NLRP6 controls pulmonary inflammation from cigarette smoke in a gut microbiota-dependent manner

Mégane Nascimento (1) , Sarah Huot-Marchand (1) , Manoussa Fanny (1) , Marjolène Straube (1) , Marc Le Bert (1) , Florence Savigny (1) , Lionel Apetoh (2) , Jacques van Snick (3) , Fabrice Trovero (4) , Mathias Chamaillard (5) , Valérie F J Quesniaux (1) , Bernhard Ryffel (1) , Philippe Gosset (6) , Aurélie Gombault (1) , Nicolas Riteau (1) , Harry Sokol (7) , Isabelle Couillin (1)

1 INEM - Immunologie et Neurogénétique Expérimentales et Moléculaires
2 CEPR - Centre d’Etude des Pathologies Respiratoires (CEPR), UMR 1100
3 Ludwig Institute for Cancer Research
4 Artimmune SAS
5 PHYCELL - Laboratoire de Physiologie Cellulaire : Canaux ioniques, inflammation et cancer - U 1003
6 CIIL - Centre d’Infection et d’Immunité de Lille - INSERM U 1019 - UMR 9017 - UMR 8204
7 CRSA - Centre de Recherche Saint-Antoine

Chronic obstructive pulmonary disease (COPD) is a major health issue primarily caused by cigarette smoke (CS) and characterized by breathlessness and repeated airway inflammation. NLRP6 is a cytosolic innate receptor controlling intestinal inflammation and orchestrating the colonic host–microbial interface. However, its roles in the lungs remain largely unexplored. Using CS exposure models, our data show that airway inflammation is strongly impaired in Nlrp6-deficient mice with drastically fewer recruited neutrophils, a key cell subset in inflammation and COPD. We found that NLRP6 expression in lung epithelial cells is important to control airway and lung tissue inflammation in an inflammasome-dependent manner. Since gut-derived metabolites regulate NLRP6 inflammasome activation in intestinal epithelial cells, we investigated the link between NLRP6, CS-driven lung inflammation, and gut microbiota composition. We report that acute CS exposure alters gut microbiota in both wild-type (WT) and Nlrp6-deficient mice and that antibiotic treatment decreases CS-induced lung inflammation. In addition, gut microbiota transfer from dysbiotic Nlrp6-deficient mice to WT mice decreased airway lung inflammation in WT mice, highlighting an NLRP6-dependent gut-to-lung axis controlling pulmonary inflammation.

Mots clés: NLRP6; lung inflammation; cigarette smoke-exposure; gut microbiota; gut to lung axis

Domaines: Pneumologie et système respiratoire; Immunité innée

Mégane Nascimento, Sarah Huot-Marchand, Manoussa Fanny, Marjolène Straube, Marc Le Bert, et al.. NLRP6 controls pulmonary inflammation from cigarette smoke in a gut microbiota-dependent manner. Frontiers in Immunology, 2023, 14, pp.1224383. ⟨10.3389/fimmu.2023.1224383⟩. ⟨hal-04543201⟩