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

Rathinam VA, et al. Nature Immunology, 11:395-403 (2010)

Speaker: Pin-Hung Lin (林品宏)                                            Time: 15:10~16:00, Dec. 22, 2010

Commentator: Pei-Jane Tsai, Ph.D. (蔡佩珍 老師)              Place: Room 601

Abstract:

Innate immune responses are important for the early control of infections through the recognition of microbial products by pattern recognition receptors. Inflammasomes are protein complexes that recognize pathogen-associated molecular patterns and promote the maturation ofproinflammatory cytokines, such as interleukin 1β (IL-1β) and IL-18¹. Previous studies have identified a pattern recognition receptor AIM2 (absent in melanoma 2) that senses foreign DNA and interacts with ASC (apoptosis-associated speck-like protein containing a caspase activation and recruitment domain) to regulate the maturation of IL-1β and IL-18 in vitro². Because, the role of AIM2 in defenses against pathogens in vivo remain unknown, the authors used AIM2-deficient mice to investigate this issue. They found that AIM2 deficiency did not alter macrophage differentiation. Consistent with previous studies, AIM2 sensed poly (dA:dT) and interacted with ASC to increase IL-1β and IL-18 maturation. When cells infected with cytosolic bacteria or DNA viruses, AIM2 inflammasome could be activated to promote the maturation of IL-1β and IL-18.Furthermore, the AIM2-deficient cells responded normally as wild-type cells to stimuli that activate other inflammasomes indicating that AIM2 is a specific sensor to cytosolic double-stranded DNA. Because cytosolic DNA is a potent trigger of type I interferons, the authors also compared the interferon responses in AIM2-deficient cells. They found that AIM2 did not mediate type I interferon responses. Finally, they infected mice with mouse cytomegalovirus and found that activation of AIM2 inflammasome reduced the viral loads in tissues through IL-18 and NK cell-dependent production of gamma interferon. Collectively, these data demonstrated that AIM2 is a cytosolic, double-stranded DNA sensor in vivo, and AIM2 inflammasome is important for early host defense against pathogens.

References:

1. Schroder K., Tschopp J. The Inflammasomes. Cell, 140: 821-832 (2010)

2. Hornung V., et al. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC, Nature. 458: 514-519 (2009)