Journal Article

Virus-derived serpin reduces immuno-coagulopathic damage in murine colitis by targeting the urokinase-type plasminogen activator receptor (uPAR) and complement

Elmadbouly, Nora, Rahman, Masmudur, Hamada, Mostafa, Zhang, Liqiang, Schlievert, Jessika, Irving, James, Spaccarelli, Laurel, Dupati, Aashika, Kong, Wei, Florsheim, Esther Borges, Saju, Rohan, Lucas, Alexandra R., Monder, Henna, Lowe, Kenneth, Zanetti, Isabela R., Garg, Aman, McFadden, Grant, Kilbourne, Jacqueline, Gisriel, Savanah, Enow, Junior, Pinteric, Aubrey, Woodrow, Cheyanne, Satyanarayanan, Ritvik Srivant, Aliskevich, Emily

2025

Overview

A virus-derived serpin, Serp-1, has proven efficacy in treating inflammatory and coagulation disorders in preclinical and clinical studies. Serp-1 evolved over millions of years to block host immune responses, targeting serine proteases in immune and coagulation pathways. Treatment with PEGylated Serp-1 (PEGSerp-1) protein reduced lung injury in both lupus lung hemorrhage and SARS-CoV-2 models. Here, PEGSerp-1 effects on immune-coagulopathic responses is examined in a mouse colitis model. Inflammatory bowel disease (IBD) is associated with life-threatening complications with severe inflammation, bleeding, vasculitis, cancer and toxic megacolon. Ser ine p rotease cascades activate coagulation and complement pathways throughout the human body and are regulated by in hibitors, termed serpins , that can reduce gut inflammation. Prophylactic PEGSerp-1 significantly improved survival in severe 5% Dextran sodium sulfate (DSS) colitis, reducing inflammation and crypt damage. Colon damage and inflammation were also reduced after either acute colitis induced by 5% DSS or repeat 2% DSS induced colitis. PEGSerp-1 reduced inflammatory M1 macrophage invasion, urokinase-type plasminogen activator receptor (uPAR), fibrinogen and complement on immunohistochemical analysis. PEGSerp-1 reduced uPAR expression in human macrophage, but not colon cells. Here we report analysis of PEGSerp-1 as a tissue and macrophage targeting therapeutic for colitis, reducing immune and coagulation induced damage in the colon.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 631/250 / 692/4020 / 692/699 / Animals / Bats / Coagulation / Colitis / Colitis - chemically induced / Colitis - drug therapy / Colitis - immunology / Colitis - pathology / Colon / Colon - drug effects / Colon - pathology / Complement System Proteins - metabolism / Dextran / Dextran Sulfate - toxicity / Disease Models, Animal / Disease prevention / Female / Fibrinogen / Hemorrhage / Humanities and Social Sciences / Humans / Immune response / Inflammation / Inflammatory bowel disease / Inflammatory bowel diseases / Inflammatory diseases / Ischemia / Kinases / Macrophages / Mice / Mice, Inbred C57BL / Mortality / multidisciplinary / Pathogenesis / Proteases / Proteins / Receptors, Urokinase Plasminogen Activator - antagonists & inhibitors / Receptors, Urokinase Plasminogen Activator - metabolism / Science / Science (multidisciplinary) / Serine proteinase inhibitors / Serpins - pharmacology / Serpins - therapeutic use / Severe acute respiratory syndrome coronavirus 2 / Sodium sulfate / Steroids / Survival analysis / Thrombosis / Transplants & implants / U-Plasminogen activator / Vasculitis / Viral infections