Endoplasmic Reticulum Stress Impairs Macrophage Efferocytosis via TRIB3-Rab27a Signaling and Exacerbates Atherosclerotic Plaque Necrosis

Endoplasmic Reticulum Stress Impairs Macrophage Efferocytosis via TRIB3-Rab27a Signaling and Exacerbates Atherosclerotic Plaque Necrosis | 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 Endoplasmic Reticulum Stress Impairs Macrophage Efferocytosis via TRIB3-Rab27a Signaling and Exacerbates Atherosclerotic Plaque Necrosis Aarushi Singhal, Umesh Dhawan, Kunzangla Bhutia, Hedayatullah Hayat, and 11 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-4616005/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Defective clearance of apoptotic cells (efferocytosis) by macrophages is a key driver of atherosclerotic plaque necrosis which is associated with adverse clinical outcomes such as myocardial infarction and stroke. The mechanistic basis of defective efferocytosis in atherosclerotic plaque macrophages is not well understood. We show that hyperlipidemia and the consequent accumulation of lipids in macrophages triggers endoplasmic reticulum stress which directly impairs efferocytosis. Mechanistically, we demonstrate that lipid accumulation-induced activation of the ATF4 branch of the unfolded protein response pathway and the consequent upregulation of Tribbles pseudokinase 3 (TRIB3) triggers the downregulation of Rab27a resulting in impaired focal exocytosis of intracellular membrane pools towards the apoptotic cell-containing nascent phagosome. The resultant impairment in phagosome closure stalls the efferocytic process. Humans with the gain-of-function Q84R TRIB3 variant contain more TRIB3 in macrophages and display decreased efferocytosis efficiency. We confirm higher TRIB3 expression in vulnerable plaques of humans and show that hematopoietic cell-specific deletion of TRIB3 in high-fat diet fed atherosclerosis-prone mice improves lesional macrophage efferocytosis efficiency and decreases plaque necrosis. Overall, our findings highlight a novel role for the ATF4-TRIB3-Rab27a signaling axis in mediating defective efferocytosis in atherosclerosis and opens new avenues for targeting this pathway for atherosclerotic plaque stabilization. Biological sciences/Immunology/Cell death and immune response Health sciences/Cardiology/Cardiovascular biology/Cardiovascular diseases/Vascular diseases/Atherosclerosis Full Text Additional Declarations There is NO Competing Interest. Supplementary Files TRIB3Efferographicalabstract.pdf Graphical Abstract ReportingSummary.pdf Reporting Summary Cite Share Download PDF Status: Posted Version 1 posted 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. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. 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-4616005","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":352200550,"identity":"e17e549b-5804-40d6-beb2-05c4ad12a52f","order_by":0,"name":"Aarushi Singhal","email":"","orcid":"","institution":"Queen Mary University of London","correspondingAuthor":false,"prefix":"","firstName":"Aarushi","middleName":"","lastName":"Singhal","suffix":""},{"id":352200551,"identity":"73151954-2da7-45f7-a965-3f99cf9763b8","order_by":1,"name":"Umesh Dhawan","email":"","orcid":"","institution":"Queen Mary University of 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