key: cord-1044133-iq2d6mik
authors: Heissig, Beate; Salama, Yousef; Takahashi, Satoshi; Osada, Taro; Hattori, Koichi
title: The multifaceted role of plasminogen in inflammation
date: 2020-08-28
journal: Cell Signal
DOI: 10.1016/j.cellsig.2020.109761
sha: a5ebb4f3ddbb6c2c1446849b895958ae528b647a
doc_id: 1044133
cord_uid: iq2d6mik

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.

Tissue damage with vascular leakage occurs after inflammation [1] and requires a fine-tuned activation and deactivation of proteases and their inhibitors released from recruited leukocytes and tissue-resident endothelial cells or fibroblasts to initiate hemostasis executed by the activation of the coagulation system, followed by the activation of the fibrinolytic system driven by plasmin, and the concomitant complement activation. Coagulation factors enhance the formation of blood clots (thrombi) that stop hemorrhage (hemostasis) due to damaged vessels. As blood flow needs to resume for proper tissue repair, thrombi are dissolved, a task taken on by the serine protease plasmin, the key serine protease of the fibrinolytic pathway.

Endothelial damage leading to excessive thrombin generation or proinflammatory cytokines, including tumor necrosis factor-alpha (TNFa) or interleukins (ILs), like IL-6 [2] enhance the release of tissue-type plasminogen activator (tPA) from storage granules in endothelial cells. tPA and other plasminogen activators enhance the conversion from the proenzyme/zymogen plasminogen into the active enzyme plasmin.

Aside from clot dissolution, recent studies demonstrate plasmin or tPA can modify the inflammatory response on various levels: They can activate proteases like e.g. matrix metalloproteinases (MMPs) thereby modifying the extracellular matrix composition [3] , promote macrophage and dendritic cell (DC) migration, function as a cytokine, and control nuclear factor kappaB (NFkB) activation due to their ability to engage with cellular receptors conveying either pro-or anti-inflammatory cellular responses including the response to Toll-like receptor (TLRs) activation.

While tPA binding to some of these receptors can enhance Plg activation (proteolytic activity), growing evidence suggests that tPA can directly modulate cytokine signaling pathways through a non-enzymatic mechanism. Finally, plasmin(ogen) and J o u r n a l P r e -p r o o f its cellular receptors contribute to the resolution of inflammation.

Depending on the experimental model, the stage of inflammatory disease, and the receptors involved, plasmin(ogen) and tPA orchestrate processes that protect against or are in favor of exacerbation of inflammatory processes, underscoring the complexity of the network induced by fibrinolytic factors at the molecular level.

Vascular damage activates the coagulation system that generates fibrin and supports the formation of a thrombus. The thrombus establishes a physical barrier for pathogens or non-self-pathogens (part of the innate immune system) and stopping bleeding (hemostasis). Inflammation shifts the hemostatic balance towards a prothrombotic and antifibrinolytic state that causesif not properly shut downcauses the devastating consumptive coagulopathy and disseminated coagulation [4] .

Tissue damage can activate the complement cascade during the inflammatory response, another cascade of enzymes of the innate immune system that enhances (complements) the ability of antibodies and phagocytic cells to clear microbes and damaged cells, induce inflammation to attract more macrophages, and activates the cell-killing membrane attack complex (MAC) to destroy the pathogen`s cell membrane ( Figure 1 ). Coagulation Cascade. While the intrinsic, contact coagulation pathway is mainly activated through exposed endothelial collagen and XII, the extrinsic pathway is activated through the release of the transmembrane receptor tissue factor (TF) from endothelial cells and its plasma cofactor Factor VII/VIIa (Figure 1 ). Extrinsic and intrinsic pathways activate Factor X, which renders the zymogen prothrombin into thrombin. Factor XII (FXII, also known as Hageman factor) is converted to its active J o u r n a l P r e -p r o o f enzyme (FXIIa) by plasma kallikrein (PKa) or by its unique ability to auto-activate following binding to artificial or biologic surfaces [5] . In disease states of infection, the surface of bacterial pathogens or polyphosphates released by them promotes the autoactivation of FXII [5] . FXIIa activation of PK forms plasma kallikrein that reciprocally activates FXII and liberates bradykinin (BK) from high molecular weight kininogen (HK). Bradykinin enhances vasodilation and increases capillary permeability, leading to edema and changes in arterial blood pressure. FXII deficiency is linked to decreased infiltration of inflammatory cells into skin windows [6] . FXII facilitates the recruitment of neutrophils, binds to the surface of pathogens (bacteria, fungi, viruses, and neutrophil extracellular traps (NETs) where it autoactivates [7] . FXII promotes neutrophil degranulation [8] .

