Abstract
For both wound healing and the formation of a fibrotic lesion, circulating monocytes enter the tissue and differentiate into fibroblast-like cells called fibrocytes and pro-fibrotic M2a macrophages, which together with fibroblasts form scar tissue. Monocytes can also differentiate into classically activated M1 macrophages and alternatively activated M2 macrophages. The proteases thrombin, which is activated during blood clotting, and tryptase, which is released by activated mast cells, potentiate fibroblast proliferation and fibrocyte differentiation, but their effect on macrophages is unknown. Here we report that thrombin, tryptase, and the protease trypsin bias human macrophage differentiation towards a pro-fibrotic M2a phenotype expressing high levels of galectin-3 from unpolarized monocytes, or from M1 and M2 macrophages, and that these effects appear to operate through protease-activated receptors. These results suggest that proteases can initiate scar tissue formation by affecting fibroblasts, fibrocytes, and macrophages.
Highlights
The failure of wounds to heal properly constitutes a major medical problem, with both acute and chronic wounds consuming treatment time and resources [1, 2]
Thrombin signals through proteaseactivated receptor-1 (PAR-1), and trypsin and tryptase signal through protease-activated receptor-2 (PAR-2) [9, 21,22,23], and we found that agonists of PAR-1 and PAR-2 potentiate fibrocyte differentiation [18]
M2a macrophages are involved in scar tissue formation in both wound healing and fibrosis [27,28,29,30]
Summary
The failure of wounds to heal properly constitutes a major medical problem, with both acute and chronic wounds consuming treatment time and resources [1, 2]. A key question in wound healing and fibrosis is the triggering mechanism that induces scar tissue formation. One of the events preceding scar tissue formation in a healing wound is the clotting cascade, in which the protease thrombin cleaves fibrinogen to fibrin. Mast cells are found in both fibrotic lesions and sites of wound healing [7,8,9]. Mast cells degranulate to release tryptase, and tryptase is upregulated in wounds and fibrotic lung tissue [7,8,9,10,11,12]. As well as other proteases such as trypsin, potentiate wound healing and scar tissue formation by increasing fibroblast proliferation and collagen secretion [9, 13,14,15], inducing platelet aggregation
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