting anaphylaxis. Complete resolution of idiopathic anaphylaxis episodes was noted in 84% of the patients. Complete resolution of palpitations, gastrointestinal, cutaneous, neuropsychiatric, respiratory and musculoskeletal symptoms was observed at a rate of 43%, 29%, 27%, 11%, 9% and 0%, respectively. Efficacy was maintained for the entire duration of the treatment in all but four responders. Adverse events were reported for 13 patients. CONCLUSIONS AND CLINICAL RELEVANCE: Omalizumab appears to prevent some life-threatening reactions associated with mastocytosis and may be a good option to treat the associated symptoms. However, the evidence relied upon is observational, uncontrolled and from a small number of patients. A randomized controlled trial is needed to better understand the place of omalizumab in mastocytosis treatment. |
Folkerts, Jelle ; Gaudenzio, Nicolas ; Maurer, Marcus ; Hendriks, Rudi W; Stadhouders, Ralph ; Tam, See-Ying ; Galli, Stephen J Rapid identification of human mast cell degranulation regulators using functional genomics coupled to high-resolution confocal microscopy. Article de journal Nature protocols, 15 (3), p. 1285–1310, 2020, ISSN: 1750-2799 (Electronic). Résumé | Liens | BibTeX @article{Folkerts2020,
title = {Rapid identification of human mast cell degranulation regulators using functional genomics coupled to high-resolution confocal microscopy.},
author = {Folkerts, Jelle and Gaudenzio, Nicolas and Maurer, Marcus and Hendriks, Rudi W and Stadhouders, Ralph and Tam, See-Ying and Galli, Stephen J},
doi = {10.1038/s41596-019-0288-6},
issn = {1750-2799 (Electronic)},
year = {2020},
date = {2020-03-01},
journal = {Nature protocols},
volume = {15},
number = {3},
pages = {1285--1310},
abstract = {Targeted functional genomics represents a powerful approach for studying gene function in vivo and in vitro. However, its application to gene expression studies in human mast cells has been hampered by low yields of human mast cell cultures and their poor transfection efficiency. We developed an imaging system in which mast cell degranulation can be visualized in single cells subjected to shRNA knockdown or CRISPR-Cas9 gene editing. By using high-resolution confocal microscopy and a fluorochrome-labeled avidin probe, one can directly assess the alteration of functional responses, i.e., degranulation, in single human mast cells (10-12 weeks old). The elimination of a drug or marker selection step avoids the use of potentially toxic treatment procedures, and the brief hands-on time of the functional analysis step enables high-throughput screening of shRNA or CRISPR-Cas9 constructs to identify genes that regulate human mast cell degranulation. The ability to analyze single cells substantially reduces the total number of cells required and enables the parallel visualization of the degranulation profiles of both edited and non-edited mast cells, offering a consistent internal control not found in other protocols. Moreover, our protocol offers a flexible choice between RNA interference (RNAi) and CRISPR-Cas9 genome editing for perturbation of gene expression using our human mast cell single-cell imaging system. Perturbation of gene expression, acquisition of microscopy data and image analysis can be completed within 5 d, requiring only standard laboratory equipment and expertise.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Targeted functional genomics represents a powerful approach for studying gene function in vivo and in vitro. However, its application to gene expression studies in human mast cells has been hampered by low yields of human mast cell cultures and their poor transfection efficiency. We developed an imaging system in which mast cell degranulation can be visualized in single cells subjected to shRNA knockdown or CRISPR-Cas9 gene editing. By using high-resolution confocal microscopy and a fluorochrome-labeled avidin probe, one can directly assess the alteration of functional responses, i.e., degranulation, in single human mast cells (10-12 weeks old). The elimination of a drug or marker selection step avoids the use of potentially toxic treatment procedures, and the brief hands-on time of the functional analysis step enables high-throughput screening of shRNA or CRISPR-Cas9 constructs to identify genes that regulate human mast cell degranulation. The ability to analyze single cells substantially reduces the total number of cells required and enables the parallel visualization of the degranulation profiles of both edited and non-edited mast cells, offering a consistent internal control not found in other protocols. Moreover, our protocol offers a flexible choice between RNA interference (RNAi) and CRISPR-Cas9 genome editing for perturbation of gene expression using our human mast cell single-cell imaging system. Perturbation of gene expression, acquisition of microscopy data and image analysis can be completed within 5 d, requiring only standard laboratory equipment and expertise. |
Meixiong, James ; Basso, Lilian ; Dong, Xinzhong ; Gaudenzio, Nicolas Nociceptor-Mast Cell Sensory Clusters as Regulators of Skin Homeostasis. Article de journal Trends in neurosciences, 43 (3), p. 130–132, 2020, ISSN: 1878-108X (Electronic). Résumé | Liens | BibTeX @article{Meixiong2020,
title = {Nociceptor-Mast Cell Sensory Clusters as Regulators of Skin Homeostasis.},
author = {Meixiong, James and Basso, Lilian and Dong, Xinzhong and Gaudenzio, Nicolas},
doi = {10.1016/j.tins.2020.01.001},
issn = {1878-108X (Electronic)},
year = {2020},
date = {2020-03-01},
journal = {Trends in neurosciences},
volume = {43},
number = {3},
pages = {130--132},
abstract = {Recent studies revealed the existence of unique functional links between mast cells and nociceptors in the skin. Here, we propose that mast cells and nociceptors form a single regulatory unit in both physiology and disease. In this model, MrgprB2/X2 signaling is a primary mechanism by which mast cells functionally interact with nociceptors to form specialized neuroimmune clusters that regulate pain, inflammation, and itch.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Recent studies revealed the existence of unique functional links between mast cells and nociceptors in the skin. Here, we propose that mast cells and nociceptors form a single regulatory unit in both physiology and disease. In this model, MrgprB2/X2 signaling is a primary mechanism by which mast cells functionally interact with nociceptors to form specialized neuroimmune clusters that regulate pain, inflammation, and itch. |
Corbi{è}re, Auriane ; Loste, Alexia ; Gaudenzio, Nicolas MRGPRX2 sensing of cationic compounds—A bridge between nociception and skin diseases? Article de journal Experimental Dermatology, 2020, ISSN: 16000625. Résumé | Liens | BibTeX @article{Corbiere2020,
title = {MRGPRX2 sensing of cationic compounds—A bridge between nociception and skin diseases?},
author = {Corbi{è}re, Auriane and Loste, Alexia and Gaudenzio, Nicolas},
doi = {10.1111/exd.14222},
issn = {16000625},
year = {2020},
date = {2020-01-01},
journal = {Experimental Dermatology},
