Size-dependent plastic exposure disrupts macrophage function and tissue-specific metabolism

Size-dependent plastic exposure disrupts macrophage function and tissue-specific metabolism | 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 Biological Sciences - Article Size-dependent plastic exposure disrupts macrophage function and tissue-specific metabolism Nikola Makdissi, Maria Francesca Viola, Lisa Steinheuer, Nelli Blank-Stein, and 21 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-6204281/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 Plastic pollution is an emerging yet understudied environmental risk to the immune system. Once ingested, nano- and microplastic particles (MNPs) can translocate from the gut to internal organs, with macrophages serving as primary targets. Kupffer cells (KCs), the liver-resident macrophages, play a central role in immune surveillance and metabolism, yet their response to MNPs remains unclear. Here, using a chronic plastic exposure model in mice, we identify KCs as the primary hepatic reservoir for MNPs. Long-term exposure alters their transcriptional profile and impairs phagocytic function, leading to metabolic dysregulation of hepatocytes. Microplastics, but not nanoplastics, reduce KC-mediated clearance of circulating cells and bacteria. Under diet-induced obesity, microplastics exacerbates hepatic lipid accumulation, while nanoplastics impair systemic glucose metabolism. Although the blood-brain barrier limits microplastic infiltration, a small fraction of ingested nanoplastics reaches the brain, where it is taken up by microglia, the brain-resident macrophages. However, we observe no signs of neuroinflammation or behavioral deficits. These findings demonstrate that chronic MNP exposure disrupts macrophage function in a size-dependent manner, with distinct consequences for liver and systemic metabolism, while the brain remains largely protected. Understanding tissue-specific vulnerabilities to MNPs is crucial for assessing their long-term health impact. Biological sciences/Immunology/Innate immune cells/Monocytes and macrophages/Kupffer cells Health sciences/Diseases/Metabolic disorders Full Text Additional Declarations There is NO Competing Interest. Tables are available in the Supplementary Files section. Supplementary Files Table1DEGsclustersSpatialTranscriptomics.xlsx Table 1: Differentially expressed genes throughout clusters identified in Xenium-based spatial transcriptomics Table2DEGsMicrogliainscRNAseq.xlsx Table 2: Differentially expressed genes in microglia following chronic plastic feeding Table3DEGsandORAofHepatocytesfromsnRNAseq.xlsx Table 3: Differentially expressed genes in hepatocytes following chronic plastic feeding Table4DEGsandORAofKCsfromsnRNAseq.xlsx Table 4: Differentially expressed genes in KCs following chronic plastic feeding Table5Antibodies.xlsx Table 5: Antibodies Table6PrimerSequences.xlsx Table 6: Primer Sequences 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. 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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-6204281","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Biological Sciences - Article","associatedPublications":[],"authors":[{"id":428335187,"identity":"6a6784cf-e084-47d8-a291-a9c532c9d570","order_by":0,"name":"Nikola Makdissi","email":"","orcid":"https://orcid.org/0000-0002-9345-038X","institution":"University of Bonn","correspondingAuthor":false,"prefix":"","firstName":"Nikola","middleName":"","lastName":"Makdissi","suffix":""},{"id":428335188,"identity":"b988f1ec-945d-4f6e-a44f-cb39687e6621","order_by":1,"name":"Maria Francesca 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metabolism","fulltext":[],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":false,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":false,"isAuthorSuppliedPdf":true,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":true,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"nature-portfolio","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"","title":"Nature Portfolio","twitterHandle":"","acdcEnabled":false,"dfaEnabled":false,"editorialSystem":"ejp","reportingPortfolio":"","inReviewEnabled":true,"inReviewRevisionsEnabled":false},"keywords":"","lastPublishedDoi":"10.21203/rs.3.rs-6204281/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-6204281/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"Plastic pollution is an emerging yet understudied environmental risk to the immune system. Once ingested, nano- and microplastic particles (MNPs) can translocate from the gut to internal organs, with macrophages serving as primary targets. Kupffer cells (KCs), the liver-resident macrophages, play a central role in immune surveillance and metabolism, yet their response to MNPs remains unclear. Here, using a chronic plastic exposure model in mice, we identify KCs as the primary hepatic reservoir for MNPs. Long-term exposure alters their transcriptional profile and impairs phagocytic function, leading to metabolic dysregulation of hepatocytes. Microplastics, but not nanoplastics, reduce KC-mediated clearance of circulating cells and bacteria. Under diet-induced obesity, microplastics exacerbates hepatic lipid accumulation, while nanoplastics impair systemic glucose metabolism. Although the blood-brain barrier limits microplastic infiltration, a small fraction of ingested nanoplastics reaches the brain, where it is taken up by microglia, the brain-resident macrophages. However, we observe no signs of neuroinflammation or behavioral deficits. These findings demonstrate that chronic MNP exposure disrupts macrophage function in a size-dependent manner, with distinct consequences for liver and systemic metabolism, while the brain remains largely protected. Understanding tissue-specific vulnerabilities to MNPs is crucial for assessing their long-term health impact.","manuscriptTitle":"Size-dependent plastic exposure disrupts macrophage function and tissue-specific metabolism","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-03-18 11:06:51","doi":"10.21203/rs.3.rs-6204281/v1","editorialEvents":[],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"nature-metabolism","isNatureJournal":true,"hasQc":false,"allowDirectSubmit":false,"externalIdentity":"natmetab","sideBox":"Learn more about [Nature Metabolism](http://www.nature.com/natmetab/)","snPcode":"","submissionUrl":"","title":"Nature Metabolism","twitterHandle":"","acdcEnabled":true,"dfaEnabled":true,"editorialSystem":"ejp","reportingPortfolio":"Nature Research","inReviewEnabled":true,"inReviewRevisionsEnabled":false}}],"origin":"","ownerIdentity":"3903bf8d-f6db-444f-8568-bbb8a758eef8","owner":[],"postedDate":"March 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"under-review","subjectAreas":[{"id":45635355,"name":"Biological sciences/Immunology/Innate immune cells/Monocytes and macrophages/Kupffer cells"},{"id":45635356,"name":"Health sciences/Diseases/Metabolic disorders"}],"tags":[],"updatedAt":"2026-05-05T09:26:42+00:00","versionOfRecord":[],"versionCreatedAt":"2025-03-18 11:06:51","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-6204281","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-6204281","identity":"rs-6204281","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}