Gas6 inflames cell interactions

Using Gas6-deficient mice, Tjwa and colleagues show that Gas6 plays a pivotal role in endothelial-cell response to inflammatory stimuli by promoting interaction of circulating cells with endothelium, amplifying local thrombosis, and increasing leukocyte infiltration into inflamed tissue.

Gas6, the product of growth-arrest–specific gene 6, is a member of the vitamin K–dependent protein family sharing significant homology with anticoagulant protein S, although it is devoid of anticoagulant properties. Gas6 is a ligand for 3 tyrosine kinase receptors (Axl, Tyro3, and Mer) whose signaling is implicated primarily in cell survival but also in cell proliferation, adhesion, and migration.¹  Gas6 is also involved in platelet aggregation, as Gas6 knockout mice show impaired response to weak activation.²  The status of Gas6 as an antiapoptotic mediator in different cell types including endothelial cells is well established, but its role in endothelial-cell function has remained incompletely characterized.

In their study in this issue of Blood, Tjwa and colleagues explore the role of Gas6 in the interplay of cells implicated in the inflammatory response: endothelial cells, leukocytes, and platelets. They first report that when exposed to TNFα, endothelial cells lacking Gas6 show reduced expression of adhesion molecules (ICAM-1 and VCAM-1) and lowered cytokine release (IL1 and IL6). In keeping with these in vitro experiments, intravital microscopy observations show that upon activation, interaction between platelets, leukocytes, and endothelial cells is impaired in the absence of Gas6. This effect is related to a defect in P-selectin expression by activated endothelial cells.

Finally, using 3 different in vivo models of inflammation (endotoxinemia, vasculitis, and heterotopic heart transplantation), Tjwa and colleagues note a decrease in leukocyte extravasation, inflammation, and thrombosis in Gas6-deficient animals. The diversity of in vivo experimental models of vascular injury used in this study reinforces the validity of its interesting results.

This newly identified function of Gas6 in vascular biology is very promising therapeutically, as it opens a new approach to treating pathologies in which endothelium inflammatory injury plays a pivotal role. Indeed, inhibition of the Gas6 pathway could be a new strategy in the treatment of sepsis, transplantation-induced organ rejection, or stroke—3 clinical situations in which endothelial protection could be beneficial and in which Gas6 has already been implicated.^3-5  However, caution is needed, as differences between humans and mice have been reported concerning the Gas6 pathway. For example, Gas6 is present in mouse platelets,²  whereas no Gas6 was detected in human platelets.⁶  Only a few results regarding Gas6 involvement in human platelet aggregation have been published,⁷  suggesting some discrepancy between species.

Several aspects of Gas6 functions remain to be clarified. How does Gas6 promote responsiveness of endothelial cells to an inflammatory stimulus? This effect is not due to an increased release of Gas6 by activated endothelial cells. Furthermore, Gas6 is already present in the circulation and no activation process has been described so far that triggers the Gas6 pathway, which raises several questions. Are there any biochemical or structural differences between circulating Gas6 and Gas6 produced by endothelial cells that may explain the absence of constitutive Axl signaling by the circulating form? Is a cofactor, such as anionic phospholipid, required in Gas6 signaling? Is a local increase in Gas6 levels needed?

Nevertheless, the present study proposes a new role for Gas6 in vascular biology and provides a solid basis for future characterization of the implication of Gas6 in this field.