abstract = {Mast cells are innate immune cells located at many barrier sites in the body and known to protect the host against environmental threats and to be involved in allergic diseases. More recently, new studies have investigated their roles in the regulation of skin inflammation and transmission of pain and itch sensations. Mast cell signalling through the Mas-related G protein-coupled receptor (MRGPR) X2 or its mouse orthologue MRGPRB2 has been reported to be one of the major mechanism by which mast cell can regulate such processes. MRGPRX2 and MRGPRB2 can induce mast cell degranulation upon binding to a broad panel of cationic molecules such as neuropeptides, bacteria-derived quorum sensing molecules, venom peptides, host defense peptides and, unfortunately, various FDA-approved drugs. Upon activation, mast cells release granule-associated proteases, lipids and multiple cytokines that can modulate vascular permeability, immune cells recruitment and activation status of tissue-projecting nociceptive sensory neurons (ie nociceptors). Here, we discuss the modality of MRGPRX2-dependent mast cell activation and its different consequences on the patterns of skin inflammation and associated diseases. We notably emphasize how MRGPRX2-dependent skin mast cell activation might trigger various pathological traits such as pruritus, pain and inflammation and therefore become a potential therapeutic target for inflammatory pain, itch, atopic dermatitis and drugs-induced injection site reactions.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Mast cells are innate immune cells located at many barrier sites in the body and known to protect the host against environmental threats and to be involved in allergic diseases. More recently, new studies have investigated their roles in the regulation of skin inflammation and transmission of pain and itch sensations. Mast cell signalling through the Mas-related G protein-coupled receptor (MRGPR) X2 or its mouse orthologue MRGPRB2 has been reported to be one of the major mechanism by which mast cell can regulate such processes. MRGPRX2 and MRGPRB2 can induce mast cell degranulation upon binding to a broad panel of cationic molecules such as neuropeptides, bacteria-derived quorum sensing molecules, venom peptides, host defense peptides and, unfortunately, various FDA-approved drugs. Upon activation, mast cells release granule-associated proteases, lipids and multiple cytokines that can modulate vascular permeability, immune cells recruitment and activation status of tissue-projecting nociceptive sensory neurons (ie nociceptors). Here, we discuss the modality of MRGPRX2-dependent mast cell activation and its different consequences on the patterns of skin inflammation and associated diseases. We notably emphasize how MRGPRX2-dependent skin mast cell activation might trigger various pathological traits such as pruritus, pain and inflammation and therefore become a potential therapeutic target for inflammatory pain, itch, atopic dermatitis and drugs-induced injection site reactions. |
Galli, Stephen J; Gaudenzio, Nicolas; Tsai, Mindy Mast Cells in Inflammation and Disease: Recent Progress and Ongoing Concerns Article de journal Annual Review of Immunology, 5 , 2020. Résumé | Liens | BibTeX @article{Galli2020,
title = {Mast Cells in Inflammation and Disease: Recent Progress and Ongoing Concerns},
author = {Stephen J Galli and Nicolas Gaudenzio and Mindy Tsai},
url = {https://doi.org/10.1146/annurev-immunol-071719-},
doi = {10.1146/annurev-immunol-071719},
year = {2020},
date = {2020-01-01},
journal = {Annual Review of Immunology},
volume = {5},
abstract = {Mast cells have existed long before the development of adaptive immunity, although they have been given different names. Thus, in the marine urochor-date Styela plicata, they have been designated as test cells. However, based on their morphological characteristics (including prominent cytoplasmic granules) and mediator content (including heparin, histamine, and neutral pro-teases), test cells are thought to represent members of the lineage known in vertebrates as mast cells. So this lineage presumably had important functions that preceded the development of antibodies, including IgE. Yet mast cells are best known, in humans, as key sources of mediators responsible for acute allergic reactions, notably including anaphylaxis, a severe and potentially fatal IgE-dependent immediate hypersensitivity reaction to apparently harmless antigens, including many found in foods and medicines. In this review, we briefly describe the origins of tissue mast cells and outline evidence that 49},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Mast cells have existed long before the development of adaptive immunity, although they have been given different names. Thus, in the marine urochor-date Styela plicata, they have been designated as test cells. However, based on their morphological characteristics (including prominent cytoplasmic granules) and mediator content (including heparin, histamine, and neutral pro-teases), test cells are thought to represent members of the lineage known in vertebrates as mast cells. So this lineage presumably had important functions that preceded the development of antibodies, including IgE. Yet mast cells are best known, in humans, as key sources of mediators responsible for acute allergic reactions, notably including anaphylaxis, a severe and potentially fatal IgE-dependent immediate hypersensitivity reaction to apparently harmless antigens, including many found in foods and medicines. In this review, we briefly describe the origins of tissue mast cells and outline evidence that 49 |
2019
|
Basso, Lilian ; Serhan, Nadine ; Tauber, Marie ; Gaudenzio, Nicolas Peripheral neurons: Master regulators of skin and mucosal immune response. Article de journal European journal of immunology, 49 (11), p. 1984–1997, 2019, ISSN: 1521-4141 (Electronic). Résumé | Liens | BibTeX @article{Basso2019,
title = {Peripheral neurons: Master regulators of skin and mucosal immune response.},
author = {Basso, Lilian and Serhan, Nadine and Tauber, Marie and Gaudenzio, Nicolas},
doi = {10.1002/eji.201848027},
issn = {1521-4141 (Electronic)},
year = {2019},
date = {2019-11-01},
journal = {European journal of immunology},
volume = {49},
number = {11},
pages = {1984--1997},
abstract = {The body is innervated by a meshwork of heterogeneous peripheral neurons (including sensory neurons) which project virtually to all the organs. Peripheral neurons have been studied extensively in the context of their primary function of initiation of voluntary and involuntary movement, transmission of sensations and induction of appropriate behavioral response such as withdrawal to avoid tissue injury or scratching to remove irritating molecules. More recently, breakthrough articles have shown that, on top of their primary function of signal transmission to the spinal cord and brain, peripheral neurons (including afferent neurons) could directly sense environmental alarms and consequently regulate the development of various type of immune responses through the release of neuropeptides or growth factors. In this review, we discuss recent advances in the neural regulation of the immune response, both in physiological and pathological contexts by taking into account the type of organs (lungs, skin and gut), subtypes of peripheral neurons (sympathetic, nociceptive and intrinsic gut neurons) or immune cells and strains of pathogens studied. We also highlight future challenges in the field and potential therapeutic innovations targeting neuro-immune interactions.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
The body is innervated by a meshwork of heterogeneous peripheral neurons (including sensory neurons) which project virtually to all the organs. Peripheral neurons have been studied extensively in the context of their primary function of initiation of voluntary and involuntary movement, transmission of sensations and induction of appropriate behavioral response such as withdrawal to avoid tissue injury or scratching to remove irritating molecules. More recently, breakthrough articles have shown that, on top of their primary function of signal transmission to the spinal cord and brain, peripheral neurons (including afferent neurons) could directly sense environmental alarms and consequently regulate the development of various type of immune responses through the release of neuropeptides or growth factors. In this review, we discuss recent advances in the neural regulation of the immune response, both in physiological and pathological contexts by taking into account the type of organs (lungs, skin and gut), subtypes of peripheral neurons (sympathetic, nociceptive and intrinsic gut neurons) or immune cells and strains of pathogens studied. We also highlight future challenges in the field and potential therapeutic innovations targeting neuro-immune interactions. |
Pundir, Priyanka ; Liu, Rui ; Vasavda, Chirag ; Serhan, Nadine ; Limjunyawong, Nathachit ; Yee, Rebecca ; Zhan, Yingzhuan ; Dong, Xintong ; Wu, Xueqing ; Zhang, Ying ; Snyder, Solomon H; Gaudenzio, Nicolas ; Vidal, Jorge E; Dong, Xinzhong A Connective Tissue Mast-Cell-Specific Receptor Detects Bacterial Quorum-Sensing Molecules and Mediates Antibacterial Immunity. Article de journal Cell host & microbe, 26 (1), p. 114–122.e8, 2019, ISSN: 1934-6069 (Electronic). Résumé | Liens | BibTeX @article{Pundir2019,
