Microglia dysfunction, neurovascular inflammation and focal neuropathologies are linked to IL-1- and IL-6-related (...), 2025, Fekete et al

Wyva · Mar 6, 2025

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

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

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.

Open access: https://www.nature.com/articles/s41593-025-01871-z

Wyva · Mar 6, 2025

This is a Hungarian study where Ádám Dénes was the senior author. I already mentioned him a couple of times on the forum, as he sometimes talks about long covid in the media (but never about ME/CFS).

Here is the accompanying press release from the website of the Hungarian Research Network (translated by ChatGPT):

Inflammation May Play a Role in the Development of Neurological Disorders Due to COVID-19

COVID-19 has affected hundreds of millions of people worldwide and often causes long-term neurological symptoms, the causes of which remain unknown. Researchers at the HUN-REN Institute of Experimental Medicine (HUN-REN KOKI) have uncovered the role of microglial cells—the main regulators of brain inflammation—in the development of COVID-19-related brain damage. Their findings, which have significant clinical implications, were published in *Nature Neuroscience*, one of the leading journals in neuroscience.

COVID-19 has been linked to various neurological symptoms, such as loss of taste and smell, dizziness, headaches, confusion, memory disorders, chronic fatigue, and autonomic nervous system dysfunctions, all of which significantly impair patients' quality of life. Clinical imaging studies have shown that brain abnormalities can develop even in the acute phase of the disease, while in post-COVID cases, reductions in cortical thickness and disturbances in brain circulation can persist for months. However, the exact causes of these neurological changes remain unknown.

The Neuroimmunology research group at HUN-REN KOKI, led by Ádám Dénes, aimed to understand the role of brain immune cells—microglia—in the inflammation and neurological symptoms caused by SARS-CoV-2 infection. To achieve this, they developed a novel method that allowed for detailed histological and molecular biological analysis of brain tissue and peripheral organ samples from patients who died as a result of COVID-19.

One of the main findings of the research was that dysfunction of microglial cells and inflammatory processes around brain blood vessels were closely linked to the severity of neural damage in the brain regions affected by COVID-19. The researchers demonstrated that the amount of P2Y12R receptors, which play a key role in microglia communication with neurons and brain blood vessels, was significantly reduced in brain areas where both viral proteins and vascular inflammation were present.

They also found that microglial dysfunction was associated with damage to mitochondria, the organelles responsible for cellular energy production. The most severe microglial damage was observed in brain regions where, in parallel with vascular inflammation, significant damage also occurred in synapses and the myelin sheath—both essential for neuronal communication. The identified neurological abnormalities varied greatly among different patients, affecting different brain regions to varying degrees. The most affected areas were the brainstem, which houses the main respiratory and circulatory centers, as well as the cerebral cortex, hypothalamus, and thalamus. Damage to these regions could be linked to the hormonal, autonomic nervous system, memory, and sleep disorders associated with COVID-19.

Furthermore, HUN-REN KOKI researchers observed that SARS-CoV-2 viral proteins were present in the cells lining blood vessel walls and in circulating immune cells, which accumulated in inflamed brain regions. In these areas, not only was microglial dysfunction detected, but also damage to the blood-brain barrier, which normally separates circulating blood from brain tissue.

The researchers were surprised to find that elevated levels of inflammatory proteins in circulation and peripheral organs were closely correlated with inflammation in brain tissue and the amount of viral genetic material (viral RNA) in individual patients. They also identified the response of inflammasomes—immune complexes that regulate inflammation and recognize viral proteins and RNA—in brain tissue, the lungs, liver, and spleen. However, they found no substantial evidence that neurons themselves were widely infected. This suggests that COVID-19 does not spread as a typical neurological infection but instead induces neurological abnormalities primarily through vascular inflammation and metabolic dysfunction and damage in brain glial cells.

"The observed inflammatory processes may contribute to the development of neurological symptoms seen both during acute SARS-CoV-2 infection and in post-COVID syndrome, such as memory impairments, difficulty concentrating, chronic fatigue, and depression, which affect many people," said Ádám Dénes, the lead researcher. He added that further studies are needed to determine the extent to which the identified brain inflammatory changes contribute to long-term cognitive and neurological disorders and how targeting these processes could help develop more effective therapeutic approaches to alleviate COVID-19-related neurological symptoms.
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Microglia dysfunction, neurovascular inflammation and focal neuropathologies are linked to IL-1- and IL-6-related (...), 2025, Fekete et al

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