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

Toth, K.; Lenart, N.; Szabadits, E.; Posfai, B.; Fekete, R.; Cserep, C.; Alatshan, A.; Benkö, S.; Hübner, C. A.; Kaila, K.; Környei, Z.; Denes, A.

doi:10.1101/2021.01.21.427597

bioRxiv · 10.1101/2021.01.21.427597

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

Toth, K.·Lenart, N.·Szabadits, E.·Posfai, B.·Fekete, R.·Cserep, C.·Alatshan, A.·Benkö, S.·Hübner, C. A.·Kaila, K.·Környei, Z.·Denes, A.

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Abstract

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.

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Toth, K., Lenart, N., Szabadits, E., Posfai, B., Fekete, R., Cserep, C., Alatshan, A., Benkö, S., Hübner, C. A., Kaila, K., Környei, Z., Denes, A.. 2021-01-21. Microglial NKCC1 shapes microglial phenotype, cerebral inflammatory responses and brain injury. https://doi.org/10.1101/2021.01.21.427597

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