# Microglia in White Matter Repair after TBI

> **NIH VA I01** · VETERANS HEALTH ADMINISTRATION · 2022 · —

## Abstract

Traumatic brain injury (TBI) affects more than 2.5 million (US civilian and veterans) annually and accounts for
30% of all injury-related fatalities. TBI patients often develop long-lasting traumatic axonal injury, loss of myelin
sheath, and inhibition of oligodendrocyte maturation, which contribute to motor, cognitive, behavioral, and
psychiatric deficits. However, the underlying mechanisms of TBI-induced white matter injury and impairment of
axonal remyelination remain poorly understood. Microglia activation plays a role in white matter injury and tissue
repair. Regulation of a switch between pro-inflammatory and adaptive phenotypes of microglia/macrophage is
important for oligodendrocyte differentiation, remyelination, as well as remodeling of synapses. We recently
discovered that Na/H exchanger isoform 1 (NHE1) protein-mediated H+ efflux maintains microglial intracellular
pH (pHi) homeostasis to promote NADPH oxidase-mediated free radical superoxide production and cytokine
secretion. We reported that selective deletion of microglial Nhe1 in the Cx3cr1-CreER;Nheflox/flox (Nhe1 KO) mice
preserved oligodendrocytes and improved sensorimotor function recovery in an experimental focal ischemic
stroke model, which may result from microglia-oligodendrocyte interactions and microglia-mediated synapse
plasticity. Our pilot study using a controlled cortical impact (CCI)-induced TBI model also reveals that Nhe1 KO
mice exhibited decreased pro-inflammatory responses and increased APC+ mature oligodendrocyte counts after
TBI. Especially, post-TBI administration of the NHE1 protein inhibitor HOE642 accelerated neurological function
recovery in mice after either stroke or TBI. These studies identified NHE1 protein as a potential therapeutic
target for modulating microglia-mediated inflammation in remyelination and tissue repair after TBI. In this
proposal, we will test a central hypothesis that: 1) activation of microglial NHE1 protein stimulates
proinflammatory responses and subsequently contributes to oligodendrocyte death and demyelination; 2)
selective deletion of microglial NHE1 protein promotes proliferation, differentiation, and survival of
oligodendrocytes; 3) inhibition of NHE1 protein activity also stimulates microglial phagocytic function for
clearance of myelin debris, which facilitates neuronal synapse pruning and remodeling after TBI. Completion of
this project will enable us to gain new knowledge about the roles of microglia-oligodendrocyte interactions in white
matter injury and tissue repair after TBI. The combined approaches with the microglial Cre-LoxP mouse line and
post-TBI pharmacological inhibition of NHE1 function will reveal therapeutic potentials of targeting NHE1 protein
for reducing white matter injury and improving tissue repair after TBI.

## Key facts

- **NIH application ID:** 10436769
- **Project number:** 5I01BX004625-03
- **Recipient organization:** VETERANS HEALTH ADMINISTRATION
- **Principal Investigator:** Dandan Sun
- **Activity code:** I01 (R01, R21, SBIR, etc.)
- **Funding institute:** VA
- **Fiscal year:** 2022
- **Award amount:** —
- **Award type:** 5
- **Project period:** 2020-01-01 → 2023-12-31

## Primary source

NIH RePORTER: https://reporter.nih.gov/project-details/10436769

## Citation

> US National Institutes of Health, RePORTER application 10436769, Microglia in White Matter Repair after TBI (5I01BX004625-03). Retrieved via AI Analytics 2026-05-22 from https://api.ai-analytics.org/grant/nih/10436769. Licensed CC0.

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