Checks and Balances between Autophagy and Inflammasomes during Infection

Abstract

Autophagy and inflammasome complex assembly are physiological processes that control homeostasis, inflammation, and immunity. Autophagy is a ubiquitous pathway that degrades cytosolic macromolecules or organelles, as well as intracellular pathogens. Inflammasomes are multi-protein complexes that assemble in the cytosol of cells upon detection of pathogen- or danger-associated molecular patterns. A critical outcome of inflammasome assembly is the activation of the serine protease caspase-1, which activates the pro-inflammatory cytokine precursors pro-IL-1β and pro-IL-18. Studies on chronic inflammatory diseases, heart diseases, Alzheimer's disease, and multiple sclerosis revealed that autophagy and inflammasomes intersect and regulate each other. In the context of infectious diseases, however, less is known about the interplay between autophagy and inflammasome assembly, although it is becoming evident that pathogens have evolved multiple strategies to inhibit and/or subvert these pathways and to take advantage of their intricate crosstalk. An improved appreciation of these pathways and their subversion by diverse pathogens is expected to help in the design of anti-infective therapeutic interventions.

Frontline Science: Autophagy is a cell autonomous effector mechanism mediated by NLRP3 to control Trypanosoma cruzi infection

“…Since autophagy is initiated at early time points after infection it could be considered as a first line of NLRP3‐mediated control of T. cruzi replication, with NO secretion acting as an additional effector mechanism to clear the parasite. Actually, the interplay between autophagy and inflammasomes have been extensively studied in the context of many physiologic and pathologic conditions, including infectious diseases . However, since both autophagy and inflammasomes participate in unique host pathogens interactions, the networks built during infections are very complex and, therefore could account for the controversial data found in the literature.…”

“…At present, the mechanisms involved in the modulation of inflammasomes by autophagy are far better known. They involve the direct degradation of inflammasome components by autolysosomes as well as the indirect “removal” of inflammasome activators, such as damaged mitochondrias, limiting the release of its DNA and reactive oxygen species . On the other hand, inflammasomes, as well as other families of PRRs, have both stimulatory and inhibitory roles in the autophagy process during infections and the outcome seems to depend on the host‐pathogen interaction, since pathogens have evolved multiple strategies to subvert these pathways .…”

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 …”

“…The NLRP3 inflammasome is a multiprotein oligomeric platform that initiates IL-1 and IL-18 production, as well as an inflammatory form of cell death in response to pathogen-and damage-derived triggers. 4 NLRP3 inflammasomes are critically involved in mounting protective immune responses to a number of pathogens and play beneficial roles in the clearance of sterile irritants. However, unrestrained NLRP3 inflammasome activation is also known to be a major driver of many inflammatory and autoimmune disorders.…”