title = {A Connective Tissue Mast-Cell-Specific Receptor Detects Bacterial Quorum-Sensing Molecules and Mediates Antibacterial Immunity.},
author = {Pundir, Priyanka and Liu, Rui and Vasavda, Chirag and Serhan, Nadine and Limjunyawong, Nathachit and Yee, Rebecca and Zhan, Yingzhuan and Dong, Xintong and Wu, Xueqing and Zhang, Ying and Snyder, Solomon H and Gaudenzio, Nicolas and Vidal, Jorge E and Dong, Xinzhong},
doi = {10.1016/j.chom.2019.06.003},
issn = {1934-6069 (Electronic)},
year = {2019},
date = {2019-07-01},
journal = {Cell host & microbe},
volume = {26},
number = {1},
pages = {114--122.e8},
abstract = {Quorum-sensing molecules (QSMs) are secreted by bacteria to signal population density. Upon reaching a critical concentration, QSMs induce transcriptional alterations in bacteria, which enable virulence factor expression and biofilm formation. It is unclear whether mammalian hosts can recognize QSMs to trigger responsive antibacterial immunity. We report that mouse mast-cell-specific G-protein-coupled receptor Mrgprb2 and its human homolog MRGPRX2 are receptors for Gram-positive QSMs, including competence-stimulating peptide (CSP)-1. CSP-1 activates Mrgprb2 and MRGPRX2, triggering mast cell degranulation, which inhibits bacterial growth and prevents biofilm formation. Such antibacterial functions are reduced in Mrgprb2-deficient mast cells, while wild-type mast cells fail to inhibit the growth of bacterial strains lacking CSP-1. Mrgprb2-knockout mice exhibit reduced bacterial clearance, while pharmacologically activating Mrgprb2 in vivo eliminates bacteria and improves disease score. These findings identify a host defense mechanism that uses QSMs as an "Achilles heel" and suggest MRGPRX2 as a potential therapeutic target for controlling bacterial infections.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Quorum-sensing molecules (QSMs) are secreted by bacteria to signal population density. Upon reaching a critical concentration, QSMs induce transcriptional alterations in bacteria, which enable virulence factor expression and biofilm formation. It is unclear whether mammalian hosts can recognize QSMs to trigger responsive antibacterial immunity. We report that mouse mast-cell-specific G-protein-coupled receptor Mrgprb2 and its human homolog MRGPRX2 are receptors for Gram-positive QSMs, including competence-stimulating peptide (CSP)-1. CSP-1 activates Mrgprb2 and MRGPRX2, triggering mast cell degranulation, which inhibits bacterial growth and prevents biofilm formation. Such antibacterial functions are reduced in Mrgprb2-deficient mast cells, while wild-type mast cells fail to inhibit the growth of bacterial strains lacking CSP-1. Mrgprb2-knockout mice exhibit reduced bacterial clearance, while pharmacologically activating Mrgprb2 in vivo eliminates bacteria and improves disease score. These findings identify a host defense mechanism that uses QSMs as an "Achilles heel" and suggest MRGPRX2 as a potential therapeutic target for controlling bacterial infections. |
Serhan, Nadine ; Basso, Lilian ; Sibilano, Riccardo ; Petitfils, Camille ; Meixiong, James ; Bonnart, Chrystelle ; Reber, Laurent L; Marichal, Thomas ; Starkl, Philipp ; Cenac, Nicolas ; Dong, Xinzhong ; Tsai, Mindy ; Galli, Stephen J; Gaudenzio, Nicolas House dust mites activate nociceptor–mast cell clusters to drive type 2 skin inflammation Article de journal Nature Immunology, 2019, ISSN: 15292916. Résumé | Liens | BibTeX @article{Serhan2019,
title = {House dust mites activate nociceptor–mast cell clusters to drive type 2 skin inflammation},
author = {Serhan, Nadine and Basso, Lilian and Sibilano, Riccardo and Petitfils, Camille and Meixiong, James and Bonnart, Chrystelle and Reber, Laurent L. and Marichal, Thomas and Starkl, Philipp and Cenac, Nicolas and Dong, Xinzhong and Tsai, Mindy and Galli, Stephen J. and Gaudenzio, Nicolas},
doi = {10.1038/s41590-019-0493-z},
issn = {15292916},
year = {2019},
date = {2019-01-01},
journal = {Nature Immunology},
abstract = {Allergic skin diseases, such as atopic dermatitis, are clinically characterized by severe itching and type 2 immunity-associated hypersensitivity to widely distributed allergens, including those derived from house dust mites (HDMs). Here we found that HDMs with cysteine protease activity directly activated peptidergic nociceptors, which are neuropeptide-producing nociceptive sensory neurons that express the ion channel TRPV1 and Tac1, the gene encoding the precursor for the neuropeptide substance P. Intravital imaging and genetic approaches indicated that HDM-activated nociceptors drive the development of allergic skin inflammation by inducing the degranulation of mast cells contiguous to such nociceptors, through the release of substance P and the activation of the cationic molecule receptor MRGPRB2 on mast cells. These data indicate that, after exposure to HDM allergens, activation of TRPV1+Tac1+ nociceptor–MRGPRB2+ mast cell sensory clusters represents a key early event in the development of allergic skin reactions.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Allergic skin diseases, such as atopic dermatitis, are clinically characterized by severe itching and type 2 immunity-associated hypersensitivity to widely distributed allergens, including those derived from house dust mites (HDMs). Here we found that HDMs with cysteine protease activity directly activated peptidergic nociceptors, which are neuropeptide-producing nociceptive sensory neurons that express the ion channel TRPV1 and Tac1, the gene encoding the precursor for the neuropeptide substance P. Intravital imaging and genetic approaches indicated that HDM-activated nociceptors drive the development of allergic skin inflammation by inducing the degranulation of mast cells contiguous to such nociceptors, through the release of substance P and the activation of the cationic molecule receptor MRGPRB2 on mast cells. These data indicate that, after exposure to HDM allergens, activation of TRPV1+Tac1+ nociceptor–MRGPRB2+ mast cell sensory clusters represents a key early event in the development of allergic skin reactions. |
2018
|
Gaudenzio, Nicolas ; Marichal, Thomas ; Galli, Stephen J; Reber, Laurent L Genetic and Imaging Approaches Reveal Pro-Inflammatory and Immunoregulatory Roles of Mast Cells in Contact Hypersensitivity. Article de journal Frontiers in immunology, 9 , p. 1275, 2018, ISSN: 1664-3224 (Print). Résumé | Liens | BibTeX @article{Gaudenzio2018,
title = {Genetic and Imaging Approaches Reveal Pro-Inflammatory and Immunoregulatory Roles of Mast Cells in Contact Hypersensitivity.},
author = {Gaudenzio, Nicolas and Marichal, Thomas and Galli, Stephen J and Reber, Laurent L},
doi = {10.3389/fimmu.2018.01275},
issn = {1664-3224 (Print)},
year = {2018},
date = {2018-01-01},
journal = {Frontiers in immunology},
volume = {9},
pages = {1275},
abstract = {Contact hypersensitivity (CHS) is a common T cell-mediated skin disease induced by epicutaneous sensitization to haptens. Mast cells (MCs) are widely deployed in the skin and can be activated during CHS responses to secrete diverse products, including some with pro-inflammatory and anti-inflammatory functions. Conflicting results have been obtained regarding pathogenic versus protective roles of MCs in CHS, and this has been attributed in part to the limitations of certain models for studying MC functions in vivo. This review discusses recent advances in the development and analysis of mouse models to investigate the roles of MCs and MC-associated products in vivo. Notably, fluorescent avidin-based two-photon imaging approaches enable in vivo selective labeling and simultaneous tracking of MC secretory granules (e.g., during MC degranulation) and MC gene activation by real-time longitudinal intravital microscopy in living mice. The combination of such genetic and imaging tools has shed new light on the controversial role played by MCs in mouse models of CHS. On the one hand, they can amplify CHS responses of mild severity while, on the other hand, can limit the inflammation and tissue injury associated with more severe or chronic models, in part by representing an initial source of the anti-inflammatory cytokine IL-10.