Abstract:Tissue‐type plasminogen activator (tPA) activates fibrinolysis and also suppresses innate immune system responses to LPS in bone marrow‐derived macrophages (BMDMs) and in vivo in mice. The objective of this study was to assess the activity of tPA as a regulator of macrophage physiology in the presence of plasmin. Enzymatically active and enzymatically inactive (EI) tPA appeared to comprehensively block the response to LPS in BMDMs, including expression of proinflammatory cytokines such as TNF‐α and IL‐1β and a… Show more
“…The structure of LRP1 includes cysteine-rich complement-type repeats, EGF repeats, b-propeller domains, and transmembrane and cytoplasmic domains. Proteolytic cleavage of the ectodomain of LRP1 by a disintegrin and metalloproteinase 10 (ADAM10), ADAM17, membrane type1-MMP, and tPA releases free LRP1 that can serve as a decoy receptor trapping ligands (like plasmin, tPA, and MMPs) in the extracellular space [ 61 ].…”
Section: The Endocytosis Receptor Lrp1 Controls the Inflammatory Respmentioning
confidence: 99%
“…2 ) due to the unique function of LRP1 to link to other receptors like NMDA-R. Mantuano et al demonstrated that the pro-inflammatory cytokine profile of LRP1 deficient macrophages is reversed in TLR4 activated macrophages [ 71 ]. In the presence of LPS-stimulated TLR4, EI-tPA that cannot promote plasmin generation and a2-macroglobulin suppresses NFkB signaling and TNFa, IL-6, CCL2/3 production by binding to the NFkB suppressing NMDA-R [ 61 , 74 ]. Fig.…”
“…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 marrow-derived macrophages [ 61 ]. Fig.…”
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.
“…The structure of LRP1 includes cysteine-rich complement-type repeats, EGF repeats, b-propeller domains, and transmembrane and cytoplasmic domains. Proteolytic cleavage of the ectodomain of LRP1 by a disintegrin and metalloproteinase 10 (ADAM10), ADAM17, membrane type1-MMP, and tPA releases free LRP1 that can serve as a decoy receptor trapping ligands (like plasmin, tPA, and MMPs) in the extracellular space [ 61 ].…”
Section: The Endocytosis Receptor Lrp1 Controls the Inflammatory Respmentioning
confidence: 99%
“…2 ) due to the unique function of LRP1 to link to other receptors like NMDA-R. Mantuano et al demonstrated that the pro-inflammatory cytokine profile of LRP1 deficient macrophages is reversed in TLR4 activated macrophages [ 71 ]. In the presence of LPS-stimulated TLR4, EI-tPA that cannot promote plasmin generation and a2-macroglobulin suppresses NFkB signaling and TNFa, IL-6, CCL2/3 production by binding to the NFkB suppressing NMDA-R [ 61 , 74 ]. Fig.…”
“…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 marrow-derived macrophages [ 61 ]. Fig.…”
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.
“…The function of tPA as an LPS response modifier is not dependent on its protease activity and is replicated by enzymatically-inactive tPA (EI-tPA). Instead, the effects of tPA on BMDMs are mediated by the N-methyl-D-aspartate receptor (NMDA-R), which is best known for its function as a neuronal synapse protein but also expressed by macrophages [12, 13]. LDL Receptor-related Protein-1 (LRP1), a transmembrane receptor that binds tPA [14–18], probably functions as an NMDA-R co-receptor, decreasing the concentration of tPA required to trigger NMDA-R-dependent cell-signaling and gene regulatory events [17–20].…”
Tissue-type plasminogen activator (tPA) is a major activator of fibrinolysis, which also attenuates the pro-inflammatory activity of lipopolysaccharide (LPS) in bone marrow-derived macrophages (BMDMs) and in vivo in mice. The activity of tPA as an LPS response modifier is independent of its proteinase activity and instead, dependent on the N-methyl-D-aspartate Receptor (NMDA-R), which is expressed by BMDMs. The major Toll-like receptor (TLR) for LPS is TLR4. Herein, we show that enzymatically-inactive (EI) tPA blocks the response of mouse BMDMs to selective TLR2 and TLR9 agonists, rapidly reversing IκBα phosphorylation and inhibiting expression of TNFα, CCL2, interleukin-1β, and interleukin-6. The activity of EI-tPA was replicated by activated α2-macroglobulin, which like EI-tPA, signals through an NMDA-R-dependent pathway. EI-tPA failed to inhibit cytokine expression by BMDMs in response to agonists that target the Pattern Recognition Receptors (PRRs), NOD1 and NOD2, providing evidence for specificity in the function of EI-tPA. Macrophages isolated from the peritoneal space (PMs), without adding eliciting agents, expressed decreased levels of cell-surface NMDA-R compared with BMDMs. These cells were unresponsive to EI-tPA in the presence of LPS. However, when PMs were treated with CSF-1, the abundance of cell-surface NMDA-R increased and the ability of EI-tPA to neutralize the response to LPS was established. We conclude that the anti-inflammatory activity of EI-tPA is selective for TLRs but not all PRRs. The ability of macrophages to respond to EI-tPA depends on the availability of cell surface NMDA-R, which may be macrophage differentiation-state dependent.
“…The fibrinolytic drug, tissue-type plasminogen activator (tPA), has been systemically administered to treat ARDS in COVID-19 and appeared to be effective in some patients [2][3][4]. Since tPA has been reported to show an antiinflammatory effect in addition to a fibrinolytic action, this potential of tPA would be helpful for improving the prognosis of COVID-19 patients [11,12].…”
A high rate of thrombotic complications, such as pulmonary embolism, has been linked to mortality in COVID-19, and appropriate treatment of thrombosis is important for lifesaving. Although heparin is frequently used to treat thrombotic pathology in COVID-19, pulmonary embolism is still seen in severe cases. Although systemic fibrinolytic therapy is a focus of attention because a thrombotic pathology is the cause of death in severe COVID-19, it should be kept in mind that fibrinolytic therapy might be harmful at advanced stage of COVID-19 where the status of disseminated intravascular coagulation (DIC) has been transmitted from suppressed-fibrinolytic to enhanced-fibrinolytic in disease progression of COVID-19. In this respect, inhalation therapy with fibrinolytic substances might be a safe and promising treatment.
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