Factor XIIa also activates FXI and C1 esterases (C1r, C1s), the first components of the macromolecular complex of C1, and the classic complement cascade ( Figure   1 ) [9] .

The complement cascade is part of the innate immune system. Complement factors (C1-9) are small proteins that enhance (complement) the ability of antibodies and macrophages to clear microbes following proteolytic activation (C1a-C9a) ( Figure 1 ): Complement enhances (complements) the antibody's ability and macrophages to clear microbes. Complement factors enhance macrophage and neutrophil chemoattraction and establish a membrane attack complex (MAC, C5b-C9) necessary for the rupture of the cell wall. Thrombin and plasmin enhance the formation of certain complement proteins (namely C3 and C5). Activated complement fragments C3a/C5a can recruit leukocytes and induced the MAC complex on macrophages [10] . One inhibitor of the classical C1 pathway of the complement is C1 inhibitor. Mutations in the C1 inhibitor gene can cause hereditary angioedema due to a reduced regulation of bradykinin by J o u r n a l P r e -p r o o f C1 inhibitor. HIV infection can alter the complement system causing further tissue damage [11] .

Thrombin converts fibrinogen into fibrin. Factor XIII, another thrombin-generated enzyme, then crosslinks the fibrin protofibrils leading to an insoluble gel that serves as a scaffold for a blood clot (thrombus). Endothelial cells that cover the inner vessel wall modulate the balance between coagulation and fibrinolysis by counteracting coagulation through binding of anti-thrombin III, releasing tissue factor pathway inhibitor, expressing thrombomodulin, activating protein C, and producing and secreting tPA [12, 13] . Protein C -produced in the liver in a Vitamin K-dependent manner -after binding to the endothelial cell protein C receptor in the presence of thrombomodulin and thrombin leads to the generation of activated protein C (APC) [14] . APC irreversibly inactivates Factor Va (Leiden) and VIIIa and thereby counteracts thrombin activity. The fibrinolytic cascade, with plasmin as its central player, is required for fibrin degradation and blood clot/thrombus dissolution to regain vascular patency after initial hemostasis is achieved [18, 19] .

Vascular endothelial cells keep tPA and Plg on their surfaces. tPA (encoded by PLAT), urokinase plasminogen activator (uPA, encoded by PLAU), or other enzymes, e.g., plasma kallikrein (PK) and coagulation factor XIIa convert the inactive zymogen Plg into the active enzyme plasmin [20] . Plg is produced by the liver and circulates in the blood. Plg is a seven-domain protein comprising an N-terminus PAN-apple domain, five tandem kringle domains, and a C-terminus catalytic domain [21] . The PAN/apple domain is proteolytically removed, and the kringle domains are responsible for fibrin binding. The PAN/apple domain-free plasmin can be further degraded by phosphoglucerate kinase to remove the catalytic domain. The remaining five kringle domains are referred to as angiostatin, an endogenous angiogenesis inhibitor [22] .

Under steady-state conditions, plasmin activity is low as there is no need for fibrin removal. When fibrin had been generated, Plg and tPA bind to fibrin which the cleavage of Plg (at the Arg561-Val562 peptide bond) into the two-chain enzyme plasmin. Plasmin is composed of an N-terminal heavy chain (12-65 kDa) and a Cterminal light chain (25 kDa) that contains the proteolytic active site [13] . Thrombinactivatable fibrinolysis inhibitor (TAFI) prevents Plg binding to fibrin. Soluble, but not fibrin-bound plasmin can be inactivated by its main inhibitor alpha2-antiplasmin [23] , and by alpha2-anti-macroblogulin.

