The receptor TREML4 amplifies TLR7-mediated signaling during antiviral responses and autoimmunity

  • Nat Immunol. 2015 May;16(5):495-504. doi: 10.1038/ni.3143.
Zaida G Ramirez-Ortiz  1 ,  Amit Prasad  1 ,  Jason W Griffith  1 ,  William F Pendergraft 3rd  2 ,  Glenn S Cowley  3 ,  David E Root  3 ,  Melissa Tai  1 ,  Andrew D Luster  1 ,  Joseph El Khoury  4 ,  Nir Hacohen  5 ,  Terry K Means  1
Affiliations
  • 1. Center for Immunology and Inflammatory Diseases and Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA.
  • 2. University of North Carolina Kidney Center, Burnett Womack Building, Chapel Hill, North Carolina, USA.
  • 3. Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
  • 4. 1] Center for Immunology and Inflammatory Diseases and Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA. [2] Division of Infectious Diseases, Massachusetts General Hospital, Boston, Massachusetts, USA.
  • 5. 1] Center for Immunology and Inflammatory Diseases and Division of Rheumatology, Allergy, and Immunology, Massachusetts General Hospital and Harvard Medical School, Charlestown, Massachusetts, USA. [2] Broad Institute of MIT and Harvard, Cambridge, Massachusetts, USA.
PMID: 25848864 DOI: 10.1038/ni.3143
Abstract

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.