AIM2 inflammasome in infection, cancer, and autoimmunity: Role in DNA sensing, inflammation, and innate immunity

Abstract

Recognition of DNA by the cell is an important immunological signature that marks the initiation of an innate immune response. AIM2 is a cytoplasmic sensor that recognizes dsDNA of microbial or host origin. Upon binding to DNA, AIM2 assembles a multi-protein complex called the inflammasome, which drives pyroptosis and proteolytic cleavage of the pro-inflammatory cytokines pro-IL-1β and pro-IL-18. Release of microbial DNA into the cytoplasm during infection by Francisella, Listeria, Mycobacterium, mouse cytomegalovirus, vaccinia virus, Aspergillus and Plasmodium species leads to activation of the AIM2 inflammasome. In contrast, inappropriate recognition of cytoplasmic self-DNA by AIM2 contributes to the development of psoriasis, dermatitis, arthritis and other autoimmune and inflammatory diseases. Inflammasome-independent functions of AIM2 have also been described, including the regulation of the intestinal stem cell proliferation and the gut microbiota ecology in the control of colorectal cancer. In this review we provide an overview of the latest research on AIM2 inflammasome and its role in infection, cancer and autoimmunity.

Retracted:HBx‐mediated decrease of AIM2 contributes to hepatocellular carcinoma metastasis

“…As a well known inflammasome, AIM2 exerts its function particularly by recognizing double‐stranded DNA of bacteria or virus, such as orthopoxvirus vaccinia virus and Francisella tularensis virus (Man et al ., 2016). AIM2 was also found to be activated when sensing the presence of HBV DNA in hepatocytes (Pan et al ., 2016).…”

The Duality of AIM2 Inflammasome: A Focus on its Role in Autoimmunity and Skin Diseases

“…1, recognition of dsDNA from pathogens by AIM2 heads to protective inflammasomemediated host responses. In contrast, improper recognition of cytoplasmic self-DNA by AIM2 leads to the development of several pathologies, such as psoriasis, dermatitis, arthritis and other autoimmune and inflammatory diseases (Man et al, 2016).…”

“…AIM2 has been shown to provide immune-surveillance to several pathogenic bacteria like Listeria monocytogenes, Streptococcus pneumonia, Staphilococcus aureus and many others (Rathinam et al, 2010;Fernandes-Alnemri et al, 2010;Kim et al, 2010;Warren et al, 2010;Hanamsagar et al, 2014;Tsuchiya et al, 2010;Man et al, 2016). These pathogens activate AIM2 via a 'non canonical' pathway owing to its requirement for type I IFN, analogous to the non-canonical NLRP3 inflammasome pathway (Man et al, 2016) and they must escape the vacuole and undergo bacteriolysis in order to induce the activation of the AIM2 inflammasome (Fang et al, 2011;Kim et al, 2010;Tsuchiya et al, 2010). Some bacteria have evolved virulence determinants to prevent release of DNA to avoid cytoplasmic and clearance by inflammasomes (Crane et al, 2014;Dotson et al, 2013), however there is limited evidence to support the existence of mechanisms used by bacteria to evade or inhibit activation of AIM2, which is overall an extraordinary antimicrobial machinery (Man et al, 2016).…”

“…Whether, AIM2 recognizes directly viral DNA derived from hepatitis B virus is still elusive: probably the viral DNA binds to AIM2 to trigger inflammasome activation, but the precise molecular mechanisms is not clear (Man et al, 2014). Therefore, to date there is evidence in the literature to indicate that only MCMV, vaccinia viruses and human papilloma viruses induce inflammasome responses in a AIM2-dependent manner (Hornung et al, 2009;Rathinam et al, 2010;Reinholz et al, 2013) and it is known that AIM2 does not respond to all DNA viruses (Man et al, 2016). However, has been reported a role for AIM2 in driving IL-1β secretion in response to RNA viruses: silencing of genes encoding AIM2 and caspase-1 reduces proteolytic cleavage and release of IL-1β in human dermal fibroblasts infected with the RNA virus Chikungunya (Ekchariyawat et al, 2015).…”

“…However, the DNA sequence should be at least 80 base pairs in length (Jin et al, 2013). The clarification of the crystal structure of AIM2 had an impact on the explanation of its activation mechanism (Man et al, 2016). This mini-review summarizes the latest research findings on the AIM2 inflammasome, focusing on its role in autoimmunity and skin diseases and discussing its therapeutic implications.…”