The AIM2 inflammasome is essential for host defense against cytosolic bacteria and DNA viruses

Abstract

Inflammasomes regulate the activity of capase-1 and maturation of interleukin-1β and interleukin-18. Recently, AIM2 was shown to bind DNA and engage ASC to form a caspase-1 activating inflammasome. Using Aim2-deficient mice, we reveal a central role for AIM2 in regulating caspase-1-dependent maturation of IL-1β and IL-18, as well as pyroptosis in response to synthetic dsDNA. AIM2 is essential for inflammasome activation in response to Fransicella tularensis, vaccinia virus, mouse cytomegalovirus and plays a partial role in sensing Listeria monocytogenes. Moreover, production of IL-18 and NK cell-dependent IFN-γ production, events critical in early control of virus replication were dependent on AIM2 during mCMV infection in vivo. Collectively, these observations reveal the importance of AIM2 in sensing both bacterial and viral pathogens and triggering innate immunity.

Pyroptotic Neuronal Cell Death Mediated by the AIM2 Inflammasome

“…6 AIM2 is activated by viral, bacterial, and host ectopic dsDNA and induces cleavage of procaspase-1, maturation of IL-1b, and pyroptosis. 7 Although AIM2 is expressed in tissue outside the immune system, 8 its functional role in either the recognition of pathogenic DNA, or autoimmune reactions to host nucleic acids, has only been established in innate immune cells. It is unknown if AIM2 regulates the innate immune response to dsDNA in other cell types, such as neurons.…”

A constant companion: immune recognition and response to cytomegalovirus with aging and implications for immune fitness

“…In mice, studies have shown a direct interaction between murine cytomegalovirus (MCMV) and NK cells, where the activating NK cell receptor Ly49H recognizes the m157 glycoprotein, thereby activating the NK cell to produce cytokines important for antiviral immunity and/or to kill (Krug et al 2004;Varani et al 2007;Zucchini et al 2008) MCMV and HCM-V AIM2 dsDNA (Rathinam et al 2010;Huang et al 2017) MCMV and HCM-V cGAS-STI-NG dsDNA (Lio et al 2016) MCMV TLR3 dsRNA (Tabeta et al 2004) MCMV TLR7 ssRNA (Zucchini et al 2008) HCMV DAI dsDNA (DeFilippis et al 2010) HCMV IFI16 dsDNA (Gariano et al 2012) the virus-infected cell through release of perforins and granzymes (Brown et al 2001;Pyzik et al 2011). Indeed, m157 deletion mutant MCMV fails to activate Ly49H+ NK cells and results in enhanced virulence (Voigt et al 2003;Bubić et al 2004).…”

Gut–Liver Axis: Role of Inflammasomes

“…Strikingly, it recognizes the mammalian DNA which acts as a contributory factor toward the pathogenesis of autoimmune diseases. 40 The association of helicase receptor RIG of dsRNA with the inflammasome adaptor molecule ASC leads to inflammasome activation which triggers caspase-1 activation. 41 Inflammasome Activates Caspase-1…”

“…65,66 In vivo studies have highlighted low levels of serum IL-18 and less secretion of interferon-g (IFN-g) by splenic NK cells in AIM2 deficient mice infected with mCMV. 66 Likewise, AIM2 deficient mice infected with F. tularensis novicida have high bacterial loads, low levels of serum IL-18 and lower survival than do wild type mice. 65 Mice deficient in ASC or caspase-1 show similar phenotype as described for the AIM2 deficient mice.…”

“…Deficiency of AIM2 has been found to increase the interferon response to dsDNA transfection or Francisella infection but elicits a normal response in the case of mCMV infection. 65,66 A recent study by Liu and group 68 established that the production of IL-1b and IL-18 in NLRP3 and NLRC4 inflammasomes plays a critical role in host defense against enteric infection caused by C. rodentium. An enteric bacterial pathogen in the intestinal tract of the mouse, C. rodentium triggers inflammatory responses similar to those seen in humans infected with enteropathogenic and enterohemorrhagic E. coli.…”