Kiichi Nakahira 1 , Jeffrey Adam Haspel 1 , Vijay AK Rathinam 2 , Seon-Jin Lee 1 , Tamas Dolinay 1 , Hilaire C Lam 1 , Joshua A Englert 1 , Marlene Rabinovitch 3 , Manuela Cernadas 1 , Hong Pyo Kim 1 , 4 , Katherine A Fitzgerald 2 , Stefan W Ryter 1 , Augustine MK Choi 1 , †
12 December 2010
Autophagy, a cellular process for organelle and protein turnover, regulates innate immune responses. We demonstrate that depletion of autophagic proteins microtubule associated protein-1 light chain 3B (LC3B) and Beclin 1 enhances caspase-1 activation and secretion of interleukin-1β and interleukin-18. Autophagic protein depletion promoted accumulation of dysfunctional mitochondria and cytosolic translocation of mitochondrial DNA (mtDNA) in response to lipopolysaccharide (LPS) and ATP in macrophages. Release of mtDNA into the cytosol depended on the NALP3 inflammasome and mitochondrial ROS. Cytosolic mtDNA contributed to IL-1β and IL-18 secretion in response to LPS and ATP. LC3B-deficient mice produced more caspase-1-dependent cytokines in two sepsis models and were susceptible to LPS-induced mortality. Our study suggests that autophagic proteins regulate NALP3-dependent inflammation by preserving mitochondrial integrity.