2. Academic Validation
  3. The receptor TREML4 amplifies TLR7-mediated signaling during antiviral responses and autoimmunity

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

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.

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