Biology subjects

Szabadits, E.

Publications and source records attributed to Szabadits, E..

3 recordsLinked to original sources

bioRxiv2023

Infection-induced vascular inflammation in COVID-19 links focal microglial dysfunction with neuropathologies through IL-1/IL-6-related systemic inflammatory states

COVID-19 is associated with diverse neurological abnormalities, which predict poor outcome in patients. However, the mechanisms whereby infection-induced inflammation could affect complex neuropathologies in COVID-19 are unclear. We hypothesized that microglia, the resident immune cells of brain, are centrally involved in this process. To study this, we developed an autopsy platform allowing the integration of molecular anatomy-, protein- and mRNA data sets in post-mortem mirror blocks of brain and peripheral organ samples from COVID-19 cases. Nanoscale microscopy, single-cell RNA sequencing and analysis of inflammatory and metabolic signatures revealed distinct mechanisms of microglial dysfunction associated with cerebral SARS-CoV-2 infection. We observed focal loss of microglial P2Y12R at sites of virus-associated vascular inflammation together with dysregulated microglia-vascular-astrocyte interactions, Cx3Cr1-fractalkine axis deficits and mitochondrial failure in severely affected medullary autonomic nuclei and other brain areas. Microglial dysfunction occurs at sites of excessive synapse- and myelin phagocytosis and loss of glutamatergic terminals. While central and systemic viral load is strongly linked in individual patients, the regionally heterogenous microglial reactivity in the brain correlated with the extent of central and systemic inflammation related to IL-1 / IL-6 via virus-sensing pattern recognition receptors (PRRs) and inflammasome activation pathways. Thus, SARS-CoV-2-induced central and systemic inflammation might lead to a primarily glio-vascular failure in the brain, which could be a common contributor to diverse COVID-19-related neuropathologies.

immunology↗

bioRxiv2022

Rapid microglial phenotype changes modulate neuronal networks and sharp wave-ripple activity in acute slice preparations

Acute brain slices represent a "workhorse" model for studying the central nervous system (CNS) from nanoscale events to complex circuits. While slice preparation inherently involves tissue injury, it is unclear how microglia, the main immune cells and damage sensors of the CNS shape tissue integrity ex vivo. To this end, we have studied the mechanisms of microglial phenotype changes and contribution to neuronal network organisation and functioning in acute brain slices. Using a novel ATP- reporter mouse line and microglia reporter mice, we show that acute slice preparation induces rapid, P2Y12 receptor (P2Y12R) dependent dislocation and migration of microglia, paralleled with marked morphological transformations driven by early ATP surges and subsequent ATP flashes. Gradual depolarization of microglia is associated with the downregulation of purinergic P2Y12R and time-dependent changes of microglia-neuron interactions, paralleled by altered numbers of excitatory and inhibitory synapses. Importantly, functional microglia not only modulate synapse sprouting, but the absence of microglia or microglial P2Y12R markedly diminishes the incidence, amplitude, and frequency of sharp wave-ripple activity in hippocampal slices. Collectively, our data suggest that microglia are inherent modulators of complex neuronal networks, and their specific actions are indispensable to maintain neuronal network integrity and activity ex vivo. These findings could facilitate new lines of research resulting in improved ex vivo methodologies and a better understanding of microglia-neuron interactions both in physiological and pathological conditions.

neuroscience↗

bioRxiv2021

Microglial NKCC1 shapes microglial phenotype, cerebral inflammatory responses and brain injury

The NKCC1 ion transporter contributes to the pathophysiology of common neurological disorders, but its function in microglia, the main inflammatory cells of the brain, has remained unclear to date. Therefore, we generated a novel transgenic mouse line in which microglial NKCC1 was deleted. We show that microglial NKCC1 shapes both baseline and reactive microglia morphology, process recruitment to the site of injury, and adaptation to osmotic stress in a cell-autonomous manner via regulating membrane potential and chloride fluxes. In addition, microglial NKCC1 deficiency results in increased expression of the D subunit of volume regulated anion channel (VRAC), NLRP3 inflammasome priming and production of interleukin-1{beta} (IL-1{beta}), rendering microglia prone to exaggerated inflammatory responses. In line with this, central (intracortical) administration of the NKCC1 blocker, bumetanide, potentiated intracortical lipopolysaccharide (LPS)-induced cytokine levels, whereas systemic bumetanide application decreased inflammation in the brain. Microglial NKCC1 KO animals exposed to experimental stroke showed significantly increased brain injury, inflammation, cerebral edema and worse neurological outcome. Thus, NKCC1 emerges as an important player in controlling microglial ion homeostasis and inflammatory responses through which microglia modulate brain injury. The contribution of microglia to central NKCC1 actions is likely to be relevant for common neurological disorders.

neuroscience↗