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Contact hypersensitivity (CHS) is a common T cell-mediated skin disease induced by epicutaneous sensitization to haptens. Mast cells (MCs) are widely deployed in the skin and can be activated during CHS responses to secrete diverse products, including some with pro-inflammatory and anti-inflammatory functions. Conflicting results have been obtained regarding pathogenic versus protective roles of MCs in CHS, and this has been attributed in part to the limitations of certain models for studying MC functions in vivo. This review discusses recent advances in the development and analysis of mouse models to investigate the roles of MCs and MC-associated products in vivo. Notably, fluorescent avidin-based two-photon imaging approaches enable in vivo selective labeling and simultaneous tracking of MC secretory granules (e.g., during MC degranulation) and MC gene activation by real-time longitudinal intravital microscopy in living mice. The combination of such genetic and imaging tools has shed new light on the controversial role played by MCs in mouse models of CHS. On the one hand, they can amplify CHS responses of mild severity while, on the other hand, can limit the inflammation and tissue injury associated with more severe or chronic models, in part by representing an initial source of the anti-inflammatory cytokine IL-10. |
Galli, Stephen J; Gaudenzio, Nicolas Human mast cells as antigen-presenting cells: When is this role important in vivo? Divers 2018, ISSN: 1097-6825 (Electronic). Liens | BibTeX @misc{Galli2018,
title = {Human mast cells as antigen-presenting cells: When is this role important in vivo?},
author = {Galli, Stephen J and Gaudenzio, Nicolas},
doi = {10.1016/j.jaci.2017.05.029},
issn = {1097-6825 (Electronic)},
year = {2018},
date = {2018-01-01},
booktitle = {The Journal of allergy and clinical immunology},
volume = {141},
number = {1},
pages = {92--93},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
|
2017
|
Reber, Laurent L; Sibilano, Riccardo ; Starkl, Philipp ; Roers, Axel ; Grimbaldeston, Michele A; Tsai, Mindy ; Gaudenzio, Nicolas ; Galli, Stephen J Imaging protective mast cells in living mice during severe contact hypersensitivity. Article de journal JCI insight, 2 (9), 2017, ISSN: 2379-3708 (Electronic). Résumé | Liens | BibTeX @article{Reber2017,
title = {Imaging protective mast cells in living mice during severe contact hypersensitivity.},
author = {Reber, Laurent L and Sibilano, Riccardo and Starkl, Philipp and Roers, Axel and Grimbaldeston, Michele A and Tsai, Mindy and Gaudenzio, Nicolas and Galli, Stephen J},
doi = {10.1172/jci.insight.92900},
issn = {2379-3708 (Electronic)},
year = {2017},
date = {2017-05-01},
journal = {JCI insight},
volume = {2},
number = {9},
abstract = {Contact hypersensitivity (CHS) is a common skin disease induced by epicutaneous sensitization to haptens. Conflicting results have been obtained regarding pathogenic versus protective roles of mast cells (MCs) in CHS, and this has been attributed in part to the limitations of certain models for studying MC functions in vivo. Here we describe a fluorescent imaging approach that enables in vivo selective labeling and tracking of MC secretory granules by real-time intravital 2-photon microscopy in living mice, and permits the identification of such MCs as a potential source of cytokines in different disease models. We show using this method that dermal MCs release their granules progressively into the surrounding microenvironment, but also represent an initial source of the antiinflammatory cytokine IL-10, during the early phase of severe CHS reactions. Finally, using 3 different types of MC-deficient mice, as well as mice in which IL-10 is ablated specifically in MCs, we show that IL-10 production by MCs can significantly limit the inflammation and tissue pathology observed in severe CHS reactions.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Contact hypersensitivity (CHS) is a common skin disease induced by epicutaneous sensitization to haptens. Conflicting results have been obtained regarding pathogenic versus protective roles of mast cells (MCs) in CHS, and this has been attributed in part to the limitations of certain models for studying MC functions in vivo. Here we describe a fluorescent imaging approach that enables in vivo selective labeling and tracking of MC secretory granules by real-time intravital 2-photon microscopy in living mice, and permits the identification of such MCs as a potential source of cytokines in different disease models. We show using this method that dermal MCs release their granules progressively into the surrounding microenvironment, but also represent an initial source of the antiinflammatory cytokine IL-10, during the early phase of severe CHS reactions. Finally, using 3 different types of MC-deficient mice, as well as mice in which IL-10 is ablated specifically in MCs, we show that IL-10 production by MCs can significantly limit the inflammation and tissue pathology observed in severe CHS reactions. |
Reber, Laurent L; Gillis, Caitlin M; Starkl, Philipp ; J{ö}nsson, Friederike ; Sibilano, Riccardo ; Marichal, Thomas ; Gaudenzio, Nicolas ; B{é}rard, Marion ; Rogalla, Stephan ; Contag, Christopher H; Bruhns, Pierre ; Galli, Stephen J Neutrophil myeloperoxidase diminishes the toxic effects and mortality induced by lipopolysaccharide. Article de journal The Journal of experimental medicine, 214 (5), p. 1249–1258, 2017, ISSN: 1540-9538 (Electronic). Résumé | Liens | BibTeX @article{Reber2017b,
title = {Neutrophil myeloperoxidase diminishes the toxic effects and mortality induced by lipopolysaccharide.},
author = {Reber, Laurent L and Gillis, Caitlin M and Starkl, Philipp and J{ö}nsson, Friederike and Sibilano, Riccardo and Marichal, Thomas and Gaudenzio, Nicolas and B{é}rard, Marion and Rogalla, Stephan and Contag, Christopher H and Bruhns, Pierre and Galli, Stephen J},
doi = {10.1084/jem.20161238},
issn = {1540-9538 (Electronic)},
year = {2017},
date = {2017-05-01},
journal = {The Journal of experimental medicine},
volume = {214},
number = {5},
pages = {1249--1258},
abstract = {Neutrophils have crucial antimicrobial functions but are also thought to contribute to tissue injury upon exposure to bacterial products, such as lipopolysaccharide (LPS). To study the role of neutrophils in LPS-induced endotoxemia, we developed a new mouse model, PMN(DTR) mice, in which injection of diphtheria toxin induces selective neutrophil ablation. Using this model, we found, surprisingly, that neutrophils serve to protect the host from LPS-induced lethal inflammation. This protective role was observed in conventional and germ-free animal facilities, indicating that it does not depend on a particular microbiological environment. Blockade or genetic deletion of myeloperoxidase (MPO), a key neutrophil enzyme, significantly increased mortality after LPS challenge, and adoptive transfer experiments confirmed that neutrophil-derived MPO contributes importantly to protection from endotoxemia. Our findings imply that, in addition to their well-established antimicrobial properties, neutrophils can contribute to optimal host protection by limiting the extent of endotoxin-induced inflammation in an MPO-dependent manner.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Neutrophils have crucial antimicrobial functions but are also thought to contribute to tissue injury upon exposure to bacterial products, such as lipopolysaccharide (LPS). To study the role of neutrophils in LPS-induced endotoxemia, we developed a new mouse model, PMN(DTR) mice, in which injection of diphtheria toxin induces selective neutrophil ablation. Using this model, we found, surprisingly, that neutrophils serve to protect the host from LPS-induced lethal inflammation. This protective role was observed in conventional and germ-free animal facilities, indicating that it does not depend on a particular microbiological environment. Blockade or genetic deletion of myeloperoxidase (MPO), a key neutrophil enzyme, significantly increased mortality after LPS challenge, and adoptive transfer experiments confirmed that neutrophil-derived MPO contributes importantly to protection from endotoxemia. Our findings imply that, in addition to their well-established antimicrobial properties, neutrophils can contribute to optimal host protection by limiting the extent of endotoxin-induced inflammation in an MPO-dependent manner. |
