AIM2 inflammasome in infection, cancer, and autoimmunity: Role in DNA sensing, inflammation, and innate immunity - PubMed (original) (raw)

Review

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

Si Ming Man et al. Eur J Immunol. 2016 Feb.

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 multiprotein complex called the inflammasome, which drives pyroptosis and proteolytic cleavage of the proinflammatory 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.

Keywords: AIM2 inflammasome; Autoimmunity; Bacterial/viral infection; Cancer; DNA sensing; Gut microbiota.

© 2015 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

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Conflict of interest statement

Conflict of interest

The authors declare no financial or commercial conflict of interest.

Figures

Figure 1

Figure 1. The molecular basis for the activation of the AIM2 inflammasome

The DNA sensor AIM2 is composed of an N-terminal pyrin domain and a C-terminal HIN-200 domain. The pyrin and HIN-200 domain of AIM2 form an intramolecular complex and are maintained in an autoinhibitory state. Cytoplasmic dsDNA induces activation of AIM2. The HIN-200 domain interacts with dsDNA in a sequence-independent manner, by binding to the sugar-phosphate backbone of dsDNA. The pyrin domain of AIM2 binds to the pyrin domain of ASC. CARD of ASC binds the CARD of pro-caspase-1, forming a macromolecular complex known as the AIM2 inflammasome. Activated caspase-1 drives cleavage of pro-IL-1β and pro-IL-18. Caspase-1 also cleaves the substrate gasdermin D. The N-terminal fragment of gasdermin D induces pyroptosis, allowing mature IL-1β and IL-18 to be released from the cell.

Figure 2

Figure 2. Regulation of the activation of the AIM2 inflammasome

The AIM2 inflammasome is activated by a number of microbial pathogens and dsDNA ligands, including the DNA virus mouse cytomegalovirus (MCMV), the cytosolic bacterium Francisella novicida and the dsDNA ligand poly(dA:dT). MCMV infection or transfection of poly(dA:dT) leads to “canonical” activation of the AIM2 inflammasome, which does not require the type I interferon (IFN) pathway. F. novicida infection activates the AIM2 inflammasome via a “non-canonical” pathway owing to its requirement for type I IFN, analogous to the non-canonical NLRP3 inflammasome pathway. Intracellular F. novicida releases DNA into the cytoplasm to activate the DNA sensors cGAS, STING and IFI204, which drive transcription of genes encoding type I IFN molecules. It remains unclear why the released DNA is unable to activate AIM2 at this stage, since AIM2 is constitutively expressed in the cell. Type I IFN provides a feedback loop to induce expression of the transcription factor IRF1, which upregulates expression of the IFN-inducible GTPases, including GBP2 and GBP5. GBP2 and GBP5 are recruited to bacterial structures, however, whether they directly target the bacterial membrane or the membrane of intact _Francisella_-containing vacuole is unclear. Nevertheless, GBPs mediate bacterial killing, resulting in abundant release of bacterial DNA for recognition by AIM2. Assembly of the AIM2 inflammasome induces caspase-1-dependent cleavage of pro-IL-1β and pro-IL-18. Caspase-1 also drives cleavage of the substrate gasdermin D to induce pyroptosis.

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