Abstract
The complete resolution of inflammation requires the uptake of apoptotic polymorphonuclear cells (PMN) 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 lipopolysaccharide 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 that macrophage-derived PROS1 is an important effector molecule in regulating the efferocytosis, maturation, and reprogramming of resolution phase macrophages, and imply that PROS1 could provide a new therapeutic target for inflammatory and fibrotic disorders.
Highlights
Inflammation normally resolves in an active process that eliminates the inflammatory effector components that harm the host [1,2,3,4]
Our results indicate that resident macrophages, inflammatory, and early resolution phase macrophages (24 h) expressed very little Pros1, whereas a sharp upregulation of Pros1 mRNA in resolving macrophages (66 h) was observed (Figure 1A)
Our findings indicate that PROS1 is produced by macrophages during the resolution of murine peritonitis, and its production and release by peritoneal macrophages as well as other cells contribute to peritoneal levels of PROS1 (Figure 1)
Summary
Inflammation normally resolves in an active process that eliminates the inflammatory effector components that harm the host [1,2,3,4] This is hallmarked by leukocyte apoptosis and clearance by macrophages [5,6,7,8]. A new resolution phase macrophage phenotype— distinguishable from either M1 or M2—and characterized by low expression of CD11b, is generated from the CD11bhigh phenotype upon the engulfment of threshold numbers of apoptotic polymorphonuclear cells (PMN) [21]. This phenotypic conversion of macrophages results in significant immune-silencing in addition to the reduction in the expression of arginase-1, surface CD11b, and F4/80 [21]. CD11blow macrophages stop producing TNFα and IL-1β, but increase the production of TGFβ and the expression of 12/15-LO, and emigrate to the lymphatics [21]
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