| First Author | Yan S | Year | 2018 |
| Journal | J Immunol | Volume | 200 |
| Issue | 3 | Pages | 1016-1026 |
| PubMed ID | 29255077 | Mgi Jnum | J:258134 |
| Mgi Id | MGI:6113139 | Doi | 10.4049/jimmunol.1701177 |
| Citation | Yan S, et al. (2018) Deficiency of the AIM2-ASC Signal Uncovers the STING-Driven Overreactive Response of Type I IFN and Reciprocal Depression of Protective IFN-gamma Immunity in Mycobacterial Infection. J Immunol 200(3):1016-1026 |
| abstractText | The nucleic acids of Mycobacterium tuberculosis can be detected by intracellular DNA sensors, such as cyclic GMP-AMP synthase and absent in melanoma 2 (AIM2), which results in the release of type I IFN and the proinflammatory cytokine IL-1beta. However, whether cross-talk occurs between AIM2-IL-1beta and cyclic GMP-AMP synthase-type I IFN signaling upon M. tuberculosis infection in vivo is unclear. In this article, we demonstrate that mycobacterial infection of AIM2(-/-) mice reciprocally induces overreactive IFN-beta and depressive IFN-gamma responses, leading to higher infection burdens and more severe pathology. We also describe the underlying mechanism whereby activated apoptosis-associated speck-like protein interacts with a key adaptor, known as stimulator of IFN genes (STING), and inhibits the interaction between STING and downstream TANK-binding kinase 1 in bone marrow-derived macrophages and bone marrow-derived dendritic cells, consequently reducing the induction of type I IFN. Of note, apoptosis-associated speck-like protein expression is inversely correlated with IFN-beta levels in PBMCs from tuberculosis patients. These data demonstrate that the AIM2-IL-1beta signaling pathway negatively regulates the STING-type I IFN signaling pathway by impeding the association between STING and TANK-binding kinase 1, which protects the host from M. tuberculosis infection. This finding has potential clinical significance. |