Early studies demonstrated that Lysine-Plg attaches with higher affinity to macrophages found in chronic inflammatory lesions than the native Glu-Plg [24] . Plg Carboxy-terminal lysines from proteins and therefore is used to identify novel Plg binding receptors [25] . The lysine binding sites within the kringle domains of Plg bind to the carboxy-terminal lysine of Plg receptors (reviewed [26, 27] ). Plg receptors include the heterotetrameric complex Annexin A2-S100A10, alpha-enolase-1, histone H2B, and the plasminogen receptor With A C-Terminal Lysine (Plg-RKT) [28] , TBPinteracting protein 49a [29] or the high mobility group box-1 protein (HMGB-1) [30] .

In chapter 8, we will later discuss recent studies on the role of Plg-RKT for macrophage migration, efferocytosis, and macrophage subtype determination [31] (see chapter 8).

tPA is synthesized as a single-chain molecule with low plasmin binding affinity [32] ensuring that in the absence of fibrin the fibrinolytic activity is low. Plasmin cleaves tPA into its two-chain form, a form that has a 10-fold higher affinity for converting Plg into plasmin than the single-chain molecule [32] . The two chain tPA has a heavy A-chain and the light B-chain. The heavy A-chain is composed of the fibronectin finger domain, an epidermal growth factor analog domain, and Kringle 1 and 2 domains [13] . The finger domain of tPA is responsible for the binding of fibrin, Annexin II, and low-density lipoprotein receptor-related protein-1 (LRP1) [33, 34] .

The kringle 1 domain of tPA is involved in the uptake of tPA in the liver [35] , while the Kringle 2 domain is important for interactions with N-methyl-D-aspartic acid receptor (NMDA-R) and PDGFs [36] . tPA also associates with the annexinA2S100A10 complex, Plg-RKT, and mannose receptors [37] [38] [39] [40] [41] . Natural inhibitors of tPA's fibrinolytic activity are plasminogen activator inhibitor-1 (PAI-1), a circulating serpin (serine protease inhibitor), and PAI-2 [32, 42] .

The specific binding of Plg and tPA to lytic edges of partly degraded fibrin via newly generated C-terminal lysine residues amplifies fibrin digestion generating diffusible J o u r n a l P r e -p r o o f and soluble fibrin fragments. Such fibrin degradation products (FDPs) include fragments D and E and D-dimers. D-dimers are two D fragments joined by a crosslink [43] often used as a measure for the presence of systemic inflammation in clinical settings.

Gene deficient mice for Plg show fibrin deposition in various tissues leading to high mortality, wasting, spontaneous gastrointestinal ulceration, rectal prolapse, severe thrombosis, and delayed wound healing [44] . Dependent on the disease model tested, mouse mutants with Plg deficiency can suppress or exacerbate inflammatory diseases.

Plg deficiency exacerbates collagen-induced arthritis [45] , and peripheral nerve injury [46] . The phenotypic abnormalities of Plg deficiency can be rescued in mice genetically deficient in both Plg and fibrinogen [47] or following pharmacological fibrin depletion in Plg knockout mice [45, 46] . On the other hand, that Plg deficiency (pharmacological or genetic) improved the outcome of inflammatory diseases in murine models of inflammatory bowel disease [48] or diseases where immune cells release vast amounts of pro-inflammatory factors resulting in a cytokine storm syndrome, like during Graft versus Host Disease (GvHD) and macrophage activation syndrome (MAS) [49, 50] . The specific role of plasmin during the cytokine storm syndrome will be further discussed in chapter 7. These studies suggested that a major function of Plg is fibrinolysis.

Aside from the established role of fibrinolytic factors for the recruitment of macrophages, fibrinolytic factors also can change the cellular, immunomodulatory environment through the expansion of mesenchymal stem cell (MSC) expansion.

MSCs orchestrate local and systemic innate and adaptive immune responses through the release of immunosuppressive molecules, growth factors, exosomes, chemokines, and complement components. We showed that MSCs express fibrinolytic factors (reviewed in [51] ) and endothelial cells, and that tPA administration promotes MSC J o u r n a l P r e -p r o o f recruitment and expansion [51, 52] . Mechanistically, the tPA-mediated release of kit ligand from endothelial cells resulted in the expansion of MSCs due to the release of basic fibroblast growth factor and platelet-derived growth factor-BB from c-kit+ activated MSCs [53] . [65] . These studies show that soluble or membranetype LRP1 can influence the inflammatory response.

