Microglial-oligodendrocyte interactions in myelination and neurological function recovery after traumatic brain injury

Shanshan Song; Md Nabiul Hasan; Lauren Yu; Satya S Paruchuri; John P Bielanin; Shamseldin Metwally; Helena C M Oft; Sydney G Fischer; Victoria M Fiesler; Tanusree Sen; Rajaneesh K Gupta; Lesley M Foley; T Kevin Hitchens; C Edward Dixon; Franca Cambi; Nilkantha Sen; Dandan Sun

doi:10.1186/s12974-022-02608-6

Microglial-oligodendrocyte interactions in myelination and neurological function recovery after traumatic brain injury

J Neuroinflammation. 2022 Oct 5;19(1):246. doi: 10.1186/s12974-022-02608-6.

Authors

Shanshan Song^#^{1

2

3}, Md Nabiul Hasan^#^{1

2

3}, Lauren Yu^{1

2}, Satya S Paruchuri^{1

2}, John P Bielanin^{1

2}, Shamseldin Metwally^{1

2}, Helena C M Oft^{1

2}, Sydney G Fischer^{1

2}, Victoria M Fiesler^{1

2

3}, Tanusree Sen⁴, Rajaneesh K Gupta⁴, Lesley M Foley⁵, T Kevin Hitchens^{5

6}, C Edward Dixon^{3

4}, Franca Cambi^{1

2

3}, Nilkantha Sen⁴, Dandan Sun^{7

8

9}

Affiliations

¹ Department of Neurology, University of Pittsburgh, 3501 Fifth Avenue, Pittsburgh, PA, 15213, USA.
² Pittsburgh Institute for Neurodegenerative Disorders, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
³ Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, 15213, USA.
⁴ Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
⁵ Animal Imaging Center, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
⁶ Department of Neurobiology, University of Pittsburgh, Pittsburgh, PA, 15213, USA.
⁷ Department of Neurology, University of Pittsburgh, 3501 Fifth Avenue, Pittsburgh, PA, 15213, USA. sund@upmc.edu.
⁸ Pittsburgh Institute for Neurodegenerative Disorders, University of Pittsburgh, Pittsburgh, PA, 15213, USA. sund@upmc.edu.
⁹ Veterans Affairs Pittsburgh Health Care System, Pittsburgh, PA, 15213, USA. sund@upmc.edu.

^# Contributed equally.

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-Cre^ERT2 control (Ctrl) mice and selective microglial Nhe1 knockout (Cx3cr1-Cre^ERT2;Nhe1^flox/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.

Keywords: Inflammation; Microglia; Na+/H+ exchanger; Oligodendrocytes; Traumatic brain injury; White matter damage.

MeSH terms

Animals
Brain Injuries, Traumatic* / metabolism
Disease Models, Animal
Mice
Mice, Inbred C57BL
Microglia / metabolism
Oligodendroglia
Recovery of Function
White Matter*

Abstract

MeSH terms

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