Aim2 suppresses cigarette smoke-induced neutrophil recruitment, neutrophil caspase-1 activation and anti-Ly6G-mediated neutrophil depletion.

Abstract

Increased inflammasome responses are strongly implicated in inflammatory diseases; however, their specific roles are incompletely understood. Therefore, we sought to examine the roles of nucleotide‐binding oligomerization domain–like receptor (NLR) family, pyrin domain–containing 3 (NLRP3) and absent in melanoma‐2 (AIM2) inflammasomes in cigarette smoke–induced inflammation in a model of experimental chronic obstructive pulmonary disease (COPD). We targeted NLRP3 with the inhibitor MCC950 given prophylactically or therapeutically and examined Aim2 −/− mice in cigarette smoke–induced experimental COPD. MCC950 treatment had minimal effects on disease development and/or progression. Aim2 −/− mice had increased airway neutrophils with decreased caspase‐1 levels, independent of changes in lung neutrophil chemokines. Suppressing neutrophils with anti‐Ly6G in experimental COPD in wild‐type mice reduced neutrophils in bone marrow, blood and lung. By contrast, anti‐Ly6G treatment in Aim2 −/− mice with experimental COPD had no effect on neutrophils in bone marrow, partially reduced neutrophils in the blood and had no effect on neutrophils or neutrophil caspase‐1 levels in the lungs. These findings identify that following cigarette smoke exposure, Aim2 is important for anti‐Ly6G–mediated depletion of neutrophils, suppression of neutrophil recruitment and mediates activation of caspase‐1 in neutrophils.