Frontline Science: Autophagy is a cell autonomous effector mechanism mediated by NLRP3 to control Trypanosoma cruzi infection.

Autophagy and inflammasome activation are cell-autonomous and cross-regulated processes involved in host resistance against infections. Our group previously described that NLRP3 inflammasome is required for the control of Trypanosoma cruzi, the causative agent of Chagas disease. However, the involvement of autophagy in this process was unclear. Here, we demonstrated that T. cruzi was able to induce an increase in LC3-II expression as well as autophagosome and autolysosome formation in peritoneal macrophages (PMs) from C57BL/6 wild-type mice. Moreover, the pharmacologic inhibition of autophagic machinery impaired the ability of PMs to control T. cruzi replication. Importantly, NLRP3 was required for the induction of a regular autophagic flux in response to T. cruzi, an effect mediated by its participation in the autolysosomes formation. Together, these results indicate autophagy as an effector mechanism mediated by NLRP3 to control T. cruzi infection.

Cytosolic flagellin-induced lysosomal pathway regulates inflammasome-dependent and -independent macrophage responses.

NAIP5/NLRC4 (neuronal apoptosis inhibitory protein 5/nucleotide oligomerization domain-like receptor family, caspase activation recruitment domain domain-containing 4) inflammasome activation by cytosolic flagellin results in caspase-1-mediated processing and secretion of IL-1ß/IL-18 and pyroptosis, an inflammatory cell death pathway. Here, we found that although NLRC4, ASC, and caspase-1 are required for IL-1ß secretion in response to cytosolic flagellin, cell death, nevertheless, occurs in the absence of these molecules. Cytosolic flagellin-induced inflammasome-independent cell death is accompanied by IL-1α secretion and is temporally correlated with the restriction of Salmonella Typhimurium infection. Despite displaying some apoptotic features, this peculiar form of cell death do not require caspase activation but is regulated by a lysosomal pathway, in which cathepsin B and cathepsin D play redundant roles. Moreover, cathepsin B contributes to NAIP5/NLRC4 inflammasome-induced pyroptosis and IL-1α and IL-1ß production in response to cytosolic flagellin. Together, our data describe a pathway induced by cytosolic flagellin that induces a peculiar form of cell death and regulates inflammasome-mediated effector mechanisms of macrophages.