Abstract
Inflammation plays a significant role in protecting hosts against pathogens. Inflammation induced by noninfectious 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 nucleotide oligomerization domain (NOD)-like receptor (NLR), an adaptor protein and pro-caspase-1. This then allows cleavage and activation of caspase-1, followed by downstream cleavage and release of proinflammatory cytokines interleukin (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 (eg, 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.
Highlights
Inflammatory innate immune responses are important in host defense against pathogens [1,2]
Similar pathways can be activated by sterile exogenous or endogenous agents, but the resulting inflammation can be detrimental through the induction of organ and tissue damage, resulting in inflammatory disease [2,3]
Zhou et al demonstrated that following pharmacological inhibition of mitochondrial complex I and III, increased mitochondrial reactive oxygen species (ROS) production is responsible for NLRP3-mediated caspase-1 activation and IL-1β release in monocytes, which can be further reversed by ROS scavenger [19]
Summary
Inflammatory innate immune responses are important in host defense against pathogens [1,2]. Recent work has shown that in most cases, activation of individual NLR inflammasomes is relatively specific, but can only occur in response to such wide-ranging stimuli through direct association with select protein mediators. Zhou et al demonstrated that following pharmacological inhibition of mitochondrial complex I and III, increased mitochondrial ROS production is responsible for NLRP3-mediated caspase-1 activation and IL-1β release in monocytes, which can be further reversed by ROS scavenger [19].
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