Ho, Chia Chi M; Chhabra, Akanksha ; Starkl, Philipp ; Schnorr, Peter-John ; Wilmes, Stephan ; Moraga, Ignacio ; Kwon, Hye-Sook ; Gaudenzio, Nicolas ; Sibilano, Riccardo ; Wehrman, Tom S; Gakovic, Milica ; Sockolosky, Jonathan T; Tiffany, Matthew R; Ring, Aaron M; Piehler, Jacob ; Weissman, Irving L; Galli, Stephen J; Shizuru, Judith A; Garcia, Christopher K Decoupling the Functional Pleiotropy of Stem Cell Factor by Tuning c-Kit Signaling. Article de journal Cell, 168 (6), p. 1041–1052.e18, 2017, ISSN: 1097-4172 (Electronic). Résumé | Liens | BibTeX @article{Ho2017,
title = {Decoupling the Functional Pleiotropy of Stem Cell Factor by Tuning c-Kit Signaling.},
author = {Ho, Chia Chi M and Chhabra, Akanksha and Starkl, Philipp and Schnorr, Peter-John and Wilmes, Stephan and Moraga, Ignacio and Kwon, Hye-Sook and Gaudenzio, Nicolas and Sibilano, Riccardo and Wehrman, Tom S and Gakovic, Milica and Sockolosky, Jonathan T and Tiffany, Matthew R and Ring, Aaron M and Piehler, Jacob and Weissman, Irving L and Galli, Stephen J and Shizuru, Judith A and Garcia, K Christopher},
doi = {10.1016/j.cell.2017.02.011},
issn = {1097-4172 (Electronic)},
year = {2017},
date = {2017-03-01},
journal = {Cell},
volume = {168},
number = {6},
pages = {1041--1052.e18},
abstract = {Most secreted growth factors and cytokines are functionally pleiotropic because their receptors are expressed on diverse cell types. While important for normal mammalian physiology, pleiotropy limits the efficacy of cytokines and growth factors as therapeutics. Stem cell factor (SCF) is a growth factor that acts through the c-Kit receptor tyrosine kinase to elicit hematopoietic progenitor expansion but can be toxic when administered in vivo because it concurrently activates mast cells. We engineered a mechanism-based SCF partial agonist that impaired c-Kit dimerization, truncating downstream signaling amplitude. This SCF variant elicited biased activation of hematopoietic progenitors over mast cells in vitro and in vivo. Mouse models of SCF-mediated anaphylaxis, radioprotection, and hematopoietic expansion revealed that this SCF partial agonist retained therapeutic efficacy while exhibiting virtually no anaphylactic off-target effects. The approach of biasing cell activation by tuning signaling thresholds and outputs has applications to many dimeric receptor-ligand systems.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Most secreted growth factors and cytokines are functionally pleiotropic because their receptors are expressed on diverse cell types. While important for normal mammalian physiology, pleiotropy limits the efficacy of cytokines and growth factors as therapeutics. Stem cell factor (SCF) is a growth factor that acts through the c-Kit receptor tyrosine kinase to elicit hematopoietic progenitor expansion but can be toxic when administered in vivo because it concurrently activates mast cells. We engineered a mechanism-based SCF partial agonist that impaired c-Kit dimerization, truncating downstream signaling amplitude. This SCF variant elicited biased activation of hematopoietic progenitors over mast cells in vitro and in vivo. Mouse models of SCF-mediated anaphylaxis, radioprotection, and hematopoietic expansion revealed that this SCF partial agonist retained therapeutic efficacy while exhibiting virtually no anaphylactic off-target effects. The approach of biasing cell activation by tuning signaling thresholds and outputs has applications to many dimeric receptor-ligand systems. |
Mukai, Kaori ; Gaudenzio, Nicolas ; Gupta, Sheena ; Vivanco, Nora ; Bendall, Sean C; Maecker, Holden T; Chinthrajah, Rebecca S; Tsai, Mindy ; Nadeau, Kari C; Galli, Stephen J Assessing basophil activation by using flow cytometry and mass cytometry in blood stored 24 hours before analysis. Article de journal The Journal of allergy and clinical immunology, 139 (3), p. 889–899.e11, 2017, ISSN: 1097-6825 (Electronic). Résumé | Liens | BibTeX @article{Mukai2017,
title = {Assessing basophil activation by using flow cytometry and mass cytometry in blood stored 24 hours before analysis.},
author = {Mukai, Kaori and Gaudenzio, Nicolas and Gupta, Sheena and Vivanco, Nora and Bendall, Sean C and Maecker, Holden T and Chinthrajah, Rebecca S and Tsai, Mindy and Nadeau, Kari C and Galli, Stephen J},
doi = {10.1016/j.jaci.2016.04.060},
issn = {1097-6825 (Electronic)},
year = {2017},
date = {2017-03-01},
journal = {The Journal of allergy and clinical immunology},
volume = {139},
number = {3},
pages = {889--899.e11},
abstract = {BACKGROUND: Basophil activation tests (BATs) have promise for research and for clinical monitoring of patients with allergies. However, BAT protocols vary in blood anticoagulant used and temperature and time of storage before testing, complicating comparisons of results from various studies. OBJECTIVE: We attempted to establish a BAT protocol that would permit analysis of blood within 24 hours of obtaining the sample. METHODS: Blood from 46 healthy donors and 120 patients with peanut allergy was collected into EDTA or heparin tubes, and samples were stored at 4°C or room temperature for 4 or 24 hours before performing BATs. RESULTS: Stimulation with anti-IgE or IL-3 resulted in strong upregulation of basophil CD203c in samples collected in EDTA or heparin, stored at 4°C, and analyzed 24 hours after sample collection. However, a CD63(hi) population of basophils was not observed in any conditions in EDTA-treated samples unless exogenous calcium/magnesium was added at the time of anti-IgE stimulation. By contrast, blood samples collected in heparin tubes were adequate for quantification of upregulation of basophil CD203c and identification of a population of CD63(hi) basophils, irrespective of whether the specimens were analyzed by means of conventional flow cytometry or cytometry by time-of-flight mass spectrometry, and such tests could be performed after blood was stored for 24 hours at 4°C. CONCLUSION: BATs to measure upregulation of basophil CD203c and induction of a CD63(hi) basophil population can be conducted with blood obtained in heparin tubes and stored at 4°C for 24 hours.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Basophil activation tests (BATs) have promise for research and for clinical monitoring of patients with allergies. However, BAT protocols vary in blood anticoagulant used and temperature and time of storage before testing, complicating comparisons of results from various studies. OBJECTIVE: We attempted to establish a BAT protocol that would permit analysis of blood within 24 hours of obtaining the sample. METHODS: Blood from 46 healthy donors and 120 patients with peanut allergy was collected into EDTA or heparin tubes, and samples were stored at 4°C or room temperature for 4 or 24 hours before performing BATs. RESULTS: Stimulation with anti-IgE or IL-3 resulted in strong upregulation of basophil CD203c in samples collected in EDTA or heparin, stored at 4°C, and analyzed 24 hours after sample collection. However, a CD63(hi) population of basophils was not observed in any conditions in EDTA-treated samples unless exogenous calcium/magnesium was added at the time of anti-IgE stimulation. By contrast, blood samples collected in heparin tubes were adequate for quantification of upregulation of basophil CD203c and identification of a population of CD63(hi) basophils, irrespective of whether the specimens were analyzed by means of conventional flow cytometry or cytometry by time-of-flight mass spectrometry, and such tests could be performed after blood was stored for 24 hours at 4°C. CONCLUSION: BATs to measure upregulation of basophil CD203c and induction of a CD63(hi) basophil population can be conducted with blood obtained in heparin tubes and stored at 4°C for 24 hours. |
Balbino, Bianca ; Sibilano, Riccardo ; Starkl, Philipp ; Marichal, Thomas ; Gaudenzio, Nicolas ; Karasuyama, Hajime ; Bruhns, Pierre ; Tsai, Mindy ; Reber, Laurent L; Galli, Stephen J Pathways of immediate hypothermia and leukocyte infiltration in an adjuvant-free mouse model of anaphylaxis. Article de journal The Journal of allergy and clinical immunology, 139 (2), p. 584–596.e10, 2017, ISSN: 1097-6825 (Electronic). Résumé | Liens | BibTeX @article{Balbino2017,
