Axl and MerTK receptor tyrosine kinases maintain human macrophage efferocytic capacity in the presence of viral triggers.

Aleksander M Grabiec,Tracy Hussell,Mark E Fife,Anu Goenka,Toshifumi Fujimori

doi:10.1002/eji.201747283

Aleksander M Grabiec, Tracy Hussell + Show 3 more

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https://doi.org/10.1002/eji.201747283

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Abstract

The requirement to remove apoptotic cells is equally important in homeostasis and inflammatory disease. In particular, during viral infections large quantities of infected cells undergo apoptosis and need to be efficiently cleared by phagocytes to prevent secondary necrosis. Although specific roles of several apoptotic cell sensors, such as the TAM (Tyro3, Axl, MerTK) receptor family, have been characterized in mouse models, little is known about their regulation and involvement in apoptotic cell uptake (efferocytosis) by human macrophages under inflammatory conditions. We show that whereas pro‐inflammatory stimuli consistently downregulated MerTK expression in human monocyte‐derived macrophages (MDMs), stimuli indicative of a viral infection, interferon‐α (IFN‐α) and the TLR3 ligand poly(I:C), specifically induced Axl expression and promoted binding of the bridging molecule Gas6. Axl induction by IFN‐α and poly(I:C) was associated with higher MDM efferocytic capacity compared to cells treated with other pro‐inflammatory stimuli, such as LPS and IFN‐γ. While MerTK blocking antibody uniformly suppressed apoptotic cell uptake by MDMs, Axl blocking antibody significantly reduced efferocytosis by poly(I:C)‐stimulated MDMs, but not by resting MDMs. Our observations demonstrate that Axl induction during viral infections contributes to maintaining macrophage capacity to engulf apoptotic cells, which may have important consequences for resolution of anti‐viral immune responses.

Highlights

Macrophages regulate immune homeostasis through multiple mechanisms, among which the timely removal of apoptotic cellsC 2018 The Authors
We initiated this study by profiling changes in expression of the TAM receptors Axl and MerTK in M-CSF-differentiated monocyte-derived macrophages (MDMs) stimulated with a range of pro- and anti-inflammatory stimuli
In all tested conditions MDMs expressed negligible levels of Tyro3 mRNA (Fig. 1H), indicating that Axl and MerTK are the sole TAM receptors involved in efferocytosis by human macrophages

Summary

Introduction

Macrophages regulate immune homeostasis through multiple mechanisms, among which the timely removal of apoptotic cellsC 2018 The Authors. Phosphatidylserine (PtdSer) and other ‘eat-me’ signals exposed on apoptotic cells are recognized by a plethora of receptors expressed by phagocytes, including proteins responsible for apoptotic cell recognition, such as the TIM (T cell/transmembrane, immunoglobulin, and mucin) and TAM (Tyro, Axl and MerTK) families [5, 6], as well as molecules involved in other processes, such as the scavenger receptor CD36, the LPS receptor CD14 and the angiogenesis regulator BAI1 (brain-specific angiogenesis inhibitor-1) [1]. Apoptotic cell recognition by TAM receptors, through the bridging molecules Protein S or growth arrest specific 6 (Gas6), leads to receptor phosphorylation and the induction of suppressor of cytokine signaling-1 (SOCS-1) and SOCS-3, which inhibit pro-inflammatory signaling pathways triggered by cytokines and toll-like receptor (TLR) ligands [6, 7]. Mice lacking multiple TAM receptors develop systemic autoimmune disease [8] and important contributions of individual TAM family members to the resolution of inflammation have recently been demonstrated in mouse models [9, 10]

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