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Apoptotic Cell Clearance in Health and Disease

Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Immunol. | doi: 10.3389/fimmu.2018.00358

Macrophage-derived protein S facilitates apoptotic PMN clearance by resolution phase macrophages and supports their reprogramming

  • 1Institute for Dental Sciences, Hebrew University of Jerusalem, Israel
  • 2Department of Biology, University of Haifa, Israel

The complete resolution of inflammation requires the uptake of apoptotic polymorphonuclear cells by local macrophages (efferocytosis) and the consequent reprogramming of the engulfing phagocytes to reparative and pro-resolving phenotypes. The tyrosine kinase receptors TYRO3, AXL and MERTK (collectively named TAM) are fundamental mediators in regulating inflammatory responses and efferocytosis. Protein S (PROS1) is a ligand for all TAM receptors that mediates various aspects of their activity. However, the involvement of PROS1 in the resolution of inflammation is incompletely understood. Here, we report the upregulation of Pros1 in macrophages during the resolution of inflammation. Selective knockout of Pros1 in the myeloid lineage significantly downregulated macrophage pro-resolving properties. Hence, Pros1-deficient macrophages engulfed fewer apoptotic PMN remnants in vivo, and exogenous PROS1 rescued impaired efferocytosis ex vivo. Moreover, Pros1-deficient peritoneal macrophages secreted higher levels of the pro-inflammatory mediators TNFα, and CCL3, while they secreted lower levels of the reparative/anti-inflammatory IL-10 following exposure to LPS in comparison to their WT counterparts. Moreover, Pros1-deficient macrophages expressed less of the anti-inflammatory/pro-resolving enzymes arginase-1 and 12/15-lipoxygenase, and produced less of the specialized pro-resolving mediator resolvin D1. Altogether, our results suggest macrophage-derived PROS1 is an important effector molecule in regulating the efferocytosis, maturation and reprogramming of resolution phase macrophages, and imply PROS1 could provide a new therapeutic target for inflammatory and fibrotic disorders.

Keywords: Inflammation, Macrophages, Protein S, PROS1, Apoptosis, Efferocytosis

Received: 02 Jul 2017; Accepted: 08 Feb 2018.

Edited by:

Janos G. Filep, Université de Montréal, Canada

Reviewed by:

Joan Clària, Hospital Clínic de Barcelona, Spain
Ian Dransfield, University of Edinburgh, United Kingdom  

Copyright: © 2018 Lumbroso, Soboh, Maimon, Schif-Zuck, Ariel and Burstyn-Cohen. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence:
Dr. Amiram Ariel, University of Haifa, Department of Biology, 199 Aba Khoushy Ave, Haifa, 3498838, Israel,
Dr. Tal Burstyn-Cohen, Hebrew University of Jerusalem, Institute for Dental Sciences, Hebrew University - Hadassah, Jerusalem, 9112102, Israel,