Deficiency of the AIM2–ASC Signal Uncovers the STING-Driven Overreactive Response of Type I IFN and Reciprocal Depression of Protective IFN-γ Immunity in Mycobacterial Infection
| Autor: | Shanshan Yan, Ronghua Zhang, Qiaoshi Lian, Zhigang Tian, Hongbo Shen, Xiaoyu Sun, Guangxun Meng, Wenlong Jin, Zheng W. Chen, Wangpeng Gu, Xuan Lin, Bing Sun |
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| Rok vydání: | 2018 |
| Předmět: |
0301 basic medicine
Tuberculosis Interleukin-1beta Immunology Protein Serine-Threonine Kinases Biology Cell Line Proinflammatory cytokine Mycobacterium tuberculosis Interferon-gamma Mice 03 medical and health sciences AIM2 0302 clinical medicine Immunity medicine Animals Humans Immunology and Allergy Mice Knockout Kinase Macrophages Membrane Proteins Interferon-beta medicine.disease biology.organism_classification Mycobacterium bovis CARD Signaling Adaptor Proteins DNA-Binding Proteins Mice Inbred C57BL Sting HEK293 Cells RAW 264.7 Cells 030104 developmental biology Signal transduction Signal Transduction 030215 immunology |
| Zdroj: | The Journal of Immunology. 200:1016-1026 |
| ISSN: | 1550-6606 0022-1767 |
| Popis: | 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-1β. However, whether cross-talk occurs between AIM2–IL-1β 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-β and depressive IFN-γ 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-β levels in PBMCs from tuberculosis patients. These data demonstrate that the AIM2–IL-1β 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. |
| Databáze: | OpenAIRE |
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