Inflammasome and autophagy regulation - a two-way street

Abstract

Inflammation plays a significant role in protecting hosts against pathogens. Inflammation induced by non-infectious, endogenous agents can be detrimental, and if excessive can result in organ and tissue damage. The inflammasome is a major innate immune pathway that can be activated via both exogenous pathogen-associated molecular patterns (PAMPs) and endogenous damage-associated molecular patterns (DAMPs). Inflammasome activation involves formation and oligomerization of a protein complex including a NOD-like receptor (NLR), an adaptor protein (ASC) and procaspase-1. This then allows cleavage and activation of caspase-1, followed by downstream cleavage and release of proinflammatory cytokines, IL-1β and IL-18, from innate immune cells. Hyperinflammation caused by unrestrained inflammasome activation is linked with multiple inflammatory diseases, including inflammatory bowel disease, Alzheimer's disease and multiple sclerosis. So there is an understandable rush to understand mechanisms that regulate such potent inflammatory pathways. Autophagy has now been identified as a main regulator of inflammasomes. Autophagy is a vital intracellular process involved in cellular homeostasis, recycling and removal of damaged organelles (e.g. mitochondria) and intracellular pathogens. Autophagy is regulated by proteins 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 fuses with lysosomes to enable degradation of the contents. Autophagic removal of intracellular DAMPs, inflammasome components or cytokines can reduce inflammasome activation. Similarly, inflammasomes can regulate the autophagic process, allowing for a two-way, mutual regulation of inflammation that may hold the key for treatment of multiple diseases.

Keywords: DAMPs; beclin-1; caspase-1; caspase-11; mitophagy.

Figure 1.

Canonical and noncanonical inflammasomes. A typical inflammasome contains a sensor protein belonging to either the NLR or ALR family of pattern recognition receptors, an adaptor protein ASC and pro-caspase-1. NAIP-NLRC4 is activated by bacterial flagellin and type III secretion system proteins, NLRP1 is activated by lethal toxin and muramyl dipeptide, AIM2 is activated by cytosolic dsDNA and NLRP3 is activated by a variety of activators including ATP, uric acid, alum, β-amyloid, MSU and nigericin. Activation of these inflammasome complexes results in proteolytic cleavage of zymogen pro-caspase-1 into its enzymatically active form, which then leads to maturation of proinflammatory cytokines IL-1β and IL-18. In the noncanonical inflammasome pathway, pro-caspase-11 expression is induced by a variety of Toll-like receptor ligands, or via type I interferon signaling. Caspase-11 is self-oligomerized and activated by cytosolic LPS, which subsequently leads to caspase-1 activation, as well as gasdermin D–mediated pyroptotic cell death in macrophages.

Figure 2.

Inflammasome and autophagy interregulation. Autophagy can negatively regulate inflammasome activation by removing mitochondrial-derived DAMPs as well as through selective degradation of inflammasome complexes and mitochondria. Autophagy machinery also directly regulates IL-1β activation, release and signaling. Conversely, inflammasome activation regulates autophagosome formation through direct or indirect interactions.