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Review
. 2019 Nov;49(11):1998-2011.
doi: 10.1002/eji.201848070. Epub 2019 Aug 14.

Role of AIM2 inflammasome in inflammatory diseases, cancer and infection

Bhesh Raj Sharma  1 , Rajendra Karki  1 , Thirumala-Devi Kanneganti  1
Affiliations
Review

Role of AIM2 inflammasome in inflammatory diseases, cancer and infection

Bhesh Raj Sharma et al. Eur J Immunol. 2019 Nov.

Abstract

AIM2 is a cytosolic innate immune receptor which recognizes double-stranded DNA (dsDNA) released during cellular perturbation and pathogenic assault. AIM2 recognition of dsDNA leads to the assembly of a large multiprotein oligomeric complex termed the inflammasome. This inflammasome assembly leads to the secretion of bioactive interleukin-1β (IL-1β) and IL-18 and induction of an inflammatory form of cell death called pyroptosis. Sensing of dsDNA by AIM2 in the cytosol is crucial to mediate protection against the invading pathogens including bacteria, virus, fungi and parasites. AIM2 also responds to dsDNA released from damaged host cells, resulting in the secretion of the effector cytokines thereby driving the progression of sterile inflammatory diseases such as skin disease, neuronal disease, chronic kidney disease, cardiovascular disease and diabetes. Additionally, the protection mediated by AIM2 in the development of colorectal cancer depends on its ability to regulate epithelial cell proliferation and gut microbiota in maintaining intestinal homeostasis independently of the effector cytokines. In this review, we will highlight the recent progress on the role of the AIM2 inflammasome as a guardian of cellular integrity in modulating chronic inflammatory diseases, cancer and infection.

Keywords: AIM2; cell death; gasdermin; inflammasome; pyroptosis.

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Conflict of interest statement

Conflicts of Interest

The authors declare no commercial or financial conflict of interest to disclose.

Figures

Figure 1.
Figure 1.
Regulation of AIM2 inflammasome activation. AIM2 is a dsDNA sensor and is composed of C-terminal HIN-200 domain and N-terminal pyrin domain. AIM2 forms an inflammasome when dsDNA from a number of microbial pathogens and host DNA from cellular damage binds to the HIN-200 domain of AIM2. The cytosolic bacterium Francisella novicida induces the production of type I IFNs via the c-GAS/STING pathway. Type I interferons activate IRF1. IRF1 then induces the upregulation of Gbp5 and Irgb10. These interferon-inducible proteins directly attack the bacterial membrane of F. novicida, releasing its DNA into the cytoplasm; its DNA binds to AIM2. The DNA virus MCMV, transfected poly(dA:dT), host DNA from cellular damage and fungal ligands from Aspergillus fumigatus activate AIM2 via a non-canonical pathway bypassing the requirement of type I IFNs. Ionizing radiation induces dsDNA breaks in host cells, leading to the redistribution of AIM2 and ASC into the DNA breakage area of nucleus. AIM2 and ASC then translocate to the cytoplasm to assemble an inflammasome complex. AIM2 activation can be inhibited by a mouse p202, a bipartite protein containing two HIN domains that interact with the HIN domain of AIM2. AIM2 can also be inhibited by human POP1 and POP3. During inflammasome activation, ASC brings caspase-1 to the inflammasome complex by CARD-CARD interactions. Activated caspase-1 then leads to the induction of pyroptosis via the proteolytic cleavage of the N-terminal domain of gasdermin-D that generates pores on the host cell membrane from which the proteolytically cleaved form of proinflammatory cytokines IL-1β and IL-18 are released.
Figure 2.
Figure 2.
Role of AIM2 in chronic kidney disease. Acute kidney injury leads to the necrosis of tubular cells and releases DNA. The released DNA is taken up by neighboring macrophages, activating the AIM2 inflammasome. The activation of the AIM2 inflammasome leads to the formation of proinflammatory cytokines, such as IL-1β and IL-18, promoting chronic kidney inflammation.
Figure 3.
Figure 3.
Role of AIM2 in atherosclerosis. dsDNA released from necrotic cells during advanced atherosclerosis activates the AIM2 inflammasome in macrophages and releases inflammasome effector cytokines, IL-1β and IL-18. These cytokines promote the formation of atherosclerotic plaque. Additionally, oxidized LDL promotes Aim2 gene expression in vascular smooth muscle cells. IFN-γ produced from activated macrophages and oxidized LDL activates MMP-2, SMAD-2 and SMAD-3, which are dependent on AIM2 and enhance the proliferation of smooth muscle cells, worsening atherosclerosis.
Figure 4.
Figure 4.
Role of AIM2 in colitis and colon cancer. AIM2-mediated IL-18 production from the intestinal epithelial cells downregulates the expression of IL-22BP and consequently enhances the availability of IL-22 in the colon. IL-22 then regulates the expression of antimicrobial peptides such as Reg3β and Reg3γ to regulate colitis. AIM2 interacts with DNA-PK in colonic epithelial cells and inhibits the phosphorylation of AKT and c-Myc, resulting in the prevention of colon tumor formation.
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References

    1. Newton K and Dixit VM, Signaling in innate immunity and inflammation. Cold Spring Harb Perspect Biol 2012. 4. - PMC - PubMed
    1. Takeuchi O and Akira S, Pattern recognition receptors and inflammation. Cell 2010. 140: 805–820. - PubMed
    1. Cridland JA, Curley EZ, Wykes MN, Schroder K, Sweet MJ, Roberts TL, Ragan MA, Kassahn KS and Stacey KJ, The mammalian PYHIN gene family: phylogeny, evolution and expression. BMC Evol Biol 2012. 12: 140. - PMC - PubMed
    1. Brunette RL, Young JM, Whitley DG, Brodsky IE, Malik HS and Stetson DB, Extensive evolutionary and functional diversity among mammalian AIM2-like receptors. J Exp Med 2012. 209: 1969–1983. - PMC - PubMed
    1. Burckstummer T, Baumann C, Bluml S, Dixit E, Durnberger G, Jahn H, Planyavsky M, Bilban M, Colinge J, Bennett KL and Superti-Furga G, An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome. Nat Immunol 2009. 10: 266–272. - PubMed

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