Regulation of endothelial inflammation by TAM receptors

Abstract

The TAM (Tyro3, Axl, Mer) receptors tyrosine kinases together with their ligands Gas6 and protein S play an important role in many cellular processes such as resolution of inflammation and phagocytosis. Notably, they were found to have an important function in vasculature, acting as a pro-survival factors and regulators of angiogenesis. Nevertheless, their role in endothelial inflammation is still poorly understood. Conflicting conclusions have been published, indicating both pro and anti-inflammatory properties of TAM-mediated signaling in endothelium. In this study we sought to elucidate the role of these receptors in endothelial inflammation by measuring the levels of pro-inflammatory markers, such as cytokines and adhesion molecules, in response to inflammatory stimuli in TAM and TAM ligand-deficient human umbilical vein endothelial cells (HUVEC). We found that Axl/Gas6 signaling acts as a pro-inflammatory agent by promoting an increased expression of adhesion molecules and cytokine secretion. Conversely, we suggest anti inflammatory tendencies of the Mer/protein S axis. Moreover, we demonstrate that starvation strongly upregulates Mer expression in HUVEC cells. Finally, we propose that TAM receptors expression is differently regulated depending on cell type, as inflammatory regulators known to induce TAM-expression in immune cells fail to upregulate TAMs in HUVECs. Taken together, we present diversification and complexity of Axl and Mer receptor functions in endothelial inflammation, thus suggesting the need for further investigations.

Popular Abstract

TAMing endothelial inflammation

TAM (Tyro3, Axl and Mer) receptors are some of the proteins attached to the cell surface. In the presented work we show an important role of these proteins in cells, which line up inner part of blood vessels (endothelial cells). We found that Axl and Mer play opposite roles. Axl receptor increases inflammation in these cells, whereas Mer decreases inflammation.

The human cell is a very complex structure, with many proteins attached to its surface, referred to as cell receptors. There are many different kinds of receptors, and one group of them is the TAM receptors family, which stands for Tyro3, Axl and Mer. They share structural similarities, however their abundance and functions vary from cell to cell. In order to activate the TAM receptor, a so called “TAM receptor ligand” must bind to it (Figure 1).

TAM receptors are involved in various processes in the human body, such as clearance of dying cells. In this process, specialized immune cells, thanks to TAM receptors on their surface, recognize dying cells and “eat” them. This process is determined by TAM ligand interaction, where the ligand binds to specific signals expressed on the dying cell, thus creating a “bridge” between both cells (Figure 1).

TAM receptors in endothelium- are they good or bad players?
TAM receptors are also expressed in endothelial cells, which line up the inner part of blood vessels, hence they are in direct contact with blood. There are many causes of inflammation in the human body, such as injuries and infections. Upon the inflammation, endothelial cells produce various proteins, which allow immune cells to become activated and help them pass through the blood vessel wall to reach the underlying tissue.

We have measured how the different TAMs regulate various proteins expressed by endothelial cells during inflammatory conditions. Previously published studies have reached opposing conclusions regarding the pro or anti-inflammatory role of TAMs in endothelium. We observed that Axl-activation seems to promote inflammation, whereas Mer-activation down regulates it. This observation brought new light on their role in vascular inflammation, which could be both good and bad. Further, we tested different pro- and anti inflammatory agents, which were reported to strongly induce TAM expression in immune cells. To our surprise, these agents did not affect the expression of TAM receptors in human endothelial cells. This conclusion led us to hypothesize that TAM expression is regulated differently depending on cell type.

Our study provides another step on the way to better understanding these receptors for future therapeutic use.
Our results provide the confirmation of pro-inflammatory properties of Axl in endothelium, thus suggesting this receptor as an interesting drug target for fighting inflammation.

Advisor: Kaisa Otteby
Master’s Degree Project in Molecular Biology 60 credits 2015
Department of Biology, Lund University

• author: Wolanin, Oktawia
• supervisor: Kaisa Otteby
• organization: Degree Projects in Molecular Biology
• course: MOBT01 20142
• year: 2015
• type: H2 - Master's Degree (Two Years)
• subject: Biology and Life Sciences
• language: English
• id: 5434045
• date added to LUP: 2015-05-27 11:24:03
• date last changed: 2015-05-27 11:24:03