10.60507/FK2/M42B8O Makdissi, Nikola Nikola Makdissi University of Bonn Viola, Maria Francesca Maria Francesca Viola University of Bonn Mass, Elvira Elvira Mass University of Bonn bonndata 2026 Medicine, Health and Life Sciences Mass, Elvira Elvira Mass University of Bonn Dagmar Wachten Dagmar Wachten Virginia Aliprandi Virginia Aliprandi Marina Mayer Marina Mayer Katharina Sieckmann Katharina Sieckmann Nele Kronau Nele Kronau 2025-12-20 2026-01-21 10.21203/RS.3.RS-6204281/V1 10.60507/FK2/M42B8O/5DJAEA 10.60507/FK2/M42B8O/OMLEBQ 10.60507/FK2/M42B8O/UKXFQW 10.60507/FK2/M42B8O/CG66KZ 10.60507/FK2/M42B8O/KKIBS7 10.60507/FK2/M42B8O/WNQ4NA 10.60507/FK2/M42B8O/ETE7QS 10.60507/FK2/M42B8O/O1WAQJ 10.60507/FK2/M42B8O/1OYC9S 5504371928 3645656872 7689540745 17033463984 8920375852 11900670912 11112351055 12704983360 18473 application/zip application/zip application/zip application/zip application/zip application/zip application/zip application/zip text/plain 1.0 Creative Commons Attribution 4.0 International License. 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. European Research Council (ERC) 851257 EMBO fellowship ATLF 873-2023 DFG GRK1873/2