1. NLRP6 negatively regulates type 2 immune responses in mice
- Author
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Pauline Chenuet, Quentin Marquant, Louis Fauconnier, Ali Youness, Manon Mellier, Tiffany Marchiol, Nathalie Rouxel, Yasmine Messaoud‐Nacer, Isabelle Maillet, Aurélie Ledru, Valérie F. J. Quesniaux, Bernhard Ryffel, William Horsnell, Frédérique Végran, Lionel Apetoh, Dieudonnée Togbe, Université d'Orléans, SCD, Artimmune SAS, Immunologie et Neurogénétique Expérimentales et Moléculaires (INEM), Université d'Orléans (UO)-Centre National de la Recherche Scientifique (CNRS), University of Cape Town, Institute of Microbiology and Infection, University of Birmingham [Birmingham], Lipides - Nutrition - Cancer [Dijon - U1231] (LNC), Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Institut Agro Dijon, Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro)-Institut national d'enseignement supérieur pour l'agriculture, l'alimentation et l'environnement (Institut Agro), Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100 (CEPR), Université de Tours (UT)-Institut National de la Santé et de la Recherche Médicale (INSERM), University of Orléans, 2016-00110366/European funding in Région Centre-Val de Loire, EX0057560/European funding in Région Centre-Val de Loire, Conseil Départemental 45, Le Studium, Program ARD2020 Biomédicament, and CNRS
- Subjects
Inflammasomes ,Immunology ,NLRP6 ,ILC2 ,Th2 ,Mice ,Th2 Cells ,inflammasome ,GATA3 ,Immunology and Allergy ,Animals ,Nippostrongylus brasiliensis ,birch pollen ,Lymphocytes ,[SDV.IMM.ALL]Life Sciences [q-bio]/Immunology/Allergology ,Mice, Knockout ,Interleukin-18 ,Pneumonia ,CD4+ T cells ,Immunity, Innate ,Cytokines ,Th17 ,Nippostrongylus ,allergic asthma ,IL-18 ,[SDV.IMM.ALL] Life Sciences [q-bio]/Immunology/Allergology - Abstract
International audience; Background: Inflammasomes are large protein complexes that assemble in the cytosol in response to danger such as tissue damage or infection. Following activation, inflammasomes trigger cell death and the release of biologically active forms of pro-inflammatory cytokines interleukin (IL)-1β and IL-18. NOD-like receptor family pyrin domain containing 6 (NLRP6) inflammasome is required for IL-18 secretion by intestinal epithelial cells, macrophages, and T cells, contributing to homeostasis and self-defense against pathogenic microbes. However, the involvement of NLRP6 in type 2 lung inflammation remains elusive.Methods: Wild-type (WT) and Nlrp6−/− mice were used. Birch pollen extract (BPE)-induced allergic lung inflammation, eosinophil recruitment, Th2-related cytokine and chemokine production, airway hyperresponsiveness, and lung histopathology, Th2 cell differentiation, GATA3, and Th2 cytokines expression, were determined. Nippostrongylus brasiliensis (Nb) infection, worm count in intestine, type 2 innate lymphoid cell (ILC2), and Th2 cells in lungs were evaluated.Results: We demonstrate in Nlrp6−/− mice that a mixed Th2/Th17 immune responses prevailed following birch pollen challenge with increased eosinophils, ILC2, Th2, and Th17 cell induction and reduced IL-18 production. Nippostrongylus brasiliensis infected Nlrp6−/− mice featured enhanced early expulsion of the parasite due to enhanced type 2 immune responses compared to WT hosts. In vitro, NLRP6 repressed Th2 polarization, as shown by increased Th2 cytokines and higher expression of the transcription factor GATA3 in the absence of NLRP6. Exogenous IL-18 administration partially reduced the enhanced airways inflammation in Nlrp6−/− mice.Conclusions: In summary, our data identify NLRP6 as a negative regulator of type 2 immune responses.
- Published
- 2022
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