Inhibition of autophagy-lysosomal function exacerbates microglial and monocyte lipid metabolism reprograming and dysfunction after brain injury

Inhibition of autophagy-lysosomal function exacerbates microglial and monocyte lipid metabolism reprograming and dysfunction after brain injury | 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 Inhibition of autophagy-lysosomal function exacerbates microglial and monocyte lipid metabolism reprograming and dysfunction after brain injury Marta Lipinski, Amir Mehrabani-Tabari, Nivedita Hegdekar, Brian R. Herb, and 18 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7682363/v1 This work is licensed under a CC BY 4.0 License Status: Under Review Version 1 posted You are reading this latest preprint version Abstract CNS has an overall higher level of lipids than all tissues except adipose and contains up to 25% of total body cholesterol. Recent data demonstrate a complex crosstalk between lipid metabolism and inflammation, suggesting potential contribution of the lipid-rich brain environment to neuroinflammation. While recent data support the importance of brain lipid environment to inflammatory changes observed in age related chronic neurodegenerative diseases, in vivo interactions between lipid environment, lipid metabolism and neuroinflammation in acute brain disease and injury remain poorly understood. Here we utilize a mouse model of traumatic brain injury (TBI) to demonstrate that acute neurotrauma leads to widespread lipid metabolism reprograming in all microglial and brain associated and infiltrating monocyte populations. Additionally, we identify unique microglial and monocyte populations with higher degree of lipid metabolism reprograming and pronounced accumulation of neutral storage lipids, including cholesteryl esters and triglycerides. These lipids accumulate not only in lipid droplets but also in the microglial and monocyte lysosomes and are associated with lysosomal dysfunction and inhibition of autophagy after TBI. Our data indicate that lipid accumulation in these cells is the result of altered lipid handling rather than lipid synthesis and is triggered by phagocytosis of lipid-rich myelin debris generated after TBI. Finally, we use mice with autophagy defects in microglia and monocytes to demonstrate that further inhibition of autophagy leads to more pronounced lipid metabolism reprograming and exacerbated cellular lipid accumulation. Our data suggest a pathological feedback loop, where lipid phagocytosis causes inhibition of autophagy-lysosomal function, which in turn exacerbates cellular lipid retention, reprograming and inflammation. Biological sciences/Neuroscience/Neuroimmunology Biological sciences/Neuroscience/Diseases of the nervous system Biological sciences/Biochemistry/Lipidomics Biological sciences/Molecular biology/Transcriptomics Biological sciences/Cell biology/Autophagy/Macroautophagy Full Text Additional Declarations There is NO Competing Interest. Supplementary Files MehrabaniTableS2.xlsx Table S2 MehrabaniTableS4.xlsx Table S4 MehrabaniTableS1.xlsx Table S1 MehrabaniMaterialsandMethods.pdf Materials & Methods MehrabaniTableS3.xlsx Table S3 MehrabaniTableS6.xlsx Table S6 MehrabaniTableS5.xlsx Table S5 MehrabaniTableS7.xlsx Table S7 NNA92663AMehrabaniSuppFiguresS1S6.pdf Supplementary Figures 1-6 Cite Share Download PDF Status: Under Review 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. 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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-7682363","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Article","associatedPublications":[],"authors":[{"id":529613383,"identity":"c2b2072d-8400-4901-9b1c-39eb3118768e","order_by":0,"name":"Marta Lipinski","email":"data:image/png;base64,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","orcid":"https://orcid.org/0000-0002-7537-9014","institution":"University of Maryland, School of Medicine, Baltimore, MD","correspondingAuthor":true,"prefix":"","firstName":"Marta","middleName":"","lastName":"Lipinski","suffix":""},{"id":529613384,"identity":"68bff2ad-93af-4905-993d-ae272aaacfe0","order_by":1,"name":"Amir Mehrabani-Tabari","email":"","orcid":"","institution":"University of Maryland, School of Medicine, Baltimore, MD","correspondingAuthor":false,"prefix":"","firstName":"Amir","middleName":"","lastName":"Mehrabani-Tabari","suffix":""},{"id":529613385,"identity":"f484e517-df09-4888-b49c-6ae6b227e4de","order_by":2,"name":"Nivedita Hegdekar","email":"","orcid":"","institution":"University of Maryland, School of Medicine, Baltimore, MD","correspondingAuthor":false,"prefix":"","firstName":"Nivedita","middleName":"","lastName":"Hegdekar","suffix":""},{"id":529613386,"identity":"9473f75e-fd9a-4bba-b427-5f486034ff2e","order_by":3,"name":"Brian R. 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Recent data demonstrate a complex crosstalk between lipid metabolism and inflammation, suggesting potential contribution of the lipid-rich brain environment to neuroinflammation. While recent data support the importance of brain lipid environment to inflammatory changes observed in age related chronic neurodegenerative diseases, in vivo interactions between lipid environment, lipid metabolism and neuroinflammation in acute brain disease and injury remain poorly understood. Here we utilize a mouse model of traumatic brain injury (TBI) to demonstrate that acute neurotrauma leads to widespread lipid metabolism reprograming in all microglial and brain associated and infiltrating monocyte populations. Additionally, we identify unique microglial and monocyte populations with higher degree of lipid metabolism reprograming and pronounced accumulation of neutral storage lipids, including cholesteryl esters and triglycerides. These lipids accumulate not only in lipid droplets but also in the microglial and monocyte lysosomes and are associated with lysosomal dysfunction and inhibition of autophagy after TBI. Our data indicate that lipid accumulation in these cells is the result of altered lipid handling rather than lipid synthesis and is triggered by phagocytosis of lipid-rich myelin debris generated after TBI. Finally, we use mice with autophagy defects in microglia and monocytes to demonstrate that further inhibition of autophagy leads to more pronounced lipid metabolism reprograming and exacerbated cellular lipid accumulation. Our data suggest a pathological feedback loop, where lipid phagocytosis causes inhibition of autophagy-lysosomal function, which in turn exacerbates cellular lipid retention, reprograming and inflammation.","manuscriptTitle":"Inhibition of autophagy-lysosomal function exacerbates microglial and monocyte lipid metabolism reprograming and dysfunction after brain injury","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-10-21 02:52:57","doi":"10.21203/rs.3.rs-7682363/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-communications","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"NCOMMS","sideBox":"Learn more about [Nature Communications](http://www.nature.com/ncomms/)","snPcode":"","submissionUrl":"https://mts-ncomms.nature.com/","title":"Nature Communications","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Communications","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"b12b23a3-2c52-40dc-8a4b-505d7ab287cf","owner":[],"postedDate":"October 21st, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":56294418,"name":"Biological sciences/Neuroscience/Neuroimmunology"},{"id":56294419,"name":"Biological sciences/Neuroscience/Diseases of the nervous system"},{"id":56294420,"name":"Biological sciences/Biochemistry/Lipidomics"},{"id":56294421,"name":"Biological sciences/Molecular biology/Transcriptomics"},{"id":56294422,"name":"Biological sciences/Cell biology/Autophagy/Macroautophagy"}],"tags":[],"updatedAt":"2025-10-21T02:52:57+00:00","versionOfRecord":[],"versionCreatedAt":"2025-10-21 02:52:57","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7682363","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7682363","identity":"rs-7682363","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}