Fekete, Rebeka and Simats, Alba and Bíró, Eduárd and Pósfai, Balázs and Cserép, Csaba and Schwarcz, Dóra Anett and Cserépné Szabadits, Eszter and Környei, Zsuzsanna and Tóth, Krisztina and Fichó, Erzsébet and Szalma, János and Vida, Sára and Kellermayer, Anna and Dávid, Csaba and Acsády, László and Kontra, Levente and Silvestre-Roig, Carlos and Moldvay, Judit and Fillinger, János and Csikász-Nagy, Attila and Hortobágyi, Tibor and Liesz, Arthur and Benkő, Szilvia and Dénes, Ádám (2025) Microglia dysfunction, neurovascular inflammation and focal neuropathologies are linked to IL-1- and IL-6-related systemic inflammation in COVID-19. NATURE NEUROSCIENCE, 28 (3). pp. 558-576. ISSN 1097-6256
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Abstract
COVID-19 is associated with diverse neurological abnormalities, but the underlying mechanisms are unclear. We hypothesized that microglia, the resident immune cells of the brain, are centrally involved in this process. To study this, we developed an autopsy platform allowing the integration of molecular anatomy, protein and mRNA datasets in postmortem mirror blocks of brain and peripheral organ samples from cases of COVID-19. We observed focal loss of microglial P2Y12R, CX3CR1–CX3CL1 axis deficits and metabolic failure at sites of virus-associated vascular inflammation in severely affected medullary autonomic nuclei and other brain areas. Microglial dysfunction is linked to mitochondrial injury at sites of excessive synapse and myelin phagocytosis and loss of glutamatergic terminals, in line with proteomic changes of synapse assembly, metabolism and neuronal injury. Furthermore, regionally heterogeneous microglial changes are associated with viral load and central and systemic inflammation related to interleukin (IL)-1 or IL-6 via virus-sensing pattern recognition receptors and inflammasomes. Thus, SARS-CoV-2-induced inflammation might lead to a primarily gliovascular failure in the brain, which could be a common contributor to diverse COVID-19-related neuropathologies.
| Item Type: | Article |
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| Additional Information: | Momentum Laboratory of Neuroimmunology, HUN-REN Institute of Experimental Medicine, Budapest, Hungary Institute for Stroke and Dementia Research, LMU University Hospital, LMU Munich, Munich, Germany Laboratory of Inflammation-Physiology, Department of Physiology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary János Szentágothai Doctoral School of Neuroscience, Semmelweis University, Budapest, Hungary Cytocast Hungary Kft, Budapest, Hungary Pázmány Péter Catholic University, Faculty of Information Technology and Bionics, Budapest, Hungary Department of Anatomy, Histology and Embryology, Semmelweis University, Budapest, Hungary Lendület Laboratory of Thalamus Research, HUN-REN Institute of Experimental Medicine, Budapest, Hungary Bioinformatics Unit, HUN-REN Institute of Experimental Medicine, Budapest, Hungary Institute for Experimental Pathology (ExPat), Center for Molecular Biology of Inflammation, WWU Muenster, Muenster, Germany I. Department of Pulmonology, National Korányi Institute of Pulmonology, Budapest, Hungary Department of Pathology, National Korányi Institute of Pulmonology, Budapest, Hungary Institute of Pathology, Faculty of Medicine, University of Szeged, Szeged, Hungary Department of Neurology, Faculty of Medicine, University of Debrecen, Debrecen, Hungary Munich Cluster for Systems Neurology (SyNergy), Munich, Germany Mercator Fellow, Institute for Stroke and Dementia Research, LMU University Hospital, LMU Munich, Munich, Germany Institute of Neuropathology, Universitätsspital Zürich, Zurich, Switzerland Export Date: 12 June 2025; Cited By: 2; Correspondence Address: Á. Dénes; Momentum Laboratory of Neuroimmunology, HUN-REN Institute of Experimental Medicine, Budapest, Hungary; email: denes.adam@koki.hun-ren.hu; CODEN: NANEF |
| Uncontrolled Keywords: | neuroimmunology; Diseases of the nervous system; |
| Subjects: | R Medicine / orvostudomány > R1 Medicine (General) / orvostudomány általában |
| SWORD Depositor: | MTMT SWORD |
| Depositing User: | MTMT SWORD |
| Date Deposited: | 19 Sep 2025 11:45 |
| Last Modified: | 19 Sep 2025 11:45 |
| URI: | https://real.mtak.hu/id/eprint/224630 |
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