title = {Pathways of immediate hypothermia and leukocyte infiltration in an adjuvant-free mouse model of anaphylaxis.},
author = {Balbino, Bianca and Sibilano, Riccardo and Starkl, Philipp and Marichal, Thomas and Gaudenzio, Nicolas and Karasuyama, Hajime and Bruhns, Pierre and Tsai, Mindy and Reber, Laurent L and Galli, Stephen J},
doi = {10.1016/j.jaci.2016.05.047},
issn = {1097-6825 (Electronic)},
year = {2017},
date = {2017-02-01},
journal = {The Journal of allergy and clinical immunology},
volume = {139},
number = {2},
pages = {584--596.e10},
abstract = {BACKGROUND: Conflicting results have been obtained regarding the roles of Fc receptors and effector cells in models of active systemic anaphylaxis (ASA). In part, this might reflect the choice of adjuvant used during sensitization because various adjuvants might differentially influence the production of particular antibody isotypes. OBJECTIVE: We developed an "adjuvant-free" mouse model of ASA and assessed the contributions of components of the "classical" and "alternative" pathways in this model. METHODS: Mice were sensitized intraperitoneally with ovalbumin at weekly intervals for 6 weeks and challenged intraperitoneally with ovalbumin 2 weeks later. RESULTS: Wild-type animals had immediate hypothermia and late-phase intraperitoneal inflammation in this model. These features were reduced in mice lacking the IgE receptor Fc$epsilon$RI, the IgG receptor Fc$gamma$RIII or the common $gamma$-chain FcR$gamma$. Fc$gamma$RIV blockade resulted in a partial reduction of inflammation without any effect on hypothermia. Depletion of monocytes/macrophages with clodronate liposomes significantly reduced the hypothermia response. By contrast, depletion of neutrophils or basophils had no significant effects in this ASA model. Both the hypothermia and inflammation were dependent on platelet-activating factor and histamine and were reduced in 2 types of mast cell (MC)-deficient mice. Finally, engraftment of MC-deficient mice with bone marrow-derived cultured MCs significantly exacerbated the hypothermia response and restored inflammation to levels similar to those observed in wild-type mice. CONCLUSION: Components of the classical and alternative pathways contribute to anaphylaxis in this adjuvant-free model, with key roles for MCs and monocytes/macrophages.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Conflicting results have been obtained regarding the roles of Fc receptors and effector cells in models of active systemic anaphylaxis (ASA). In part, this might reflect the choice of adjuvant used during sensitization because various adjuvants might differentially influence the production of particular antibody isotypes. OBJECTIVE: We developed an "adjuvant-free" mouse model of ASA and assessed the contributions of components of the "classical" and "alternative" pathways in this model. METHODS: Mice were sensitized intraperitoneally with ovalbumin at weekly intervals for 6 weeks and challenged intraperitoneally with ovalbumin 2 weeks later. RESULTS: Wild-type animals had immediate hypothermia and late-phase intraperitoneal inflammation in this model. These features were reduced in mice lacking the IgE receptor Fc$epsilon$RI, the IgG receptor Fc$gamma$RIII or the common $gamma$-chain FcR$gamma$. Fc$gamma$RIV blockade resulted in a partial reduction of inflammation without any effect on hypothermia. Depletion of monocytes/macrophages with clodronate liposomes significantly reduced the hypothermia response. By contrast, depletion of neutrophils or basophils had no significant effects in this ASA model. Both the hypothermia and inflammation were dependent on platelet-activating factor and histamine and were reduced in 2 types of mast cell (MC)-deficient mice. Finally, engraftment of MC-deficient mice with bone marrow-derived cultured MCs significantly exacerbated the hypothermia response and restored inflammation to levels similar to those observed in wild-type mice. CONCLUSION: Components of the classical and alternative pathways contribute to anaphylaxis in this adjuvant-free model, with key roles for MCs and monocytes/macrophages. |
2016
|
Marichal, Thomas ; Gaudenzio, Nicolas ; {El Abbas}, Sophie ; Sibilano, Riccardo ; Zurek, Oliwia ; Starkl, Philipp ; Reber, Laurent L; Pirottin, Dimitri ; Kim, Jinah ; Chambon, Pierre ; Roers, Axel ; Antoine, Nadine ; Kawakami, Yuko ; Kawakami, Toshiaki ; Bureau, Fabrice ; Tam, See-Ying ; Tsai, Mindy ; Galli, Stephen J Guanine nucleotide exchange factor RABGEF1 regulates keratinocyte-intrinsic signaling to maintain skin homeostasis. Article de journal The Journal of clinical investigation, 126 (12), p. 4497–4515, 2016, ISSN: 1558-8238 (Electronic). Résumé | Liens | BibTeX @article{Marichal2016,
title = {Guanine nucleotide exchange factor RABGEF1 regulates keratinocyte-intrinsic signaling to maintain skin homeostasis.},
author = {Marichal, Thomas and Gaudenzio, Nicolas and {El Abbas}, Sophie and Sibilano, Riccardo and Zurek, Oliwia and Starkl, Philipp and Reber, Laurent L and Pirottin, Dimitri and Kim, Jinah and Chambon, Pierre and Roers, Axel and Antoine, Nadine and Kawakami, Yuko and Kawakami, Toshiaki and Bureau, Fabrice and Tam, See-Ying and Tsai, Mindy and Galli, Stephen J},
doi = {10.1172/JCI86359},
issn = {1558-8238 (Electronic)},
year = {2016},
date = {2016-12-01},
journal = {The Journal of clinical investigation},
volume = {126},
number = {12},
pages = {4497--4515},
abstract = {Epidermal keratinocytes form a structural and immune barrier that is essential for skin homeostasis. However, the mechanisms that regulate epidermal barrier function are incompletely understood. Here we have found that keratinocyte-specific deletion of the gene encoding RAB guanine nucleotide exchange factor 1 (RABGEF1, also known as RABEX-5) severely impairs epidermal barrier function in mice and induces an allergic cutaneous and systemic phenotype. RABGEF1-deficient keratinocytes exhibited aberrant activation of the intrinsic IL-1R/MYD88/NF-$kappa$B signaling pathway and MYD88-dependent abnormalities in expression of structural proteins that contribute to skin barrier function. Moreover, ablation of MYD88 signaling in RABGEF1-deficient keratinocytes or deletion of Il1r1 restored skin homeostasis and prevented development of skin inflammation. We further demonstrated that epidermal RABGEF1 expression is reduced in skin lesions of humans diagnosed with either atopic dermatitis or allergic contact dermatitis as well as in an inducible mouse model of allergic dermatitis. Our findings reveal a key role for RABGEF1 in dampening keratinocyte-intrinsic MYD88 signaling and sustaining epidermal barrier function in mice, and suggest that dysregulation of RABGEF1 expression may contribute to epidermal barrier dysfunction in allergic skin disorders in mice and humans. Thus, RABGEF1-mediated regulation of IL-1R/MYD88 signaling might represent a potential therapeutic target.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Epidermal keratinocytes form a structural and immune barrier that is essential for skin homeostasis. However, the mechanisms that regulate epidermal barrier function are incompletely understood. Here we have found that keratinocyte-specific deletion of the gene encoding RAB guanine nucleotide exchange factor 1 (RABGEF1, also known as RABEX-5) severely impairs epidermal barrier function in mice and induces an allergic cutaneous and systemic phenotype. RABGEF1-deficient keratinocytes exhibited aberrant activation of the intrinsic IL-1R/MYD88/NF-$kappa$B signaling pathway and MYD88-dependent abnormalities in expression of structural proteins that contribute to skin barrier function. Moreover, ablation of MYD88 signaling in RABGEF1-deficient keratinocytes or deletion of Il1r1 restored skin homeostasis and prevented development of skin inflammation. We further demonstrated that epidermal RABGEF1 expression is reduced in skin lesions of humans diagnosed with either atopic dermatitis or allergic contact dermatitis as well as in an inducible mouse model of allergic dermatitis. Our findings reveal a key role for RABGEF1 in dampening keratinocyte-intrinsic MYD88 signaling and sustaining epidermal barrier function in mice, and suggest that dysregulation of RABGEF1 expression may contribute to epidermal barrier dysfunction in allergic skin disorders in mice and humans. Thus, RABGEF1-mediated regulation of IL-1R/MYD88 signaling might represent a potential therapeutic target. |
