Inflammasome and Autophagy Regulation: A Two-way Street

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.

NLRP3 sets the table for a parasitic meal

“…Much of the focus, albeit limited, has been centered on how autophagy regulates inflammasome formation and activity. These previous studies clearly show that deficits in molecules involved in autophagy can lead to unrestrained inflammasome activation and subsequent immunopathology . In contrast, much less is currently known about how inflammasome activation affects autophagy.…”

“…Another possibility is that autophagic flux is a general stress response to the formation of large oligomeric inflammasomes in cells. Indeed, recent studies have proposed the idea that autophagy plays key roles in the degradation of inflammasome machinery and NLRP3‐associated triggers, such as damaged mitochondria, and that this adaptive pathway helps to maintain cellular homeostasis …”

“…These previous studies clearly show that deficits in molecules involved in autophagy can lead to unrestrained inflammasome activation and subsequent immunopathology. 4,5 In contrast, much less is currently known about how inflammasome activation affects autophagy. In this issue, Matteucci and colleagues shed new light on this topic by showing that NLRP3-deficient macrophages display defective autophagic flux due to an inability to form autolysosomes ( Fig.…”

“…Indeed, recent studies have proposed the idea that autophagy plays key roles in the degradation of inflammasome machinery and NLRP3-associated triggers, such as damaged mitochondria, and that this adaptive pathway helps to maintain cellular homeostasis. 4,5 Another unresolved question has to do with how NLRP3-driven autophagy limits T. cruzi infection in macrophages. It is clear from a number of studies that autophagy/xenophagy can directly impede pathogen spread by coordinating the breakdown of the intruder in autolysosomes.…”

“…[1][2][3] In summary, the work presented by Matteucci and colleagues in this issue identifies NLRP3 as a novel regulator of autophagy during T. cruzi infection. 1 Recent studies have identified autophagy as a negative regulator of inflammasome signaling 4,5 ; however, less is currently known in regards to how inflammasome activation impacts autophagy.…”