Survival and Migration of Human Dendritic Cells Are Regulated by an IFN-α-Inducible Axl/Gas6 Pathway

Abstract

Axl, a prototypic member of the transmembrane tyrosine kinase receptor family, is known to regulate innate immunity. In this study, we show that Axl expression is induced by IFN-α during human dendritic cell (DC) differentiation from monocytes (IFN/DC) and that constitutively Axl-negative, IL-4-differentiated DC (IL-4/DC) can be induced to up-regulate Axl by IFN-α. This effect is inhibited by TLR-dependent maturation stimuli such as LPS, poly(I:C), TLR7/8 ligand, and CD40L. LPS-induced Axl down-regulation on the surface of human IFN-α-treated DC correlates with an increased proteolytic cleavage of Axl and with elevated levels of its soluble form. GM6001 and TAPI-1, general inhibitors of MMP and ADAM family proteases, restored Axl expression on the DC surface and diminished Axl shedding. Furthermore, stimulation of Axl by its ligand, Gas6, induced chemotaxis of human DC and rescued them from growth factor deprivation-induced apoptosis. Our study provides the first evidence that Gas6/Axl-mediated signaling regulates human DC activities, and identifies Gas6/Axl as a new DC chemotaxis pathway. This encourages one to explore whether dysregulation of this novel pathway in human DC biology is involved in autoimmunity characterized by high levels of IFN-α.

Receptor Tyrosine Kinases, TYRO3, AXL, and MER, Demonstrate Distinct Patterns and Complex Regulation of Ligand-induced Activation

“…It is known that TAM receptors are differentially expressed in mature immune, nervous, reproductive, and vascular systems (11), and have different patterns of transcriptional regulation. For example, mammary epithelial cells express MER only in the involution stage, whereas AXL is up-regulated by IFN-␣ in dentritic cells (13,58). Moreover, it remains to be determined whether in cells that co-express more than one TAM receptor, the receptors can heterodimerize, and if so, how this affects ligand receptor interactions as well as post-receptor signaling.…”

Characterization of porcine GAS6 cDNA gene and its expression analysis in weaned piglets

“…It plays broad roles in cell survival and proliferation, cell adhesion and migration, the stability of coagulation, the release of inflammatory factors, and physiological and pathological reaction processes (Eng et al, 2008;Ganopolsky et al, 2008;Xiong et al, 2008;Anwar et al, 2009;Scutera et al, 2009;Uehara et al, 2009;Wu et al, 2011). Manfioletti et al (1993) suggested that the GAS6 protein contained 678 amino acids, with 81% homology to mouse protein and 44% homology to the human anticoagulant S protein (S protein is a negative regulator of blood, regulating the vitamin K-dependent pathway).…”

Growth-Arrest-Specific 6 (GAS6) Protein in ARDS Patients: Determination of Plasma Levels and Influence of PEEP Setting

“…4 Models of endotoxemia also suggest an important role in modulation of the immune response. [4][5][8][9][10][11] Given the involvement of GAS6 receptors in experimental sepsis, and the potentially major role of leukocyte apoptosis in the pathophysiology of severe sepsis, previous clinical studies have focused on GAS6 in septic and non-septic critical care patients. 3,[6][7] As compared to healthy subjects, GAS6 levels were higher in critical care patients with one or several failing organs, the highest values being observed in patients with severe sepsis.…”