The complex role of AIM2 in autoimmune diseases and cancers

Abstract

Absent in melanoma 2 (AIM2) is a novel member of interferon (IFN)-inducible PYHIN proteins. In innate immune cells, AIM2 servers as a cytoplasmic double-stranded DNA sensor, playing a crucial role in the initiation of the innate immune response as a component of the inflammasome. AIM2 expression is increased in patients with systemic lupus erythematosus (SLE), psoriasis, and primary Sjogren's syndrome, indicating that AIM2 might be involved in the pathogenesis of autoimmune diseases. Meanwhile, AIM2 also plays an antitumorigenesis role in an inflammasome independent-manner. In melanoma, AIM2 is initially identified as a tumor suppressor factor. However, AIM2 is also found to contribute to lung tumorigenesis via the inflammasome-dependent release of interleukin 1β and regulation of mitochondrial dynamics. Additionally, AIM2 reciprocally dampening the cGAS-STING pathway causes immunosuppression of macrophages and evasion of antitumor immunity during antibody treatment. To summarize the complicated effect and role of AIM2 in autoimmune diseases and cancers, herein, we provide an overview of the emerging research progress on the function and regulatory pathway of AIM2 in innate and adaptive immune cells, as well as tumor cells, and discuss its pathogenic role in autoimmune diseases, such as SLE, psoriasis, primary Sjogren's syndrome, and cancers, such as melanomas, non-small-cell lung cancer, colon cancer, hepatocellular carcinoma, renal carcinoma, and so on, hopefully providing potential therapeutic and diagnostic strategies for clinical use.

Keywords: AIM2; autoimmune diseases; cGAS-STING; cancers.

Figure 1

Assembly and activation of the AIM2 inflammasome. Sensing abnormal dsDNA in the cytoplasm triggers the assembly of the AIM2 inflammasome. The adapter protein ASC and the effector protein procaspase‐1 are recruited to participate in this activation process. AIM2, absent in melanoma 2; ASC, apoptosis‐associated speck‐like protein containing a CARD; dsDNA, double stranded DNA; GSDMD, gasdermin‐D; IL, interleukin

Figure 2

Regulation of the AIM2 inflammasome in macrophages. Cytosolic dsDNA from pathogens or host cells is sensed by AIM2, which attracts ASC and procaspase‐1 to trigger mature IL‐18 and IL‐1β production or GSDMD‐mediated pyroptosis. In GSDMD‐deficient macrophages, AIM2 induces caspase‐1‐dependent caspase‐3 activation whereas AIM2 drives caspase‐8‐dependent caspase‐3 activation without caspase‐1, resulting in apoptosis. The AIM2 inflammasome negatively regulates the cGAS/STING‐driven type I IFN response and can be inhibited by the IFN‐inducible proteins POP3 and IFI16‐β in humans or p202 in mice. AIM2, absent in melanoma 2; ASC, apoptosis‐associated speck‐like protein containing a CARD; dsDNA, double stranded DNA; GSDMD, gasdermin‐D; IFN, interferon; IL, interleukin

Figure 3

Tumorigenesis and antitumorigenesis of AIM2 in mammary tumors. The mature IL‐1β driven by AIM2 inflammasome promotes HIF‐1α expression through the NF‐κB/COX‐2 pathway. The association between mitochondria and AIM2 contributes to the MAPK/ERK signaling response that leads to tumorigenesis in NSCLC. In contrast, in colon cancer, DNA‐PK, as well as PI3K, are inhibited by AIM2, triggering the inactivation of AKT and c‐Myc, thereby preventing tumorigenesis. Additionally, the mTOR‐S6K1‐HIF‐1α pathway is inhibited by the AIM2 inflammasome, which plays an antitumorigenic role in hepatocellular carcinoma. AIM2, absent in melanoma 2; ASC, apoptosis‐associated speck‐like protein containing a CARD; dsDNA, double stranded DNA; GSDMD, gasdermin‐D; IFN, interferon; IL, interleukin