25 janvier 2011: Prof. Greg Lemke
Tuesday, January 25th 2011, 12h30
Prof. Greg Lemke
The Salk Institute, La Jolla California
"TAM receptor signaling in the immune and nervous systems"
Pathogen encounter by dendritic cells (DCs) and macrophages of the immune system triggers a rapid inflammatory response that is essential to combating infection. However, this response must be tightly regulated, since unrestrained Toll-like receptor (TLR) and cytokine receptor signaling generates a chronic inflammatory milieu that often leads to autoimmune disease. We have found that the TAM receptor tyrosine kinases - Tyro3, Axl, and Mer - broadly inhibit both TLR and TLR-induced cytokine receptor cascades1, 2. 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 up-regulates components of the TAM system, which in turn usurp 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 pro-inflammatory pathway to provide an intrinsic feedback inhibitor of both TLR- and cytokine-driven immune responses. They have important implications for both TAM regulation of viral infection and for the use of TAM-based therapies in the treatment of autoimmune disease. Genetic studies have demonstrated that the TAM system is also required for the phagocytosis of apoptotic cells (ACs) by DCs and macrophages, and that the suppressive effects of ACs on DC and macrophage activation are almost entirely dependent on TAM receptor engagement2. TAM action in the phagocytosis of ACs extends to other organ systems, including the nervous and reproductive systems. In the nervous system, TAM signaling in retinal pigment epithelial (RPE) cells of the eye is required for the circadian phagocytosis of photoreceptor outer segment membranes, and mutations in the TAM receptor Mer lead to retinitis pigmentosa in humans.