Microglia dysfunction, neurovascular inflammation and focal neuropathologies are linked to IL-1- and IL-6-related systemic inflammation in COVID-19
Year: 2025
Type: article
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. The authors show that brain inflammation in COVID-19 correlates with viral load, systemic inflammation and virus-sensing pattern recognition receptors. Microglial dysfunction occurs at sites of vascular inflammation with myelin injury and synapse loss.
Source: Nature Neuroscience
Authors: Rebeka Fekete, Alba Simats, Eduárd Bíró, Balázs Pósfai, Csaba Cserép, Anett D. Schwarcz, Eszter Szabadits, Zsuzsanna Környei, Krisztina Tóth, Erzsébet Fichó, János Szalma, Sára Vida, Anna Kellermayer, Csaba Dávid, László Acsády, Levente Kontra, Carlos Silvestre-Roig, Judit Moldvay, János Fillinger, Attila Csikász-Nagy, Tibor Hortobágyi, Arthur Liesz, Szilvia Benkő, Ádám Dénes
Institutions: HUN-REN Institute of Experimental Medicine, Institut für Schlaganfall- und Demenzforschung, Ludwig-Maximilians-Universität München, University of Debrecen, Semmelweis University, Pázmány Péter Catholic University, Hungarian Research Network, University of Münster, University of Szeged, Országos Korányi Tbc és Pulmonológiai Intézet, University Hospital Zurich, Munich Cluster for Systems Neurology, LMU Klinikum
Language: English
Subfield: Neurology
Field: Neuroscience
Domain: Life Sciences
Open Access status: hybrid
Estimated APC paid: $12,690
Funders: Deutsche Forschungsgemeinschaft, Gedeon Richter, Hungarian Scientific Research Fund, Magyar Tudományos Akadémia, Nemzeti Kutatási Fejlesztési és Innovációs Hivatal, Richter Gedeon Talentum Alapítvány, Innovációs és Technológiai Minisztérium, Nemzeti Kutatási, Fejlesztési és Innovaciós Alap, National Research, Development and Innovation Office, H2020 European Research Council
Awards: G1181525405, G1202780504, G1725887934, G1789099517, G1993314343, G2588154941, G2703170250, G2809197807, G2910790082, G3018177516, T cell-driven inflammatory mechanisms promote recovery after acute brain injury, G331281203, G3382091778, G3866822827, G3957005801, G408142515, G4281931129, G4352420037, G4423405455, G5073618569, G5993334427, G6063356598, G712622730, FOR 2879: ImmunoStroke: Von der Immunzelle zur Schlaganfallregeneration, G7220334851, G7702897597, G8035829606, TRR 274: Kontrollpunkte der ZNS Reparatur, G8328183531
OpenAlex ID: W4408201072