10.60507/FK2/M42B8OMakdissi, NikolaNikolaMakdissiUniversity of BonnViola, Maria FrancescaMaria FrancescaViolaUniversity of BonnMass, ElviraElviraMassUniversity of Bonnbonndata2026Medicine, Health and Life SciencesMass, ElviraElviraMassUniversity of BonnDagmar WachtenDagmarWachtenVirginia AliprandiVirginiaAliprandiMarina MayerMarinaMayerKatharina SieckmannKatharinaSieckmannNele KronauNeleKronau2025-12-202026-01-2110.21203/rs.3.rs-6204281/v111900670912127049833601111235105576895407451703346398455043719283645656872184738920375852application/zipapplication/zipapplication/zipapplication/zipapplication/zipapplication/zipapplication/ziptext/plainapplication/zip1.0CC BY 4.0Plastic 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)851257EMBO fellowshipATLF 873-2023DFGGRK1873/2