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Original Research ARTICLE Provisionally accepted The full-text will be published soon. Notify me

Front. Neurol. | doi: 10.3389/fneur.2018.00964

Early microglial activation following closed-head concussive injury is dominated by pro-inflammatory M-1 type

 Sindhu K. Madathil1*, Bernard S. Wilfred1, Sarah E. Urankar1, Weihong Yang1,  Lai Yee Leung1, Janice Gilsdorf1 and  Deborah Shear1
  • 1Walter Reed Army Institute of Research, United States

Microglial activation is a pathological hallmark of traumatic brain injury (TBI). Following brain injury, activated microglia/macrophages adopt different phenotypes, generally categorized as M-1, or classically activated, and M-2, or alternatively activated. While the M-1, or pro-inflammatory phenotype is detrimental to recovery, M-2, or the anti-inflammatory phenotype, aids in brain repair. Recent findings also suggest the existence of mixed phenotype following brain injury, where activated microglia simultaneously express both M-1 and M-2 markers. The present study sought to determine microglial activation states at early time points (6-72 h) following single or repeated concussive injury in rats. Closed-head concussive injury was modeled in rats using projectile concussive impact injury, with either single or repeated impacts (4 impacts, 1 h apart). Brain samples were examined using immunohistochemical staining, inflammatory gene profiling and real-time polymerase chain reaction analyses to detect concussive injury induced changes in microglial activation and phenotype in cortex and hippocampal regions. Our findings demonstrate robust microglial activation following concussive brain injury. Moreover, we show that multiple concussions induced a unique rod-shaped microglial morphology that was also observed in other diffuse brain injury models. Histological studies revealed a predominance of MHC-II positive M-1 phenotype in the post-concussive microglial milieu following multiple impacts. Although there was simultaneous expression of M-1 and M-2 markers, gene expression results indicate a clear dominance in M-1 pro-inflammatory markers following both single and repeated concussions. While the increase in M-1 markers quickly resolved after a single concussion, they persisted following repeated concussions, indicating a pro-inflammatory environment induced by multiple concussions that may delay recovery and contribute to long-lasting consequences of concussion.

Keywords: Microglia, Inflammation, polarization, concussion, Traumatic Brain Injury

Received: 20 Jul 2018; Accepted: 26 Oct 2018.

Edited by:

George E. Barreto, Pontificia Universidad Javeriana, Colombia

Reviewed by:

Eric P. Thelin, University of Cambridge, United Kingdom
Yumin Zhang, Uniformed Services University of the Health Sciences, United States  

Copyright: © 2018 Madathil, Wilfred, Urankar, Yang, Leung, Gilsdorf and Shear. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

* Correspondence: Dr. Sindhu K. Madathil, Walter Reed Army Institute of Research, Silver Spring, United States, ammukm@gmail.com