Sibilano, Riccardo ; Gaudenzio, Nicolas ; DeGorter, Marianne K; Reber, Laurent L; Hernandez, Joseph D; Starkl, Philipp M; Zurek, Oliwia W; Tsai, Mindy ; Zahner, Sonja ; Montgomery, Stephen B; Roers, Axel ; Kronenberg, Mitchell ; Yu, Mang ; Galli, Stephen J A TNFRSF14-FcɛRI-mast cell pathway contributes to development of multiple features of asthma pathology in mice. Article de journal Nature communications, 7 , p. 13696, 2016, ISSN: 2041-1723 (Electronic). Résumé | Liens | BibTeX @article{Sibilano2016,
title = {A TNFRSF14-FcɛRI-mast cell pathway contributes to development of multiple features of asthma pathology in mice.},
author = {Sibilano, Riccardo and Gaudenzio, Nicolas and DeGorter, Marianne K and Reber, Laurent L and Hernandez, Joseph D and Starkl, Philipp M and Zurek, Oliwia W and Tsai, Mindy and Zahner, Sonja and Montgomery, Stephen B and Roers, Axel and Kronenberg, Mitchell and Yu, Mang and Galli, Stephen J},
doi = {10.1038/ncomms13696},
issn = {2041-1723 (Electronic)},
year = {2016},
date = {2016-12-01},
journal = {Nature communications},
volume = {7},
pages = {13696},
abstract = {Asthma has multiple features, including airway hyperreactivity, inflammation and remodelling. The TNF superfamily member TNFSF14 (LIGHT), via interactions with the receptor TNFRSF14 (HVEM), can support T(H)2 cell generation and longevity and promote airway remodelling in mouse models of asthma, but the mechanisms by which TNFSF14 functions in this setting are incompletely understood. Here we find that mouse and human mast cells (MCs) express TNFRSF14 and that TNFSF14:TNFRSF14 interactions can enhance IgE-mediated MC signalling and mediator production. In mouse models of asthma, TNFRSF14 blockade with a neutralizing antibody administered after antigen sensitization, or genetic deletion of Tnfrsf14, diminishes plasma levels of antigen-specific IgG(1) and IgE antibodies, airway hyperreactivity, airway inflammation and airway remodelling. Finally, by analysing two types of genetically MC-deficient mice after engrafting MCs that either do or do not express TNFRSF14, we show that TNFRSF14 expression on MCs significantly contributes to the development of multiple features of asthma pathology.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Asthma has multiple features, including airway hyperreactivity, inflammation and remodelling. The TNF superfamily member TNFSF14 (LIGHT), via interactions with the receptor TNFRSF14 (HVEM), can support T(H)2 cell generation and longevity and promote airway remodelling in mouse models of asthma, but the mechanisms by which TNFSF14 functions in this setting are incompletely understood. Here we find that mouse and human mast cells (MCs) express TNFRSF14 and that TNFSF14:TNFRSF14 interactions can enhance IgE-mediated MC signalling and mediator production. In mouse models of asthma, TNFRSF14 blockade with a neutralizing antibody administered after antigen sensitization, or genetic deletion of Tnfrsf14, diminishes plasma levels of antigen-specific IgG(1) and IgE antibodies, airway hyperreactivity, airway inflammation and airway remodelling. Finally, by analysing two types of genetically MC-deficient mice after engrafting MCs that either do or do not express TNFRSF14, we show that TNFRSF14 expression on MCs significantly contributes to the development of multiple features of asthma pathology. |
Reber, Laurent L; Gaudenzio, Nicolas ; Starkl, Philipp ; Galli, Stephen J Neutrophils are not required for resolution of acute gouty arthritis in mice. Divers 2016, ISSN: 1546-170X (Electronic). Liens | BibTeX @misc{Reber2016,
title = {Neutrophils are not required for resolution of acute gouty arthritis in mice.},
author = {Reber, Laurent L and Gaudenzio, Nicolas and Starkl, Philipp and Galli, Stephen J},
doi = {10.1038/nm.4216},
issn = {1546-170X (Electronic)},
year = {2016},
date = {2016-12-01},
booktitle = {Nature medicine},
volume = {22},
number = {12},
pages = {1382--1384},
keywords = {},
pubstate = {published},
tppubtype = {misc}
}
|
Gaudenzio, Nicolas ; Sibilano, Riccardo ; Marichal, Thomas ; Starkl, Philipp ; Reber, Laurent L; Cenac, Nicolas ; McNeil, Benjamin D; Dong, Xinzhong ; Hernandez, Joseph D; Sagi-Eisenberg, Ronit ; Hammel, Ilan ; Roers, Axel ; Valitutti, Salvatore ; Tsai, Mindy ; Espinosa, Eric ; Galli, Stephen J Different activation signals induce distinct mast cell degranulation strategies. Article de journal The Journal of clinical investigation, 126 (10), p. 3981–3998, 2016, ISSN: 1558-8238 (Electronic). Résumé | Liens | BibTeX @article{Gaudenzio2016,
title = {Different activation signals induce distinct mast cell degranulation strategies.},
author = {Gaudenzio, Nicolas and Sibilano, Riccardo and Marichal, Thomas and Starkl, Philipp and Reber, Laurent L and Cenac, Nicolas and McNeil, Benjamin D and Dong, Xinzhong and Hernandez, Joseph D and Sagi-Eisenberg, Ronit and Hammel, Ilan and Roers, Axel and Valitutti, Salvatore and Tsai, Mindy and Espinosa, Eric and Galli, Stephen J},
doi = {10.1172/JCI85538},
issn = {1558-8238 (Electronic)},
year = {2016},
date = {2016-10-01},
journal = {The Journal of clinical investigation},
volume = {126},
number = {10},
pages = {3981--3998},
abstract = {Mast cells (MCs) influence intercellular communication during inflammation by secreting cytoplasmic granules that contain diverse mediators. Here, we have demonstrated that MCs decode different activation stimuli into spatially and temporally distinct patterns of granule secretion. Certain signals, including substance P, the complement anaphylatoxins C3a and C5a, and endothelin 1, induced human MCs rapidly to secrete small and relatively spherical granule structures, a pattern consistent with the secretion of individual granules. Conversely, activating MCs with anti-IgE increased the time partition between signaling and secretion, which was associated with a period of sustained elevation of intracellular calcium and formation of larger and more heterogeneously shaped granule structures that underwent prolonged exteriorization. Pharmacological inhibition of IKK-$beta$ during IgE-dependent stimulation strongly reduced the time partition between signaling and secretion, inhibited SNAP23/STX4 complex formation, and switched the degranulation pattern into one that resembled degranulation induced by substance P. IgE-dependent and substance P-dependent activation in vivo also induced different patterns of mouse MC degranulation that were associated with distinct local and systemic pathophysiological responses. These findings show that cytoplasmic granule secretion from MCs that occurs in response to different activating stimuli can exhibit distinct dynamics and features that are associated with distinct patterns of MC-dependent inflammation.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Mast cells (MCs) influence intercellular communication during inflammation by secreting cytoplasmic granules that contain diverse mediators. Here, we have demonstrated that MCs decode different activation stimuli into spatially and temporally distinct patterns of granule secretion. Certain signals, including substance P, the complement anaphylatoxins C3a and C5a, and endothelin 1, induced human MCs rapidly to secrete small and relatively spherical granule structures, a pattern consistent with the secretion of individual granules. Conversely, activating MCs with anti-IgE increased the time partition between signaling and secretion, which was associated with a period of sustained elevation of intracellular calcium and formation of larger and more heterogeneously shaped granule structures that underwent prolonged exteriorization. Pharmacological inhibition of IKK-$beta$ during IgE-dependent stimulation strongly reduced the time partition between signaling and secretion, inhibited SNAP23/STX4 complex formation, and switched the degranulation pattern into one that resembled degranulation induced by substance P. IgE-dependent and substance P-dependent activation in vivo also induced different patterns of mouse MC degranulation that were associated with distinct local and systemic pathophysiological responses. These findings show that cytoplasmic granule secretion from MCs that occurs in response to different activating stimuli can exhibit distinct dynamics and features that are associated with distinct patterns of MC-dependent inflammation. |
