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Glia Maturation Factor (GMF) Regulates Microglial Expression Phenotypes and the Associated Neurological Deficits in a Mouse Model of Traumatic Brain Injury

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Abstract

Traumatic brain injury (TBI) induces inflammatory responses through microglial activation and polarization towards a more inflammatory state that contributes to the deleterious secondary brain injury. Glia maturation factor (GMF) is a pro-inflammatory protein that is responsible for neuroinflammation following insult to the brain, such as in TBI. We hypothesized that the absence of GMF in GMF-knockout (GMF-KO) mice would regulate microglial activation state and the M1/M2 phenotypes following TBI. We used the weight drop model of TBI in C57BL/6 mice wild-type (WT) and GMF-KO mice. Immunofluorescence staining, Western blot, and ELISA assays were performed to confirm TBI-induced histopathological and neuroinflammatory changes. Behavioral analysis was done to check motor coordination ability and cognitive function. We demonstrated that the deletion of GMF in GMF-KO mice significantly limited lesion volume, attenuated neuronal loss, inhibited gliosis, and activated microglia adopted predominantly anti-inflammatory (M2) phenotypes. Using an ELISA method, we found a gradual decrease in pro-inflammatory cytokines (TNF-α and IL-6) and upregulation of anti-inflammatory cytokines (IL-4 and IL-10) in GMF-KO mice compared with WT mice, thus, promoting the transition of microglia towards a more predominantly anti-inflammatory (M2) phenotype. GMF-KO mice showed significant improvement in motor ability, memory, and cognition. Overall, our results demonstrate that GMF deficiency regulates microglial polarization, which ameliorates neuronal injury and behavioral impairments following TBI in mice and concludes that GMF is a regulator of neuroinflammation and an ideal therapeutic target for the treatment of TBI.

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Acknowledgments

The US Government is authorized to reproduce and distribute reprints for Government purposes notwithstanding any copyright notation heron. The authors express their gratitude for the Acute Effects of Neurotrauma Consortium in assisting and coordinating the conduct of this project at Fort Leonard Wood. Dr. Zaheer (AZ) is the recipient of the VA Research Career Scientist Award.

Funding

The research was sponsored by the Leonard Wood Institute in cooperation with the US Army Research Laboratory and was accomplished under Cooperative Agreement Number W911NF-14-2-0034.

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Authors and Affiliations

  1. Department of Neurology, School of Medicine, University of Missouri, Columbia, Missouri 65211, USA

    Mohammad Ejaz Ahmed, Govindhasamy Pushpavathi Selvakumar, Duraisamy Kempuraj, Sudhanshu P. Raikwar, Ramasamy Thangavel, Kieran Bazley, Kristopher Wu, Osaid Khan, Asher Khan, Smita Zaheer, Shankar Iyer & Asgar Zaheer

  2. Center for Translational Neuroscience, School of Medicine, University of Missouri, Columbia, Missouri 65211, USA

    Mohammad Ejaz Ahmed, Govindhasamy Pushpavathi Selvakumar, Duraisamy Kempuraj, Sudhanshu P. Raikwar, Ramasamy Thangavel, Kieran Bazley, Kristopher Wu, Osaid Khan, Asher Khan, Smita Zaheer, Shankar Iyer & Asgar Zaheer

  3. Harry S. Truman Memorial Veterans Hospital, Columbia, Missouri 65211, USA

    Mohammad Ejaz Ahmed, Govindhasamy Pushpavathi Selvakumar, Duraisamy Kempuraj, Sudhanshu P. Raikwar, Ramasamy Thangavel, Shankar Iyer & Asgar Zaheer

  4. Phelps Health, Rolla, Missouri 65401, USA

    Casey Burton & Donald James

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Ahmed, M.E., Selvakumar, G.P., Kempuraj, D. et al. Glia Maturation Factor (GMF) Regulates Microglial Expression Phenotypes and the Associated Neurological Deficits in a Mouse Model of Traumatic Brain Injury. Mol Neurobiol 57, 4438–4450 (2020). https://doi.org/10.1007/s12035-020-02040-y

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