Previous studies with knockout mice implicated the TAM (Tyro3, Axl, Mer) family of receptor tyrosine kinases in regulation of innate immune responses. Rothlin et al. characterized the function of the receptor family in dendritic cells and showed that they stimulate the production of SOCS (suppressor of cytokine signaling) proteins, which are inhibitors of Toll-like receptor (TLR) signaling, thereby contributing to termination of the innate immune response. Splenic dendritic cells from single-, double-, or triple-knockout mice showed progressively severe hyperresponsiveness to stimuli that activate TLR3, TLR4, or TLR9, suggesting that the TAM family members are important inhibitors of multiple TLR pathways. In isolated mouse dendritic cells, only Mer and Axl were detected, and overnight activation of these cells with the TAM ligands Gas6 or ProS inhibited cytokine production stimulated by activation of TLR3, TLR4, or TLR9. The inhibition of TLR signaling by activation of the TAM proteins required new gene expression and protein synthesis, and screening for likely TLR inhibitors revealed that both the genes encoding SOCS1 and SOCS3 were stimulated in response to exposure of dendritic cells to Gas6. Gas6 stimulated the phosphorylation of the transcription factor STAT1, and STAT1 was required for TAM-mediated activation of SOCS1 and SOCS3 gene expression. TAM-mediated activation of STAT1 required the type I interferon (IFN) receptor subunit INFAR1, because Gas6 failed to stimulate SOCS1 expression in dendritic cells from infar1 knockout mice. A TAM ligand-dependent interaction was detected between Axl and INFAR1 (by coimmunoprecipitation assay). Abundance of Axl mRNA was increased after TLR activation through a mechanism requiring STAT1 and INFAR1. IFN-mediated induction of SOCS1 expression was substantially lost in TAM knockout dendritic cells. Coapplication of IFNα and Gas6 to dendritic cells increased SOCS1 mRNA production more than either ligand alone; however, expression of cytokine signaling stimulators by IFNα was inhibited by coapplication of Gas6. The authors suggest that there is a three-step inflammatory cycle: (i) activation of TLR signaling by a pathogen, (ii) amplification of the signal through production of IFN, and (iii) increased synthesis of the TAM proteins and production of SOCS proteins to inhibit TLR signaling. See O'Neill for commentary.
C. V. Rothlin, S. Ghosh, E. I. Zuniga, M. B. A. Oldstone, G. Lemke, TAM receptors are pleiotropic inhibitors of the innate immune response. Cell 131, 1124-1136 (2007). [PubMed]
L. A. J. O'Neill, TAMpering with Toll-like receptor signaling. Cell 131, 1039-1041 (2007). [PubMed]