“Other Than NLRP3” Inflammasomes: Multiple Roles in Brain Disease

Abstract

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.

NLRP3 Inflammasome’s Activation in Acute and Chronic Brain Diseases—An Update on Pathogenetic Mechanisms and Therapeutic Perspectives with Respect to Other Inflammasomes

“…Moreover, these same neural cell types more intensely express various other-than-NLRP3 inflammasomes. The latter can also exert significant neuroinflammation-sustaining effects, as specific NLRP3 inhibitors do not hinder other-than-NLRP3 inflammasomes’ activities [ 24 ]. We previously reviewed the known roles of various other-than-NLRP3 inflammasomes in human brain disease [ 24 ].…”

“…The latter can also exert significant neuroinflammation-sustaining effects, as specific NLRP3 inhibitors do not hinder other-than-NLRP3 inflammasomes’ activities [ 24 ]. We previously reviewed the known roles of various other-than-NLRP3 inflammasomes in human brain disease [ 24 ]. That work inspired us to delve deeply also into the role(s) of the brain’s NLRP3 inflammasome.…”

“…Moreover, fundamental cytological divergences in size, shape, connections, and functions distinguish the diverse types of neural cells of the human cortex from their rodent counterparts [ 476 ]. Human brain’s molecular regulatory mechanisms, e.g., those involved in receptor signal transduction [ 133 ] and inflammasome regulation [ 24 , 27 , 477 ] (see also Box 1 and Box 2 ), also remarkably diverge from those of rodents. Moreover, human neurodegenerative diseases do not plague rodents in nature.…”

“…We recently reviewed the multiple roles of the NLRP1, NLRP2, AIM-2, and NLRC4 inflammasomes in human and rodent brain diseases [ 24 ]. Our work showed that several inflammasomes can partake in brain neuroinflammatory processes.…”

“…Young mice brains physiologically express basal levels of NLRP3 inflammasome activity to upkeep conditioning-induced neuronal plasticity and memory consolidation in the ventral hippocampus and basolateral amygdala [ 130 ]. Discordant opinions exist about inflammasomes’ roles in human brain diseases, as specific molecular lines of evidence are scanty [ 24 , 131 , 132 ].…”