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. Epub 2015 Apr 6.

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Autoantibodies / metabolism
  • Autoimmunity / genetics
  • Cells, Cultured
  • Cytokines / metabolism
  • Humans
  • Immunity, Innate / genetics
  • Inflammation Mediators / metabolism
  • Interferon Type I / metabolism
  • Lupus Erythematosus, Systemic / immunology*
  • Macrophages / physiology*
  • Macrophages / virology
  • Membrane Glycoproteins / metabolism*
  • Mice
  • Mice, Inbred C57BL
  • Mice, Inbred MRL lpr
  • Mice, Knockout
  • Myeloid Differentiation Factor 88 / metabolism
  • Orthomyxoviridae / immunology*
  • Orthomyxoviridae Infections / immunology*
  • RNA, Small Interfering / genetics
  • Receptors, Immunologic / genetics
  • Receptors, Immunologic / metabolism*
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction / genetics
  • Toll-Like Receptor 7 / metabolism*
  • p38 Mitogen-Activated Protein Kinases / metabolism

Substances

  • Autoantibodies
  • Cytokines
  • Inflammation Mediators
  • Interferon Type I
  • Membrane Glycoproteins
  • Myeloid Differentiation Factor 88
  • RNA, Small Interfering
  • Receptors, Immunologic
  • STAT1 Transcription Factor
  • Tlr7 protein, mouse
  • Toll-Like Receptor 7
  • Treml4 protein, mouse
  • p38 Mitogen-Activated Protein Kinases