2025
Nature Neuroscience

Microglia dysfunction, neurovascular inflammation and focal neuropathologies are linked to IL-1- and IL-6-related systemic inflammation in COVID-19

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

Keywords:

Diseases of the nervous system; Neuroimmunology; COVID-19; SARS-CoV-2; microglia; P2Y12R; CX3CR1–CX3CL1 axis; mitochondrial injury; phagocytosis; glutamatergic terminals; interleukin; IL-1; IL-6; pattern recognition receptors; inflammasomes; gliovascular failure; neuropathologies

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.