Lipoxin A4, Maresin 1, and Resolvin D1 As Key Factors for the Actions of Plasminogen/Plasmin on Inflammation Resolution

Abstract

The plasminogen/plasmin (Plg/Pla) system plays a fundamental role in modulating fibrinolysis and many other biological processes, including extracellular matrix degradation, cell migration, and tissue repair. Recent studies highlight the role of the Plg/Pla system in key steps of inflammation resolution, which is mediated, at least in part, by the glucocorticoid-induced protein annexin A1. However, it is unclear whether Plg/Pla might also modulate specialized proresolving mediators (SPMs) derived from omega-3 and omega-6 fatty acids, including lipoxin A4 (LXA4), maresin 1 (MaR1), and resolvin D1 (RvD1). Therefore, we investigated the ability of Plg/Pla to modulate the synthesis of LXA4, MaR1, and RvD1, as well as the involvement of these SPMs in the proresolving effects elicited by Plg or Pla using both in vitro and in vivo strategies. Treatment of bone marrow-derived macrophages (BMDMs) with Plg/Pla (4 μg/mL) induced the release of LXA4, MaR1, and RvD1 as well as increased mRNA levels of their lipoxygenase (LO) synthesizing enzymes 5-LO and 15-LO. Plg treatment also increased the levels of the anti-inflammatory cytokine IL-10 and reduced the levels of the pro-inflammatory cytokine TNF-α in BMDMs. Moreover, Plg decreased the levels of TNF-α and IL-1β induced by lipopolysaccharide (LPS) stimulus of the human monocytic cell line THP-1. Interestingly, LXA4 was able to induce Plg release in THP-1 cells. Notably, Pla (4 μg, i.p.) was able to increase the efferocytosis of apoptotic neutrophils in wild-type (SV129) mice, but not in 5-LO deficient mice (5-LO-/-). Taken together, these findings suggest that Plg and Pla increase the levels of SPMs and IL-10, and modulate the levels of LPS-elicited pro-inflammatory cytokines. Mechanistically, the action of Plg/Pla on efferocytosis was 5-LO dependent, suggesting that SPMs mediate this proresolving effect of Plg/Pla. Moreover, the reciprocal modulation between the Plg/Pla system and SPMs pathways elucidated should be explored in future studies on candidate targets for therapies for inflammatory diseases. Keywords: Inflammation resolution; plasminogen/plasmin system; pro-resolving lipid mediators. Financial support: FAPEMIG, CNPq, CAPES.