Related Experiment Video
Updated: Aug 26, 2025
Assessing Microglial Phagocytosis of Myelin Debris in vitro Under Repeated Magnetic Stimulation
Published on: June 17, 2025
Microglial-oligodendrocyte interactions in myelination and neurological function recovery after traumatic brain
Shanshan Song1,2,3, Md Nabiul Hasan1,2,3, Lauren Yu1,2
1Department of Neurology, University of Pittsburgh, 3501 Fifth Avenue, Pittsburgh, PA, 15213, USA.
Abstract:
Differential microglial inflammatory responses play a role in regulation of differentiation and maturation of oligodendrocytes (OLs) in brain white matter. How microglia-OL crosstalk is altered by traumatic brain injury (TBI) and its impact on axonal myelination and neurological function impairment remain poorly understood. In this study, we investigated roles of a Na+/H+ exchanger (NHE1), an essential microglial pH regulatory protein, in microglial proinflammatory activation and OL survival and differentiation in a murine TBI model induced by controlled cortical impact. Similar TBI-induced contusion volumes were detected in the Cx3cr1-CreERT2 control (Ctrl) mice and selective microglial Nhe1 knockout (Cx3cr1-CreERT2;Nhe1flox/flox, Nhe1 cKO) mice. Compared to the Ctrl mice, the Nhe1 cKO mice displayed increased resistance to initial TBI-induced white matter damage and accelerated chronic phase of OL regeneration at 30 days post-TBI. The cKO brains presented increased anti-inflammatory phenotypes of microglia and infiltrated myeloid cells, with reduced proinflammatory transcriptome profiles. Moreover, the cKO mice exhibited accelerated post-TBI sensorimotor and cognitive functional recovery than the Ctrl mice. These phenotypic outcomes in cKO mice were recapitulated in C57BL6J wild-type TBI mice receiving treatment of a potent NHE1 inhibitor HOE642 for 1-7 days post-TBI. Taken together, these findings collectively demonstrated that blocking NHE1 protein stimulates restorative microglial activation in oligodendrogenesis and neuroprotection, which contributes to accelerated brain repair and neurological function recovery after TBI.
Insights
Blocking the Na+/H+ exchanger (NHE1) in microglia promotes brain repair after traumatic brain injury (TBI). This reduces inflammation, aids oligodendrocyte regeneration, and accelerates functional recovery.
Area of Science:
- Neuroscience
- Immunology
- Cell Biology
Background:
- Microglial inflammatory responses influence oligodendrocyte (OL) differentiation and maturation in white matter.
- The impact of traumatic brain injury (TBI) on microglia-OL crosstalk, axonal myelination, and neurological function is not well understood.
- The Na+/H+ exchanger 1 (NHE1), a key microglial pH regulator, is implicated in TBI-induced inflammation and OL responses.
Purpose of the Study:
- To investigate the role of microglial NHE1 in TBI-induced inflammation and its effects on oligodendrocyte survival and differentiation.
- To evaluate the therapeutic potential of targeting NHE1 for TBI recovery.
Main Methods:
- Utilized a murine model of TBI induced by controlled cortical impact.
- Generated selective microglial Nhe1 knockout (Nhe1 cKO) mice (Cx3cr1-CreERT2;Nhe1flox/flox) and control littermates (Cx3cr1-CreERT2).
- Administered a potent NHE1 inhibitor (HOE642) to wild-type TBI mice.
- Assessed TBI-induced contusion volumes, white matter damage, oligodendrocyte regeneration, microglial phenotypes, and sensorimotor and cognitive functions.
Main Results:
- Nhe1 cKO mice showed reduced initial white matter damage and enhanced chronic phase of OL regeneration post-TBI compared to controls.
- Microglia and infiltrated myeloid cells in Nhe1 cKO brains exhibited anti-inflammatory phenotypes and reduced pro-inflammatory gene expression.
- Nhe1 cKO mice demonstrated accelerated sensorimotor and cognitive functional recovery after TBI.
- Pharmacological inhibition of NHE1 with HOE642 in wild-type TBI mice recapitulated the beneficial outcomes observed in Nhe1 cKO mice.
Conclusions:
- Blocking NHE1 in microglia promotes a shift towards restorative microglial activation, enhancing oligodendrogenesis and neuroprotection.
- Targeting NHE1 facilitates accelerated brain repair and neurological function recovery following TBI.
- NHE1 inhibition represents a promising therapeutic strategy for mitigating TBI-induced damage and promoting recovery.
Related Concept Videos
01:15Neurogenesis and Regeneration of Nervous Tissue
01:04Glial Cells