The AIM2 inflammasome is critical for innate immunity to Francisella tularensis. Nat Immunol

Department of Biochemistry and Molecular Biology, Thomas Jefferson University, Philadelphia, Pennsylvania, USA.
Nature Immunology (Impact Factor: 20). 03/2010; 11(5):385-93. DOI: 10.1038/ni.1859
Source: PubMed


Francisella tularensis, the causative agent of tularemia, infects host macrophages, which triggers production of the proinflammatory cytokines interleukin 1beta (IL-1beta) and IL-18. We elucidate here how host macrophages recognize F. tularensis and elicit this proinflammatory response. Using mice deficient in the DNA-sensing inflammasome component AIM2, we demonstrate here that AIM2 is required for sensing F. tularensis. AIM2-deficient mice were extremely susceptible to F. tularensis infection, with greater mortality and bacterial burden than that of wild-type mice. Caspase-1 activation, IL-1beta secretion and cell death were absent in Aim2(-/-) macrophages in response to F. tularensis infection or the presence of cytoplasmic DNA. Our study identifies AIM2 as a crucial sensor of F. tularensis infection and provides genetic proof of its critical role in host innate immunity to intracellular pathogens.

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    • "concentration inhibits IL-1b secretion and pro-IL-1b translation induced by M. bovis in THP-1 macrophages The NLRP3 and AIM2 inflammasomes are activated upon mycobacterial infection in murine macrophages, and they are both inhibited by high extracellular K ? concentrations as described by Fermandes-Alnemri et al.and Petrilli et al. (Fernandes-Alnemri et al. 2010; Petrilli et al. 2007). We found that IL-1b secretion was reduced by high extracellular K ? "

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    • "Therefore, these proteins can theoretically bind nucleic acids and recruit ASC to trigger the formation of an inflammasome . Indeed, AIM2 can form an inflammasome whose assembly is stimulated by recognition of cytosolic DNA of bacterial or viral origin (Fernandes-Alnemri et al. 2010; Jones et al. 2010; Rathinam et al. 2010; Sauer et al. 2010), or self-DNA from apoptotic cells (Choubey 2012; Zhang et al. 2013). Recent crystal structures of AIM2 complexed with DNA have provided particular insight into the mechanism of AIM2 inflammasome activation. "
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    • "mROS has also been implicated in activation of the NLRP3 inflammsome (Heid et al., 2013). Others have routinely demonstrated that activation of the inflammasome by Fn in mouse cells is mediated exclusively by AIM2 and not NLRP3 (Fernandes-Alnemri et al., 2010; Atianand et al., 2011). Nevertheless, given the association of mROS with the NLRP3 inflammasome, we also assessed if NLRP3 contributed to cleavage of caspase-1 and secretion of IL-1β among Fn infected cells. "
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