Cytosolic DNA sensing by AIM2 inflammasome is integral to anti-microbial defense (157.5)

Abstract Cytosolic DNA of microbial and eukaryotic origins elicits strong inflammatory responses characterized by the production of type I interferons and IL-1β/IL-18. The maturation of proforms of IL-1β and IL-18 into bioactive forms is mediated by a multiprotein complex in the cytosol called inflammasomes. Recently, AIM2 (absent in melanoma 2) protein was shown to recognize cytosolic DNA and form an inflammasome complex. To understand the role of AIM2 in innate immunity, we generated AIM2 deficient mice. Using the AIM2-deficient mice, we demonstrate that AIM2 inflammasome is an essential and non-redundant mechanism mediating IL-1β and IL-18 responses to cytosolic DNA from bacterial and viral infections. In contrast, cytosolic DNA-induced activation of NF-κB and IRF-3 are normal in AIM2-/- cells indicating that AIM2 is least likely to play a role in type I interferon production elicited by cytosolic DNA. Importantly, AIM2 deficient mice infected with vaccinia virus (VV) or mouse cytomegalovirus (mCMV) demonstrated a marked reduction in serum IL-18 levels and in number of IFN-γ producing splenic NK cells, which are critical events in the early control of VV and mCMV infection. Correspondingly, AIM2 deficiency hampered the control of virus replication in the infected mice. Overall, we demonstrate that AIM2 inflammasome is an integral component of cytosolic DNA sensing in microbial infections.