[HTML][HTML] TAM receptors are pleiotropic inhibitors of the innate immune response

CV Rothlin, S Ghosh, EI Zuniga, MBA Oldstone… - Cell, 2007 - cell.com
CV Rothlin, S Ghosh, EI Zuniga, MBA Oldstone, G Lemke
Cell, 2007cell.com
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 …
Summary
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.
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