TLR3 regulates mycobacterial RNA-induced IL-10 production through the PI3K/AKT signaling pathway |
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| Institution: | 1. Shanghai TB Key Laboratory, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China;2. Department of Microbiology and Immunology, Tongji University School of Medicine, Shanghai, China;3. Clinical Translational Research Center, Shanghai Pulmonary Hospital, Tongji University School of Medicine, Shanghai, China;4. Department of Immunology, Max Planck Institute for Infection Biology, Berlin, Germany;1. Department of Pharmacology, Center for Translational Targeted Therapeutics, Nanomedicine of the Institute for Translational Medicine and Therapeutics, University of Pennsylvania, Philadelphia, PA, United States;2. Department of Medicine, Pulmonary, Allergy and Critical Care Division, University of Pennsylvania, Philadelphia, PA, United States;3. Fischell Department of Bioengineering, University of Maryland, College Park, MD, United States;4. Department of Biochemistry and Cell Biology, Geisel School of Medicine at Dartmouth, Lebanon, NH, United States |
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| Abstract: | Cytokine induction in response to Mycobacterium tuberculosis (Mtb) infection is critical for pathogen control, by (i) mediating innate immune effector functions and (ii) instructing specific adaptive immunity. IL-10 is an important anti-inflammatory cytokine involved in pathogenesis of tuberculosis (TB). Here, we show that TLR3, a sensor of extracellular viral or host RNA with stable stem structures derived from infected or damaged cells, is essential for Mtb-induced IL-10 production. Upon Mycobacterium bovis Bacillus Calmette–Guérin (BCG) infection, TLR3?/? macrophages expressed lower IL-10 but higher IL-12p40 production, accompanied by reduced phosphorylation of AKT at Ser473. BCG-infected TLR3?/? mice exhibited reduced IL-10 but elevated IL-12 expression compared to controls. Moreover, higher numbers of splenic Th1 cells and reduced pulmonary bacterial burden and tissue damage were observed in BCG-infected TLR3?/? mice. Finally, BCG RNA induced IL-10 in macrophages via TLR3-mediated activation of PI3K/AKT. Our findings demonstrate a critical role of TLR3-mediated regulation in the pathogenesis of mycobacterial infection involving mycobacterial RNA, which induces IL-10 through the PI3K/AKT signaling pathway. |
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