The multifaceted role of plasminogen in inflammation

Abstract

A fine-tuned activation and deactivation of proteases and their inhibitors are involved in the execution of the inflammatory response. The zymogen/proenzyme plasminogen is converted to the serine protease plasmin, a key fibrinolytic factor by plasminogen activators including tissue-type plasminogen activator (tPA). Plasmin is part of an intricate protease network controlling proteins of initial hemostasis/coagulation, fibrinolytic and complement system. Activation of these protease cascades is required to mount a proper inflammatory response. Although best known for its ability to dissolve clots and cleave fibrin, recent studies point to the importance of fibrin-independent functions of plasmin during acute inflammation and inflammation resolution. In this review, we provide an up-to-date overview of the current knowledge of the enzymatic and cytokine-like effects of tPA and describe the role of tPA and plasminogen receptors in the regulation of the inflammatory response with emphasis on the cytokine storm syndrome such as observed during coronavirus disease 2019 or macrophage activation syndrome. We discuss tPA as a modulator of Toll like receptor signaling, plasmin as an activator of NFkB signaling, and summarize recent studies on the role of plasminogen receptors as controllers of the macrophage conversion into the M2 type and as mediators of efferocytosis during inflammation resolution.

Fibrinolytic Serine Proteases, Therapeutic Serpins and Inflammation: Fire Dancers and Firestorms

“…Genetic deficiencies in fibrinolytic regulation lead to bleeding disorders, organ dysfunction, and damage, and acquired disorders cause tissue fibrosis, dysregulated bleeding, cirrhosis, amyloidosis, and certain cancers ( 123 ). Several recent reviews discuss the role of the fibrinolytic system in inflammation and the immune response ( 124 , 125 ). Similarly, small molecules inhibitors of fibrinolytic serine proteases such as tranexamic acid are under investigation for therapeutic modulation of the fibrinolytic processes that are associated with effects on the immune response ( 126 ).…”

Early Pro-Inflammatory Remodeling of HDL Proteome in a Model of Diet-Induced Obesity: 2H2O-Metabolic Labeling-Based Kinetic Approach

“…It also inhibits the detrimental effects of the complement system on the membranes that result in increased permeability of vessels and the initiation of inflammatory atherosclerotic processes [36]. Plasminogen serves as a precursor for plasmin, a serine protease that helps to dissolve clots in circulation [37]. The increased turnover of these proteins in our study suggests their compensatory enhanced synthesis in response to HFD-induced inflammation.…”

LPS Tolerance Inhibits Cellular Respiration and Induces Global Changes in the Macrophage Secretome

“…While the “Immune Response of Myeloid Cells” is significantly affected in either condition ( p -values of <0.001), the LR condition had an increased response (z-score 1.134) but the LT condition had a decreased response (z-score −0.348) (visualized in Figure 6 B, Supplementary Table S2 ). By examining a heatmap of the proteins measured from each condition, it was found that while the LR group had several signaling molecules, including CXCL3, CXCL10, and TNF, the LT group had decreased recovery of these signaling molecules along with decreased secretion (compared to the untreated control) of the urokinase-type plasminogen activator (PLAU) ( Figure 6 B), a secreted enzyme that activates plasmin, a protein that is critical for the complement system [ 30 ]. These results confirm that either type of LPS treatment induces the inflammatory response, but the response after sequential LPS treatment is significantly reduced.…”