AIM2 Inflammasome's First Decade of Discovery: Focus on Oral Diseases

Abstract

A common feature of many acute and chronic oral diseases is microbial-induced inflammation. Innate immune responses are the first line of defense against pathogenic microorganisms and are initiated by pattern recognition receptors (PRRs) that specifically recognize pathogen-associated molecular patterns and danger-associated molecular patterns. The activation of certain PRRs can lead to the assembly of macromolecular oligomers termed inflammasomes, which are responsible for pro-inflammatory cytokine maturation and secretion and thus activate host inflammatory responses. About 10 years ago, the absent in melanoma 2 (AIM2) was independently discovered by four research groups, and among the "canonical" inflammasomes [including AIM2, NLR family pyrin domain (NLRP)1, NLRP3, NLR family apoptosis inhibitory protein (NAIP)/NLR family, caspase activation and recruitment domain (CARD) containing (NLRC)4, and pyrin], AIM2 so far is the only one that simultaneously acts as a cytosolic DNA sensor due to its DNA-binding ability. Undoubtedly, such a double-faceted role gives AIM2 greater mission and more potential in the mediation of innate immune responses. Therefore, AIM2 has garnered much attention from the broad scientific community during its first 10 years of discovery (2009-2019). How the AIM2 inflammasome is related to oral diseases has aroused debate over the past few years and is under active investigation. AIM2 inflammasome may potentially be a key link between oral diseases and innate immunity. In this review, we highlight the current knowledge of the AIM2 inflammasome and its critical role in the pathogenesis of various oral diseases, which might offer future possibilities for disease prevention and targeted therapy utilizing this continued understanding.

Inflammasomes in Alveolar Bone Loss

“…One proposed hypothesis suggests that, in response to bacterial infection, type I IFN is synthesized and drives the expression of IFN regulatory factor 1 (IRF1) via an autocrine pathway through activation of the cyclic GMP-AMP synthase (cGAS)/stimulator of IFN genes (STING)/STING-TANK binding kinase 1 (TBK1)/IRF3 axis ( 27 ). Upon IRF1 expression, guanylate-binding protein 2 (GBP2)/GBP5 and immunity-related GTPase family member b10 (IRGB10) are produced and disrupt the bacterial membrane and vacuoles containing bacteria ( 26 , 28 ). Therefore, a large quantity of dsDNA is exposed and sensed by the AIM2 inflammasome.…”

Inflammasome Contribution to the Activation of Th1, Th2, and Th17 Immune Responses

“…The role of this complex is to liberate Cas1, which becomes active and cleaves pro-IL-1β and pro-IL-18 releasing active cytokines ( Harton et al, 2002 ; Ting et al, 2008 ; Schroder and Tschopp, 2010 ; Shenoy et al, 2012 ; Zheng et al, 2020 ). In addition to the release of cytokines, inflammasome activation is accompanied by a specific form of cell death called pyroptosis ( Wang et al, 2020 ). Pyroptosis is characterized by Cas1 cleavage of the gasdermin D (GSDMD) protein ( Broz, 2015 ), which leads to cell lysis and subsequent release of cytoplasmic components, including mature forms of IL-1β and IL-18 ( Sansonetti et al, 2000 ).…”

Therapeutic implications of inflammasome in inflammatory bowel disease

“…In normal inactive state, AIM2 HIN confines AIM2 PYD domain, restricting its ability to form PYD‐PYD interactions 84 . The binding of dsDNA to AIM2 HIN by oligonucleotide/oligosaccharide binding folds of HIN or independent interactions, release PYD domain further enabling it to form PYD‐PYD interactions 85 . Binding of AIM2 PYD to ASC completes the formation of an active inflammasome assembly to perform downstream actions.…”

“…84 The binding of dsDNA to AIM2 HIN by oligonucleotide/oligosaccharide binding folds of HIN or independent interactions, release PYD domain further enabling it to form PYD-PYD interactions. 85 Binding of AIM2 PYD to ASC completes the formation of an active inflammasome assembly to perform downstream actions. However, few studies contradicted the autoinhibitory model of AIM2 PYD activation, the studies suggested the oligomerization-driven activation of AIM2 PYD assembly.…”