Earlier studies established a link between clotting/fibrinolysis related-proteases and TLR signaling. One study reported that antithrombin III inhibited the response to LPS in the monocytic cell line THP-1 [66] . C1 inhibition was shown to prevent LPS shock [67] , and fibrinogen was shown to activate TLR4 [68] . Ward et al. reported that plasmin exerted proinflammatory functions in monocytes, and potentiated TLR2 and TLR4 signaling [69] . These studies indicated that coagulation factors modulate the J o u r n a l P r e -p r o o f inflammatory TLR response.

TLR activation enhances the nuclear translocation of transcription factors, like activator protein-1, NFkB, or interferon regulatory factor 3 (IFR3). Of interest, the LRP1 β chain is processed by the presenilin-dependent γ-secretase to generate a small fragment-LRP1 C-terminal intracellular domain, which promotes the nuclear export of inflammatory transcription factor IFR3 blocking the transcription of inflammatory genes [70] .

To further understand how fibrinolytic factors can alter TLR signaling, it is important to note that LRP1 is linked to uPA receptor urokinase-type plasminogen activator receptor (uPAR) or N-Methyl-D-Aspartate receptor (NMDA-R) via the adapter protein postsynaptic density protein 95. Due to this linkage, LRP1 can internalize these receptors after ligand binding [71] , and control the presence and signaling of these cellular receptors [37] .

Earlier studies demonstrated that a2-macroglobulin decreases calcium responses to the glutamate receptor NMDA-R by the expression of NMDA-R1 in rat hippocampal neurons [72] . Later, it was shown that enzymatically inactive tPA (El-tPA) and a2macroglobulin treatment caused the formation of a complex between LRP1, PSD-95, and NMDA-Rs that activates tyrosine receptor kinase (Trk) receptors and stimulates ERK1/2 activity in neurons [73] . ERK1/2 activation can enhance MMP9 expression [52, 56, 58] . These studies indicated El-tPA modifies cellular signaling via LRP1.

Recent studies elegantly showed that tPA-mediated LRP1 signaling modulates the inflammatory response after TLR stimulation (Figure 2 Similarly, EI-tPA and activated α2-macroglobulin binding to NMDA-R blocks ligand-induced TLR2 and TLR9 and NFkB signaling, but not that of PPRs like NOD1 or NOD2 [75] .

Endothelial cells, fibroblasts, osteoblasts, smooth muscle, and macrophages produce the macrophage-colony stimulating factor (M-CSF; also known as CSF1). M-CSF signals through the M-CSF receptor (reviewed by Hamilton [76] ), and is required for macrophage survival, proliferation, monocytic cell differentiation, and myeloid cell mobilization into circulation. M-CSF enhances NMDA-R expression in macrophages [75] . This study demonstrated EI-tPA engagement with NMDA-R on macrophages keeps cells in a resting, non-inflammatory stage, and that M-CSF could alter the response to fibrinolytic factors.

While TLR-mediated effects of tPA on NFkB signaling did not require plasmin, active plasmin can mount a pro-inflammatory response in macrophages or astrocytes through protease-activated receptor-1 (PAR1) (Figure 3 ). PAR1 is a key thrombin receptor on platelets and mediates thrombin-induced platelet aggregation. Plg receptors like uPAR or a-enolase present Plg to extracellular tPA, or uPA or intracellular uPA causing the conversion of Plg into active plasmin. In turn, plasmin similar to thrombin, MMP1 [77] , MMP13 [78] , Cathepsin G, and neutrophil elastase [79] can cleave the N-terminal ectodomain part of PAR-1 and activate intracellular signaling pathways [80] like the NFkB pathway [81] . Plasmin-mediated PAR-1 activation induces IL-8 expression in human dental pulp fibroblast-like cells [82] and activates NFkB, ERK1/2, and p38 mitogen-activated protein kinase in bone marrowderived macrophages [61] .

Our group demonstrated that plasmin treatment of TLR4 or TLR9 ligand-stimulated macrophages showed enhanced NFkB activation [49, 50] supporting the notion of plasmin as a proinflammatory mediator. We showed that plasmin inhibition prevents the progression of inflammatory bowel disease in murine models in part through MMP9 activation [48] .

