期刊
NATURE IMMUNOLOGY
卷 16, 期 5, 页码 495-U211出版社
NATURE PUBLISHING GROUP
DOI: 10.1038/ni.3143
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资金
- US National Institutes of Health [U01HG004085, U01HG004080]
- National Institutes of Allergy and Infectious Diseases [R01-AI084884, U24 AI082660, T32-AI007061]
- National Institutes of Arthritis, Musculoskeletal and Skin Diseases [K01-AR051367, K01-AR066716]
- National Institute of Diabetes and Digestive and Kidney Diseases [F32-DK097891]
- Lupus Research Institute
- Alliance for Lupus Research
- American Society of Nephrology
The molecules and pathways that fine-tune innate inflammatory responses mediated by Toll-like receptor 7 (TLR7) remain to be fully elucidated. Using an unbiased genome-scale screen with short hairpin RNA (shRNA), we identified the receptor TREML4 as an essential positive regulator of TLR7 signaling. Macrophages from Treml4(-/-) mice were hyporesponsive to TLR7 agonists and failed to produce type I interferons due to impaired phosphorylation of the transcription factor STAT1 by the mitogen-activated protein kinase p38 and decreased recruitment of the adaptor MyD88 to TLR7. TREML4 deficiency reduced the production of inflammatory cytokines and autoantibodies in MRL/lpr mice, which are prone to systemic lupus erythematosus (SLE), and inhibited the antiviral immune response to influenza virus. Our data identify TREML4 as a positive regulator of TLR7 signaling and provide insight into the molecular mechanisms that control antiviral immunity and the development of autoimmunity.
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