Inflammatory Macrophage-derived Plasminogen Activator Inhibitor-1 Exacerbates Inflammation through Efferocytosis Inhibition

Inflammatory Macrophage-derived Plasminogen Activator Inhibitor-1 Exacerbates Inflammation through Efferocytosis Inhibition | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Article Inflammatory Macrophage-derived Plasminogen Activator Inhibitor-1 Exacerbates Inflammation through Efferocytosis Inhibition Takashi Yahata, Abd Aziz Ibrahim, Hiromi Miura, Tomoya Terada, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7305973/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 27 Mar, 2026 Read the published version in Cell Death Discovery → Version 1 posted 11 You are reading this latest preprint version Editorial Note 15 August, 2025. The authors have provided a corrected Figure 4 for preprint version 1. The corrected Figure 4 file is now available as a supplemental file. Editorial notes are used to provide important context regarding the topic of a preprint or to alert readers to potential issues concerning that preprint or a downstream publication associated with it. For more information on editorial notes, see our Editorial Policies . Abstract Plasminogen activator inhibitor-1 (PAI-1) is significantly upregulated during inflammatory responses, and elevated PAI-1 levels are associated with poor prognosis in various diseases. However, the precise mechanisms by which PAI-1 exacerbates inflammation remain unclear. In this study, we investigated the role of PAI-1 in inflammation using a mouse model of skeletal muscle injury. We found that CCR2⁺Ly6C⁺ inflammatory macrophages infiltrated the injured tissues and produced substantial amounts of PAI-1. Notably, deficiency of PAI-1 specifically in these macrophages resulted in attenuated inflammation and accelerated tissue repair, despite the continued presence of PAI-1 in body fluids, indicating a local, macrophage-driven effect. Low-density lipoprotein receptor-related protein 1 (LRP-1), expressed on macrophages, serves as a common receptor for both PAI-1 and calreticulin (CRT). CRT is exposed on the surface of dead cells and functions as an “eat me” signal recognized by macrophages via LRP-1. We found that PAI-1 binds to LRP-1 with higher affinity than CRT, thereby competitively inhibiting CRT recognition and suppressing efferocytosis—the process by which macrophages clear dead cells—ultimately leading to prolonged inflammation. Importantly, administration of the PAI-1 inhibitor TM5614 restored efferocytosis and significantly improved tissue regeneration. These findings reveal that PAI-1 produced by infiltrating inflammatory macrophages contributes to sustained inflammation by blocking efferocytosis and identify PAI-1 as a promising therapeutic target for the treatment of inflammatory diseases. Biological sciences/Immunology/Inflammation Biological sciences/Immunology/Innate immune cells Inflammation PAI-1 macrophage efferocytosis phagocytosis small compound inhibitor Full Text Additional Declarations (Not answered) Supplementary Files SupplementalTableS1.docx Supplemental Table S1 1036340fig0t0tyrd.pdf Figure 4 CORRECTION. August 15, 2025. Cite Share Download PDF Status: Published Journal Publication published 27 Mar, 2026 Read the published version in Cell Death Discovery → Version 1 posted Unknown event 21 Jan, 2026 Editorial decision: Reject after peer review 29 Sep, 2025 Review # 2 received at journal 26 Sep, 2025 Review # 1 received at journal 07 Sep, 2025 Reviewer # 2 agreed at journal 01 Sep, 2025 Reviewer # 1 agreed at journal 28 Aug, 2025 Reviewers invited by journal 28 Aug, 2025 Submission checks completed at journal 08 Aug, 2025 First submitted to journal 07 Aug, 2025 Unknown event 06 Aug, 2025 Editor assigned by journal 06 Aug, 2025 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7305973","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":497771113,"identity":"9dbbb68d-e808-441e-acef-505ac5415107","order_by":0,"name":"Takashi Yahata","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA2UlEQVRIiWNgGAWjYFACHhBhA6YPgJiMDcRoOcCQJkGylsMSENuIAQbHzx78/KHmfB0/z+GHBxhq7BiYZxOwxuBMXrLEgWO3JSR72wwOMBxLZmCcc4CAlgM5BhIH2G5LGJwHshnYDjAwzkggoOX8G+MfB/6dA2ph/3CA4R8xWm7kmEkcbDsgYXC2x+AAYxsRWiRvvDGzONuXLDmz50zBgcS+ZB6CfuE7n2N8o+KbHT8/T/rmDx++2ckZEgoxBRQjgU7iMZyBXweDPIaR8hIEtIyCUTAKRsGIAwBBt0rfuXtQbQAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-9332-0358","institution":"Tokai University","correspondingAuthor":true,"prefix":"","firstName":"Takashi","middleName":"","lastName":"Yahata","suffix":""},{"id":497771114,"identity":"87ecda3a-736a-4d77-a773-6615411780a7","order_by":1,"name":"Abd Aziz Ibrahim","email":"","orcid":"","institution":"Tokai University","correspondingAuthor":false,"prefix":"","firstName":"Abd","middleName":"Aziz","lastName":"Ibrahim","suffix":""},{"id":497771115,"identity":"f2e07498-59c7-4354-a3e5-333723bf934d","order_by":2,"name":"Hiromi Miura","email":"","orcid":"","institution":"Tokai University","correspondingAuthor":false,"prefix":"","firstName":"Hiromi","middleName":"","lastName":"Miura","suffix":""},{"id":497771116,"identity":"01b2039e-502a-4cfe-969e-f79f42bc5530","order_by":3,"name":"Tomoya Terada","email":"","orcid":"","institution":"Tokai University","correspondingAuthor":false,"prefix":"","firstName":"Tomoya","middleName":"","lastName":"Terada","suffix":""},{"id":497771117,"identity":"e57bd22d-a822-44f9-812c-294c0a5fb868","order_by":4,"name":"Hiroyuki Hosokawa","email":"","orcid":"","institution":"Tokai University","correspondingAuthor":false,"prefix":"","firstName":"Hiroyuki","middleName":"","lastName":"Hosokawa","suffix":""},{"id":497771118,"identity":"906f113e-8e9f-4350-ac77-8344780cd713","order_by":5,"name":"Masato Ohtsuka","email":"","orcid":"","institution":"Tokai University","correspondingAuthor":false,"prefix":"","firstName":"Masato","middleName":"","lastName":"Ohtsuka","suffix":""},{"id":497771119,"identity":"20aa8d4b-d5a7-4fa6-8895-7f612651432a","order_by":6,"name":"Toshio Miyata","email":"","orcid":"","institution":"Tohoku University","correspondingAuthor":false,"prefix":"","firstName":"Toshio","middleName":"","lastName":"Miyata","suffix":""}],"badges":[],"createdAt":"2025-08-06 05:40:06","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-7305973/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7305973/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1038/s41420-026-03076-0","type":"published","date":"2026-03-27T04:00:00+00:00"}],"editorialNote":"\u003cp\u003e15 August, 2025. 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