Khazen, Roxana ; M{ü}ller, Sabina ; Gaudenzio, Nicolas ; Espinosa, Eric ; Puissegur, Marie-Pierre ; Valitutti, Salvatore Melanoma cell lysosome secretory burst neutralizes the CTL-mediated cytotoxicity at the lytic synapse. Article de journal Nature communications, 7 , p. 10823, 2016, ISSN: 2041-1723 (Electronic). Résumé | Liens | BibTeX @article{Khazen2016,
title = {Melanoma cell lysosome secretory burst neutralizes the CTL-mediated cytotoxicity at the lytic synapse.},
author = {Khazen, Roxana and M{ü}ller, Sabina and Gaudenzio, Nicolas and Espinosa, Eric and Puissegur, Marie-Pierre and Valitutti, Salvatore},
doi = {10.1038/ncomms10823},
issn = {2041-1723 (Electronic)},
year = {2016},
date = {2016-03-01},
journal = {Nature communications},
volume = {7},
pages = {10823},
abstract = {Human melanoma cells express various tumour antigens that are recognized by CD8(+) cytotoxic T lymphocytes (CTLs) and elicit tumour-specific responses in vivo. However, natural and therapeutically enhanced CTL responses in melanoma patients are of limited efficacy. The mechanisms underlying CTL effector phase failure when facing melanomas are still largely elusive. Here we show that, on conjugation with CTL, human melanoma cells undergo an active late endosome/lysosome trafficking, which is intensified at the lytic synapse and is paralleled by cathepsin-mediated perforin degradation and deficient granzyme B penetration. Abortion of SNAP-23-dependent lysosomal trafficking, pH perturbation or impairment of lysosomal proteolytic activity restores susceptibility to CTL attack. Inside the arsenal of melanoma cell strategies to escape immune surveillance, we identify a self-defence mechanism based on exacerbated lysosome secretion and perforin degradation at the lytic synapse. Interfering with this synaptic self-defence mechanism might be useful in potentiating CTL-mediated therapies in melanoma patients.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
Human melanoma cells express various tumour antigens that are recognized by CD8(+) cytotoxic T lymphocytes (CTLs) and elicit tumour-specific responses in vivo. However, natural and therapeutically enhanced CTL responses in melanoma patients are of limited efficacy. The mechanisms underlying CTL effector phase failure when facing melanomas are still largely elusive. Here we show that, on conjugation with CTL, human melanoma cells undergo an active late endosome/lysosome trafficking, which is intensified at the lytic synapse and is paralleled by cathepsin-mediated perforin degradation and deficient granzyme B penetration. Abortion of SNAP-23-dependent lysosomal trafficking, pH perturbation or impairment of lysosomal proteolytic activity restores susceptibility to CTL attack. Inside the arsenal of melanoma cell strategies to escape immune surveillance, we identify a self-defence mechanism based on exacerbated lysosome secretion and perforin degradation at the lytic synapse. Interfering with this synaptic self-defence mechanism might be useful in potentiating CTL-mediated therapies in melanoma patients. |
Starkl, Philipp ; Marichal, Thomas ; Gaudenzio, Nicolas ; Reber, Laurent Lionel ; Sibilano, Riccardo ; Tsai, Mindy ; Galli, Stephen Joseph IgE antibodies, Fc$epsilon$RI$alpha$, and IgE-mediated local anaphylaxis can limit snake venom toxicity. Article de journal The Journal of allergy and clinical immunology, 137 (1), p. 246–257.e11, 2016, ISSN: 1097-6825 (Electronic). Résumé | Liens | BibTeX @article{Starkl2016,
title = {IgE antibodies, Fc$epsilon$RI$alpha$, and IgE-mediated local anaphylaxis can limit snake venom toxicity.},
author = {Starkl, Philipp and Marichal, Thomas and Gaudenzio, Nicolas and Reber, Laurent Lionel and Sibilano, Riccardo and Tsai, Mindy and Galli, Stephen Joseph},
doi = {10.1016/j.jaci.2015.08.005},
issn = {1097-6825 (Electronic)},
year = {2016},
date = {2016-01-01},
journal = {The Journal of allergy and clinical immunology},
volume = {137},
number = {1},
pages = {246--257.e11},
abstract = {BACKGROUND: Type 2 cytokine-related immune responses associated with development of antigen-specific IgE antibodies can contribute to pathology in patients with allergic diseases and to fatal anaphylaxis. However, recent findings in mice indicate that IgE also can enhance defense against honeybee venom. OBJECTIVE: We tested whether IgE antibodies, IgE-dependent effector mechanisms, and a local anaphylactic reaction to an unrelated antigen can enhance defense against Russell viper venom (RVV) and determined whether such responses can be influenced by immunization protocol or mouse strain. METHODS: We compared the resistance of RVV-immunized wild-type, IgE-deficient, and Fcer1a-deficient mice after injection of a potentially lethal dose of RVV. RESULTS: A single prior exposure to RVV enhanced the ability of wild-type mice, but not mice lacking IgE or functional Fc$epsilon$RI, to survive challenge with a potentially lethal amount of RVV. Moreover, IgE-dependent local passive cutaneous anaphylaxis in response to challenge with an antigen not naturally present in RVV significantly enhanced resistance to the venom. Finally, we observed different effects on resistance to RVV or honeybee venom in BALB/c versus C57BL/6 mice that had received a second exposure to that venom before challenge with a high dose of that venom. CONCLUSION: These observations illustrate the potential benefit of IgE-dependent effector mechanisms in acquired host defense against venoms. The extent to which type 2 immune responses against venoms can decrease pathology associated with envenomation seems to be influenced by the type of venom, the frequency of venom exposure, and the genetic background of the host.},
keywords = {},
pubstate = {published},
tppubtype = {article}
}
BACKGROUND: Type 2 cytokine-related immune responses associated with development of antigen-specific IgE antibodies can contribute to pathology in patients with allergic diseases and to fatal anaphylaxis. However, recent findings in mice indicate that IgE also can enhance defense against honeybee venom. OBJECTIVE: We tested whether IgE antibodies, IgE-dependent effector mechanisms, and a local anaphylactic reaction to an unrelated antigen can enhance defense against Russell viper venom (RVV) and determined whether such responses can be influenced by immunization protocol or mouse strain. METHODS: We compared the resistance of RVV-immunized wild-type, IgE-deficient, and Fcer1a-deficient mice after injection of a potentially lethal dose of RVV. RESULTS: A single prior exposure to RVV enhanced the ability of wild-type mice, but not mice lacking IgE or functional Fc$epsilon$RI, to survive challenge with a potentially lethal amount of RVV. Moreover, IgE-dependent local passive cutaneous anaphylaxis in response to challenge with an antigen not naturally present in RVV significantly enhanced resistance to the venom. Finally, we observed different effects on resistance to RVV or honeybee venom in BALB/c versus C57BL/6 mice that had received a second exposure to that venom before challenge with a high dose of that venom. CONCLUSION: These observations illustrate the potential benefit of IgE-dependent effector mechanisms in acquired host defense against venoms. The extent to which type 2 immune responses against venoms can decrease pathology associated with envenomation seems to be influenced by the type of venom, the frequency of venom exposure, and the genetic background of the host. |
Régulation neuronale du système immunitaire
Nous sommes fiers de vous annoncer que Nadine SERHAN est lauréate du prix l’Oréal-UNESCO:
Un grand merci au journal: “La Dépêche” pour son article sur l’eczéma atopique, destiné à faire découvrir cette maladie au grand public.
