The AIM2 inflammasome is a central regulator of intestinal homeostasis through the IL-18/IL-22/STAT3 pathway

Abstract

Inflammasomes are important for maintaining intestinal homeostasis, and dysbiosis contributes to the pathology of inflammatory bowel disease (IBD) and increases the risk for colorectal cancer. Inflammasome defects contribute to chronic intestinal inflammation and increase the susceptibility to colitis in mice. However, the inflammasome sensor absent in melanoma 2 (AIM2) protects against colorectal cancer in an inflammasome-independent manner through DNA-dependent protein kinase and Akt pathways. Yet, the roles of the AIM2 inflammasome in IBD and the early phases of colorectal cancer remain ill-defined. Here we show that the AIM2 inflammasome has a protective role in the intestine. During steady state, Aim2 deletion results in the loss of IL-18 secretion, suppression of the IL-22 binding protein (IL-22BP) in intestinal epithelial cells and consequent loss of the STAT3-dependent antimicrobial peptides (AMPs) Reg3β and Reg3γ, which promotes dysbiosis-linked colitis. During dextran sulfate sodium-induced colitis, a dysfunctional IL-18/IL-22BP pathway in Aim2−/− mice promotes excessive IL-22 production and elevated STAT3 activation. Aim2−/− mice further exhibit sustained STAT3 and Akt activation during the resolution of colitis fueled by enhanced Reg3b and Reg3g expression. This self-perpetuating mechanism promotes proliferation of intestinal crypt cells and likely contributes to the recently described increase in susceptibility of Aim2−/− mice to colorectal cancer. Collectively, our results demonstrate a central role for the AIM2 inflammasome in preventing dysbiosis and intestinal inflammation through regulation of the IL-18/IL-22BP/IL-22 and STAT3 pathway and expression of select AMPs.

Review Article. Absent in melanoma 2 (AIM2) in the intestine: diverging actions with converging consequences

“…Furthermore, the authors suggest a selfperpetuating mechanism as they show that Reg3 family members can induce STAT3 (and Akt) phosphorylation. This positive feedback loop thus sustains AMP expression but can also induce cell proliferation, tissue repair and may therefore also contribute to colorectal cancer development [60]. days post treatment in contrast to the study by Hu et al where this was also happening in naïve AIM2 knockout mice [37,39].…”

“…Dysbiosis has also been observed in three independent studies with AIM2 knockout mice, although the specific differentially abundant bacterial populations differed between each study [37,59,60]. Man et al describe increased levels of Akkermansia muciniphila and without the release of pro-inflammatory cytoplasmic components [5,6].…”

“…All three studies confirmed that these microbial alterations had a significant influence on the disease that was modeled (colitis or CRC). For example, the importance of AIM2 in intestinal inflammation has recently been studied in acute dextran sodium sulfate (DSS)-induced colitis models [59,60]. AIM2 knockout mice have higher inflammatory scores and increased levels of inflammatory cytokines and chemokines.…”

“…Besides the previously mentioned dysbiosis in AIM2 knockout mice, a significant role for the intestinal microbiota in the colitissusceptible AIM2 knockout phenotype was proven by both natural and artificial microbial transfer experiments between AIM2 knockout and WT mice. Co-housing of AIM2 knockout mice with WT littermates reduced some signs of DSS-induced inflammation in AIM2 knockout mice whereas maternal or fecal transfer of AIM2 knockout microbiota into WT mice led to more severe colitis [59,60]. Hu et al provide a mechanism whereby AIM2 inflammasome mediated IL-18 (and IL-1β) activation drives the production of antimicrobial peptides (AMPs) such as Reg3β, Reg3γ, S100a8 and S100a9 that act as guardians against intestinal dysbiosis and thus might protect against dysbiosis-associated diseases [59].…”

Innate immunity and inflammation

“…This suggests that distinct regulatory mechanisms triggered by microbial or sterile stimulation dictate differential activation of the NLRP3 inflammasome, and more quantitative analysis of the activation process of other inflammasomes may be warranted. One of these is the AIM2 inflammasome examined by Ratsimandresy et al 12 in mucosal immunity. The activation of inflammasomes in hematopoietic cells is known to exacerbate intestinal inflammation, while those in intestinal epithelial cells promote the production of IL-18 essential for tissue regeneration and reduced colorectal cancer incidence.…”