Inflammasome and Autophagy Regulation: A Two-way Street

摘要

Inflammation plays a significant role in protecting hosts against pathogens. Inflammation induced by noninfectious endogenousagents can be detrimental and, if excessive, can result in organ and tissue damage. The inflammasome is a major innateimmune pathway that can be activated via both exogenous pathogen-associated molecular patterns (PAMPs) and endogenousdamage-associated molecular patterns (DAMPs). Inflammasome activation involves formation and oligomerization of a proteincomplex including a nucleotide oligomerization domain (NOD)-like receptor (NLR), an adaptor protein and pro-caspase-1. Thisthen allows cleavage and activation of caspase-1, followed by downstream cleavage and release of proinflammatory cytokinesinterleukin (IL)-1β and IL-18 from innate immune cells. Hyperinflammation caused by unrestrained inflammasome activation islinked with multiple inflammatory diseases, including inflammatory bowel disease, Alzheimer’s disease and multiple sclerosis. Sothere is an understandable rush to understand mechanisms that regulate such potent inflammatory pathways. Autophagy hasnow been identified as a main regulator of inflammasomes. Autophagy is a vital intracellular process involved in cellular homeostasis,recycling and removal of damaged organelles (eg, mitochondria) and intracellular pathogens. Autophagy is regulated byproteins that are important in endosomal/phagosomal pathways, as well as by specific autophagy proteins coded for by autophagy-related genes. Cytosolic components are surrounded and contained by a double-membraned vesicle, which then fuseswith lysosomes to enable degradation of the contents. Autophagic removal of intracellular DAMPs, inflammasome componentsor cytokines can reduce inflammasome activation. Similarly, inflammasomes can regulate the autophagic process, allowing fora two-way mutual regulation of inflammation that may hold the key for treatment of multiple diseases.