The innate immune response to pathogens represents the first line of defense against infectious diseases. The most potent mediators of this response are the TLRs, a set of “pattern-recognition receptors” that detect invariant molecular signatures displayed by invading pathogens and activate host defenses. Axl is an important member of the receptor tyrosine-kinase family constituted by Tyro3, Axl, and Mer (TAM family). It has been verified in vivo that loss of function of the three TAM receptors, Tyro3, Axl, and Mer, results in profound dysregulation of the immune response. Moreover recently it has been demonstrated that, in murine macrophages and dendritic cells (DC), TAM receptor signaling limits the TLR-induced production of proinflammatory cytokines through the induction of the inhibitory proteins suppressor of cytokine signaling SOCS1 and SOCS3. We evaluated the effect of these interesting molecules on human DC. Our study revealed that IFN generated DC, but not IL-4 generated DC, acquire cell surface Axl during their differentiation, but IFN- did not affect the expression of Tyro3 and Mer, whose level was comparable in both IFN/DC and IL-4/DC.TLR-dependent maturation stimuli (LPS, polyI:C, TLR7/8 ligand) significantly down-regulate the Axl expression on IFN/DC through increased proteolytic cleavage and that Gas6, the vitamin K-dependent Axl ligand, regulates TLR-induced cytokine release by human DC in vitro. These data indicate that the Axl/Gas6 system is involved in the regulation of the early immune response to pathogens.
Involvement of the Axl/gas6 pathway in the TLR-mediated immune response.
SCUTERA, SARA AGATA CATERINA;ZUCCA, Mario;MUSSO, Tiziana
2009-01-01
Abstract
The innate immune response to pathogens represents the first line of defense against infectious diseases. The most potent mediators of this response are the TLRs, a set of “pattern-recognition receptors” that detect invariant molecular signatures displayed by invading pathogens and activate host defenses. Axl is an important member of the receptor tyrosine-kinase family constituted by Tyro3, Axl, and Mer (TAM family). It has been verified in vivo that loss of function of the three TAM receptors, Tyro3, Axl, and Mer, results in profound dysregulation of the immune response. Moreover recently it has been demonstrated that, in murine macrophages and dendritic cells (DC), TAM receptor signaling limits the TLR-induced production of proinflammatory cytokines through the induction of the inhibitory proteins suppressor of cytokine signaling SOCS1 and SOCS3. We evaluated the effect of these interesting molecules on human DC. Our study revealed that IFN generated DC, but not IL-4 generated DC, acquire cell surface Axl during their differentiation, but IFN- did not affect the expression of Tyro3 and Mer, whose level was comparable in both IFN/DC and IL-4/DC.TLR-dependent maturation stimuli (LPS, polyI:C, TLR7/8 ligand) significantly down-regulate the Axl expression on IFN/DC through increased proteolytic cleavage and that Gas6, the vitamin K-dependent Axl ligand, regulates TLR-induced cytokine release by human DC in vitro. These data indicate that the Axl/Gas6 system is involved in the regulation of the early immune response to pathogens.
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