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NLRP6 negatively regulates type 2 immune responses in mice
Author(s) -
Chenuet Pauline,
Marquant Quentin,
Fauconnier Louis,
Youness Ali,
Mellier Ma,
Marchiol Tiffany,
Rouxel Nathalie,
MessaoudNacer Yasmine,
Maillet Isabelle,
Ledru Aurélie,
Quesniaux Valérie F. J.,
Ryffel Bernhard,
Horsnell William,
Végran Frédérique,
Apetoh Lionel,
Togbe Dieudonnée
Publication year - 2022
Publication title -
allergy
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 3.363
H-Index - 173
eISSN - 1398-9995
pISSN - 0105-4538
DOI - 10.1111/all.15388
Subject(s) - gata3 , immunology , innate lymphoid cell , biology , nippostrongylus brasiliensis , immune system , inflammasome , inflammation , thymic stromal lymphopoietin , cytokine , chemokine , eosinophil , innate immune system , transcription factor , asthma , biochemistry , gene
Abstract 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.