TAM receptors are pleiotropic inhibitors of the innate immune response.
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.
Rothlin
Carla V
CV
Molecular Neurobiology Laboratory, The Salk Institute, La Jolla, CA 92037, USA.
Ghosh
Sourav
S
Zuniga
Elina I
EI
Oldstone
Michael B A
MB
Lemke
Greg
G
D000818:Animals; D003713:Dendritic Cells / Q000378:metabolism*; D005786:Gene Expression Regulation; D007113:Immunity, Innate; D007249:Inflammation / Q000517:prevention & control*; D051379:Mice; D018345:Mice, Knockout; D015513:Oncogene Proteins / Q000502:physiology; D011518:Proto-Oncogene Proteins / Q000502:physiology; D020794:Receptor Protein-Tyrosine Kinases / Q000378:metabolism* / Q000502:physiology; D053633:Receptor, Interferon alpha-beta / Q000378:metabolism; D050794:STAT1 Transcription Factor / Q000378:metabolism; D015398:Signal Transduction; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins / Q000378:metabolism; D051193:Toll-Like Receptors / Q000502:physiology*; D054875:Ubiquitination; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase
C508032:Ifnar1 protein, mouse; D015513:Oncogene Proteins; D011518:Proto-Oncogene Proteins; D050794:STAT1 Transcription Factor; C491590:Socs1 protein, mouse; C491411:Socs3 protein, mouse; C494080:Stat1 protein, mouse; D000071222:Suppressor of Cytokine Signaling 1 Protein; D000071223:Suppressor of Cytokine Signaling 3 Protein; D050826:Suppressor of Cytokine Signaling Proteins; D051193:Toll-Like Receptors; D053633:Receptor, Interferon alpha-beta; C490767:Mertk protein, mouse; D020794:Receptor Protein-Tyrosine Kinases; C513478:Tyro3 protein, mouse; D000076202:c-Mer Tyrosine Kinase; D000094963:Axl Receptor Tyrosine Kinase; C000722290:AXL receptor tyrosine kinase, mouse