Given the proinflammatory role of plasmin, studies evaluated the effect of plasmin inhibition to prevent immunosuppression after traumatic brain injury, ischemic stroke, and cardiac surgery. In a model of brain injury, treatment with tranexamic acid (TXA), the lysine analog that blocks the binding of Plg and the ultimate generation of plasmin on fibrin, increased migration and proliferation of conventional dendritic cells (cDCs), antigen-presenting cells and T cells in the draining cervical lymph nodes [83] .

Acute ischemic stroke similarly can trigger immunosuppression. Using a mouse model of middle cerebral artery occlusion tPA administration worsened the already due to inflammation established immunosuppressive state by reducing lymphocyte and monocyte counts in circulation, enhancing plasma IL-10 and TNFa levels and decreasing DC subtypes [84] .

Extensive surgery is fraught with a high risk of infection, depicting a state of immunosuppression. In patients undergoing cardiac surgery, the administration of TXA prevents reduced surgery-induced infection rates and surgery-associated immunosuppression [85] . TXA treatment in patients after surgery and in healthy volunteers reduced CD4+ and CD8 memory cells, and CCR7+ regulatory T cells, but increased CCR7 expression on NK cells, attenuated TNFa, IL6 and IL-1b upregulation after surgery. Finally, TXA increased the monocyte/dendritic activation marker CD83 but reduced the maturation marker HLA-DR. In summary, plasmin J o u r n a l P r e -p r o o f inhibition can mitigate immunosuppression after certain ischemic events including surgery.

Infections cause tissue damage not only because of the virulence of the germ or toxin but also because of the immunological host response to the infectious stimulant.

Activated macrophages, T cells and endothelial cells can mount such a host response and cytokines are key elements of the derailed immunological host response. The clinical syndrome is therefore called the cytokine storm or the cytokine release syndrome. Cytokines itself can cause typical clinical symptoms: Fever was attributed to TNFa and IL-6 rises. IL-2 can induce capillary leakage syndrome with hypotension and kidney failure. Forward amplification by these cytokines occurs. Released proinflammatory cytokines further activate newly recruited or resident macrophages, DCs, or endothelial cells to secrete more pro-inflammatory cytokines like IL-1 [86, 87] .

A common feature of severe cytokine storm is endothelial cell death. Vascular damage requires the coagulation system for tissue repair. But over-activation of the coagulation system with the generation of massive thrombi can establish DIC leading to the depletion of platelets (thrombopenia) and coagulation factors. Hemostatic imbalance also creates lung and kidney damage due to complement-mediated injury.

In 1993, Ferrara's group first introduced the term cytokine storm to describe the derailed immunological host response during graft-versus-host disease (GvHD), a condition occurring after an allogeneic transplant [88] . In GvHD, the donated bone marrow or peripheral blood stem cells view the recipient's body as foreign, and the donated cells attack the recipient's body. Our group observed increased circulating plasmin levels in mice and men with acute GvHD [49] . Pharmacological plasmin J o u r n a l P r e -p r o o f inhibition protected against acute GVHD-associated lethality in mice by reducing the infiltration of inflammatory cells in part due to enhanced MCP1 signaling and augmented release of membrane-associated pro-inflammatory cytokines including TNFa and Fas-ligand partially due to the activation of MMPs.

Other diseases can cause CRS ranging from rheumatological disorders [89] , immune- Aside from a massive cytokine elevation of typical proinflammatory cytokines like TNFa, IL-1, IL-6, and GM-CSF, these patients show typical derailment of the coagulation system. The cytokine storm data found in COVID-19 patients seem to indicate increased levels of thrombi, and damage to the vascular endothelium, the involvement of cytokines and immuno-thrombosis [92, 93] . Pathology analysis of COVID-19 patients' lungs shows widespread thrombosis with microangiopathy. It is yet to be determined whether plasmin in COVID-19 is a friend or foe as recently summarized in a review by Medcalf et al. [94] .

