The Emerging Relevance of AIM2 in Liver Disease

Abstract

Absent in melanoma 2 (AIM2) is a cytosolic receptor that recognizes double-stranded DNA (dsDNA) and triggers the activation of the inflammasome cascade. Activation of the inflammasome results in the maturation of inflammatory cytokines, such as interleukin (IL)-1 β and IL-18, and a form of cell death known as pyroptosis. Owing to the conserved nature of its ligand, AIM2 is important during immune recognition of multiple pathogens. Additionally, AIM2 is also capable of recognizing host DNA during cellular damage or stress, thereby contributing to sterile inflammatory diseases. Inflammation, either in response to pathogens or due to sterile cellular damage, is at the center of the most prevalent and life-threatening liver diseases. Therefore, during the last 15 years, the study of inflammasome activation in the liver has emerged as a new research area in hepatology. Here, we discuss the known functions of AIM2 in the pathogenesis of different hepatic diseases, including non-alcoholic fatty liver disease (NAFLD) and non-alcoholic steatohepatitis (NASH), hepatitis B, liver fibrosis, and hepatocellular carcinoma (HCC).

Keywords: AIM2; HCC; NAFLD; NASH; absent in melanoma 2; cirrhosis; fibrosis; hepatitis; inflammasome; liver disease.

Figure 1

Mechanism of AIM2 inflammasome assembly. Two mechanisms of AIM2 activation have been described. In the presence of dsDNA of any origin, AIM2 loses its auto-inhibitory conformation and the PYD can interact with the PYD of the adaptor ASC (A). In addition, a high concentration of AIM2 in the cytosol can also trigger AIM2 oligomerization and ASC recruitment without dsDNA (B). In both cases, the next step is the formation of large ASC specks and the recruitment of pro-caspase-1 molecules owing to CARD–CARD interactions. Pro-caspase-1 molecules then undergo auto-cleavage to generate active caspase-1. Active caspase-1 has a dual function: it cleaves pro-IL-1β and pro-IL-18 into the mature IL-1β and IL-18 cytokines, and processes GSDMD, releasing the N-terminal fragment. N-terminal GSDMD interacts with the plasma membrane and induces the formation of pores, which allows the passive release of IL-1β and IL-18 and also induces pyroptotic cell death and release of cellular contents and alarmins. AIM2—absent in melanoma 2. ASC—apoptosis-associated speck-like protein containing a CARD. CARD—caspase recruitment domain. dsDNA—double-stranded DNA. GSDMD—gasdermin D. HIN—hematopoietic expression, interferon-inducible, and nuclear localization. IL—interleukin. PYD—pyrin domain.

Figure 2

Negative regulation of the AIM2 inflammasome. Several mechanisms have been described with the potential to negatively regulate AIM2. (A) The HIN-only protein p202 is present in mouse and is able to directly interact with both the HIN domain of AIM2 as well as with dsDNA, but is unable to recruit ASC; therefore, it can inhibit AIM2 inflammasome activation by blocking the HIN domain of AIM2 and/or by competing for dsDNA. The synthetic ODN TTAGGG can also inhibit AIM2 function by blocking the AIM2–dsDNA interaction. (B) TRIM11 is ubiquitinated in the presence of DNA and binds to AIM2. Then, p62 binds to the ubiquitinated TRIM11–AIM2 complex and targets this complex for degradation in the autophagosome, dampening AIM2 inflammasome formation. (C) PYD-only proteins (POPs) are decoy proteins that interfere with AIM2 function by blocking PYD–PYD interactions with ASC. Similarly, CARD-only proteins (COPs) are decoy proteins that block CARD–CARD interactions between ASC and pro-caspase-1. AIM2—absent in melanoma 2. ASC—apoptosis-associated speck-like protein containing a CARD. CARD—caspase recruitment and activation domain. dsDNA—double-stranded DNA. HIN—hematopoietic expression, interferon-inducible and nuclear localization. ODN—oligodeoxynucleotide. PYD—pyrin domain. POP—pyrin only protein. COP—CARD-only protein TRIM11—tripartite motif 11. Ub—ubiquitination.