NLRP6 inflammasome is a critical player in pulmonary inflammation to cigarette smoke in mice

Introduction Chronic obstructive pulmonary disease is a major health problem and has been predicted to become the third cause of death in the world by 2020. Using mice model of cigarette smoke and elastase-induced injury, we previously showed that interleukin (IL-) 1beta is essential to inflammation, remodelling and emphysema. In addition, secretion of mature IL-1beta, inflammation and emphysema were reduced in mice deficient for the inflammasome adaptor molecule ASC but not in mice deficient for the receptor NLRP3, suggesting that another NLRP can be involved in inflammasome scaffolding and IL-1beta maturation. Recently, it was shown that genetic ablation of NLRP6 in mice profoundly reduces inflammasome activation in the intestine, and increases the animals’ susceptibility to colitis. However, the role of NLRP6 in lung inflammation and repair upon injury remains completely undiscovered. Methods Wild type mice (B6) or Nlpr6 deficient mice (Nlrp6 ko) were exposed to the smoke of 4 cigarettes (3R4F), 3 times a day during 4 days. Mice were sacrificed 16 hours after the last exposure and inflammatory and remodeling parameters were evaluated. Broncho-alveolar lavage fluids (BALF) were done and cell infiltration was determined. Myeloperoxidase (MPO) activities and content of pro-inflammatory cytokines and remodeling factors were measured in BALF and lung homogenates. Results In comparison to wild type mice, Nlrp6 deficient mice presented greatly reduced cell recruitment and in particular reduced macrophage and neutrophil influx into the BALF. MPO activities and levels of the proinflammatorty cytokine IL-1beta and of the B cell activating factor (BAFF) into BALF and lung homogenates were also diminished. Moreover the production of the remodeling factors a matrix metalloproteinase, member 9 (MMP-9) and tissue inhibitor of metalloproteinase member 1 (TIMP-1) were attenuated in Nlrp6 KO mice. Conclusion Our results demonstrate for the first time that NLRP6 is a critical player in acute inflammation and remodeling induced by cigarette smoke exposure. Better understanding of the role of NLRP6 may allow identifying new therapeutic targets for potential curative treatments in very severe and irreversible disease such as COPD or emphysema.