Cytokine storm syndrome resembles hemophagocytic lymphohistiocytosis or macrophage activation syndrome. Typical clinical symptoms of MAS patients are: fever, organomegaly, multi-organ failure, hyperferritinemia, pancytopenia, increases in triglycerides, fibrinogen, ferritin, serum aspartate aminotransferase, and hemophagocytosis (the uptake of erythrocytes into macrophages) in bone marrow aspirates [91] . Respiratory symptoms range from mild cases with cough and tachypnea to acute respiratory distress syndrome with dyspnea, hypoxemia, and bilateral opacities on chest X-ray. Organ failure includes the kidney or heart, and accompanying hemodynamic instability, capillary leak, and consumptive J o u r n a l P r e -p r o o f coagulopathy are also often reported [95] . MAS can occur following severe viral inflammation. Viral RNA/DNA can activate TLR9. We established a murine MAS model by repeatedly administering the TLR9 activating dinucleotide CpG combined with D-galactosamine, a substance triggering hepatocyte apoptosis and TNFa activation, to test the potential involvement of plasmin in the pathogenesis of MAS [50] . Plasmin levels were increased during MAS progression in mice. We found that plasmin inhibition prevented tissue destruction and lethality in MAS mice while suppressing the cytokine peak [50] . Plasminogen activator administration aggravated the disease. In vitro, the addition of plasmin and TLR9 ligands activated NFkB signaling in macrophages with enhanced production of transmembrane TNFa, CCL2, IL-1, IL-6, and Fas ligand. This in turn augmented uPA [96] , and PAI-1 expression [97] . Most importantly, our study indicated that plasmin inhibition blocked the vicious cycle of cytokine storm syndrome and hyperfibrinolysis in tandem with coagulation in the MAS model [50] .

During inflammation resolution, apoptotic cells need to be cleaned up in a process known as efferocytosis. Apoptotic cells activate serum-derived Plg. The generated plasmin promotes apoptotic cell clearance [98, 99] . Das et al. showed that Plg deficient cells showed impaired phagocytic activity [99] . Recent studies showed that the transmembrane Plg receptor Plg-RKT [101] induce macrophage polarization from the M1 to the M2 type and efferocytosis in the pleurisy model required Plg-RKT and Plg as shown using gene-deficient mice [102] .

While fibrin depositions are part of the normal acute inflammatory reaction, provisional laid down fibrin needs to be removed by MMPs and plasmin to restore tissue homeostasis. Fibrin laid down within exudates tends to form adhesions between layers of membranes that cover inflamed organs. The balance between fibrin deposition and degradation is a critical factor in adhesion formation after surgery leading to adhesive small bowel obstruction. Scars can form that lead to adhesive small bowel obstruction, a common problem known by surgeons after intestinal surgery. Increases in activated resident macrophages were found at the surgical site [103] . These activated macrophages secrete epidermal growth factor (EGF), which induced the upregulation of its receptor EGF receptor (HER1) on peritoneal mesothelial cells. HER1-activated mesothelial cells secreted more PAI-1, which together with tPA recruited more macrophages to the surgical site establishing a vicious cycle of impaired fibrinolysis and macrophage accumulation at the adhesive site that can cumulate in adhesive small bowel obstruction. These studies demonstrate that plasmin contributes to the resolution phase of inflammation by its proteolytic ability (fibrin degradation), its ability to enhance the M1 into M2 macrophage switch, and accelerate the cleaning up of apoptotic neutrophils (efferocytosis). Factors of the coagulation, complement, and fibrinolytic system interact. The imbalance of these proteins can be the cause or the reason for thrombosis and inflammation. During inflammation, tissue damage inflicted by microbes or nonmicrobial stressors activates the coagulation system. Thrombin generates fibrin and enhances platelet activation and their growth factor release through protease activated receptors (PARs). Tissue-type plasminogen activator (tPA) and urokinase plasminogen activator (uPA) activate the inactive proenzyme/zymogen plasminogen (Plg) into active plasmin (Plm). Plasminogen activators are inhibited by plasminogen activator inhibitor-1, -2 (PAI-1, PAI-2), and protein C inhibitor (PCI). Plm functions include its ability to activate complement C3a and C5a, degrade fibrin into fibrinogen degradation products leading to fibrin fragments like the D-dimers, convert the proenzymes of matrix metalloproteinases (MMPs) to their active forms, regulate extracellular matrix (ECM) turnover (remodeling), and contribute to inflammation resolution (efferocytosis, M1 to M2 switch). 

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We thank Robert Whittier for proofreading the manuscript. This study was supported