Negative regulation of the inflammasome: keeping inflammation under control

Abstract

In addition to its roles in controlling infection and tissue repair, inflammation plays a critical role in diverse and distinct chronic diseases, such as cancer, metabolic syndrome, and neurodegenerative disorders, underscoring the harmful effect of an uncontrolled inflammatory response. Regardless of the nature of the stimulus, initiation of the inflammatory response is mediated by assembly of a multimolecular protein complex called the inflammasome, which is responsible for the production of inflammatory cytokines, such as interleukin-1β (IL-1β) and IL-18. The different stimuli and mechanisms that control inflammasome activation are fairly well understood, but the mechanisms underlying the control of undesired inflammasome activation and its inactivation remain largely unknown. Here, we review recent advances in our understanding of the molecular mechanisms that negatively regulate inflammasome activation to prevent unwanted activation in the resting state, as well as those involved in terminating the inflammatory response after a specific insult to maintain homeostasis.

Characterization of Innate and Adaptive Immune Responses in PYNOD-Deficient Mice

“…Our current results are consistent with recent reports (6) and suggest that the basal PYNOD expression in macrophages is not essential for determining the magnitude of these responses. The apparent discrepancy of our previous and current results can be explained by the presence of redundant regulatory mechanisms for caspase-1 activation (18,19). For example, pyrin and caspase-12 are reported to negatively regulate caspase-1 activation, and their defects cause heightened IL-1b production in mice (20,21).…”

Exome sequencing of lymphomas from three dog breeds reveals somatic mutation patterns reflecting genetic background

“…TBC1D26 paralogs are mutated in 17% of all samples, with the ENSCAFG00000025100 paralog being the most commonly mutated, and the mutations cluster in a few domains. Additionally, each T-cell lymphoma predisposed breed is significantly mutated in a different member of the NLRP gene family, which is primarily associated with a role in innate immunity (Pedraza-Alva et al 2015) as well as reproduction (Duéñez-Guzmán and Haig 2014).…”

Molecular mechanisms regulating NLRP3 inflammasome activation

“…131,135 More detailed information on the negative regulation of the NLRP3 inflammasome, including the roles of microRNAs and autophagy, has been detailed in recent reviews. 136 Together, efforts to identify new negative regulators of NLRP3 inflammasome activation may provide novel strategies to treat acute and chronic inflammatory diseases associated with aberrant activation of the NLRP3 inflammasome. Figure 3 presents a schematic model for various molecular pathways that negatively regulate the NLRP3 inflammasome.…”