OTHER-THAN-NLRP3 INFLAMMASOMES: MULTIPLE ROLES IN BRAIN DISEASE

Human neuroinflammatory and neurodegenerative diseases, whose prevalence keeps rising, are still unsolved pathobiological/therapeutical problems. Among others, recent etiology hypotheses stressed as their main driver a chronic neuroinflammation, which is mediated by innate immunity-related protein oligomers: the inflammasomes. A panoply of exogenous and/or endogenous harmful agents activates inflammasomes’ assembly, signaling, and IL- 1β/IL-18 production and neural cells’ pyroptotic death. The underlying concept is that inflammasomes’ chronic activation advances neurodegeneration while their short-lasting operation restores tissue homeostasis. Hence, from a therapeutic standpoint, it is crucial to understand inflammasomes’ regulatory mechanisms. About this, a deluge of recent studies focused on the NLRP3 inflammasome with suggestions that its pharmacologic block would hinder neurodegeneration. Yet hitherto no evidence proves this view. Moreover, known inflammasomes are numerous, and the mechanisms regulating their expression and function may vary with the involved animal species and strains, as well as organs and cells, and the harmful factors triggered as a result. Therefore, while presently leaving out some little-studied inflammasomes, this review focuses on the “other than NLRP3” inflammasomes that participate in neuroinflammation’s complex mechanisms: NLRP1, NLRP2, NLRC4, and AIM2. Although human-specific data about them are relatively scant, we stress that only a holistic view including several human brain inflammasomes and other potential pathogenetic drivers will lead to successful therapies for neuroinflammatory and neurodegenerative diseases.

Human neuroinflammatory and neurodegenerative diseases, whose prevalence keeps rising, are still unsolved pathobiological/therapeutical problems. Among others, recent etiology hypotheses stressed as their main driver a chronic neuroinflammation which is mediated by innate immunity-related protein oligomers, the inflammasomes. Panoply of exogenous and/or endogenous harmful agents activate inflammasomes' assembly, signaling, IL-1beta/IL-18 production, and neural cells' pyroptotic death. The underlying concept is that inflammasomes' chronic activation advances neurodegeneration while their short-lasting operation restores tissue homeostasis. Hence, from a therapeutic standpoint is crucial to understand inflammasomes' regulatory mechanisms. About this, a deluge of recent studies focused on NLRP3 inflammasome with suggestions that its pharmacological block would hinder neurodegeneration. Yet hitherto no evidence proves this view. Moreover, known inflammasomes are numerous and the mechanisms regulating their expression/function may vary with the involved animal species/strains, organs/cells, and triggering harmful factors. Therefore, while presently leaving out some little studied inflammasomes, this review focuses on "other-than-NLRP3" inflammasomes, i.e. NLRP1, NLRP2, NLRC4, and AIM2, which also participate in neuroinflammation's complex mechanisms. Albeit human-specific data about them are relatively scanty, we stress that only a holistic view including the several human brain inflammasomes and other potential pathogenetic drivers will lead to successful therapies for neuroinflammatory and neurodegenerative diseases.