TAM receptors are pleiotropic inhibitors of the innate immune response

Cell. 2007 Dec 14;131(6):1124-36. doi: 10.1016/j.cell.2007.10.034.

Abstract

The activation of Toll-like receptors (TLRs) in dendritic cells (DCs) triggers a rapid inflammatory response to pathogens. However, this response must be tightly regulated because unrestrained TLR signaling generates a chronic inflammatory milieu that often leads to autoimmunity. We have found that the TAM receptor tyrosine kinases-Tyro3, Axl, and Mer-broadly inhibit both TLR and TLR-induced cytokine-receptor cascades. Remarkably, TAM inhibition of inflammation is transduced through an essential stimulator of inflammation-the type I interferon receptor (IFNAR)-and its associated transcription factor STAT1. TLR induction of IFNAR-STAT1 signaling upregulates the TAM system, which in turn usurps the IFNAR-STAT1 cassette to induce the cytokine and TLR suppressors SOCS1 and SOCS3. These results illuminate a self-regulating cycle of inflammation, in which the obligatory, cytokine-dependent activation of TAM signaling hijacks a proinflammatory pathway to provide an intrinsic feedback inhibitor of both TLR- and cytokine-driven immune responses.

Publication types

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

MeSH terms

  • Animals
  • Dendritic Cells / metabolism*
  • Gene Expression Regulation
  • Immunity, Innate*
  • Inflammation / prevention & control*
  • Mice
  • Mice, Knockout
  • Oncogene Proteins / physiology
  • Proto-Oncogene Proteins / physiology
  • Receptor Protein-Tyrosine Kinases / metabolism*
  • Receptor Protein-Tyrosine Kinases / physiology
  • Receptor, Interferon alpha-beta / metabolism
  • STAT1 Transcription Factor / metabolism
  • Signal Transduction
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins / metabolism
  • Toll-Like Receptors / physiology*
  • Ubiquitination
  • c-Mer Tyrosine Kinase

Substances

  • Ifnar1 protein, mouse
  • Oncogene Proteins
  • Proto-Oncogene Proteins
  • STAT1 Transcription Factor
  • Socs1 protein, mouse
  • Socs3 protein, mouse
  • Stat1 protein, mouse
  • Suppressor of Cytokine Signaling 1 Protein
  • Suppressor of Cytokine Signaling 3 Protein
  • Suppressor of Cytokine Signaling Proteins
  • Toll-Like Receptors
  • Receptor, Interferon alpha-beta
  • Mertk protein, mouse
  • Receptor Protein-Tyrosine Kinases
  • Tyro3 protein, mouse
  • axl receptor tyrosine kinase
  • c-Mer Tyrosine Kinase