Cytosolic flagellin-induced lysosomal pathway regulates inflammasome-dependent and independent macrophage responses (P4141)

Abstract

Abstract NAIP5/NLRC4 inflammasome activation by cytosolic flagellin results in caspase-1-mediated processing and secretion of IL-1β/IL-18 and pyroptosis, an inflammatory cell death pathway. Here, we found that although NLRC4, ASC and caspase-1 are required for IL-1β secretion in response to cytosolic flagellin, cell death nevertheless occurs in the absence of these molecules. Cytosolic flagellin-induced inflammasome-independent cell death was accompanied by IL-1α secretion and was temporally correlated with the restriction of S. Typhimurium infection. Despite displaying some apoptotic features, this peculiar form of cell death did not require caspase activation but was regulated by a lysosomal pathway, in which cathepsin B and cathepsin D play redundant roles. Moreover, cathepsin B contributed to NAIP5/NLRC4-inflammasome-induced pyroptosis, and IL-1α and IL-1β production in response to cytosolic flagellin. Together, our data describe a novel pathway induced by cytosolic flagellin that induces a peculiar form of cell death and regulates inflammasome-mediated effector mechanisms of macrophages.