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J Neurol Sci. 2015 Oct 15;357(1-2):41-9. doi: 10.1016/j.jns.2015.06.062. Epub 2015 Jun 30.

Temporal profile of M1 and M2 responses in the hippocampus following early 24h of neurotrauma.

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Sanders-Brown Center on Aging, University of Kentucky, Lexington, KY 40536, USA; Spinal Cord Brain Injury Research Center, University of Kentucky, Lexington, KY 40536, USA. Electronic address:


Traumatic brain injury (TBI) elicits complex inflammatory assets (M1 and M2 responses) in the brain that include the expression of various cytokines/chemokines and the recruitment of blood cells, contributing secondary injury cascades (SIC), and also recovery processes. The modulation of such inflammatory assets might be a therapeutic option following TBI. The present study assesses a temporal profile of various molecular markers of M1 and M2 response in the hippocampus after TBI. Following a unilateral controlled cortical impact (CCI) on young rats, hippocampal tissues of each brain were harvested at 2, 4, 6, 10, and 24h post trauma. Including shams (craniotomy only), half of the rats were assessed for gene expression and half for the protein of various markers for M1 [interferon-gamma (IFNγ), tumor necrosis factor-α (TNFα), interleukin (IL)-1-β (IL-1β), and IL-6] and M2 [IL-4, IL-10, IL-13, arginase 1 (Arg1), YM1, FIZZ1, and mannose receptor C-1 (MRC1)] responses. Analysis revealed that molecular markers of M1 and M2 responses have heterogeneous injury effects in the hippocampus and that "time-post-injury" is an important factor in determining inflammation status. With the heterogeneous gene expression of pro-inflammatory cytokines, M1 response was significantly elevated at 2h and declined at 24h after TBI, however, their levels remained higher than the sham rats. Except IFNγ, proteins of M1 cytokines were significantly elevated in the first 24h, and peaked between 2-6h [TNFα (2h), IL-1β (6h), and IL-6 (4-6h)]. With the heterogeneous relative gene expression of Arg1, YM1, FIZZ1, and MRC1, levels of M2 cytokines were peaked at 24h post TBI. IL-10 and IL-13 expression appeared biphasic in the first 24h. Protein values of IL-4 and IL-13 peaked at 24h and IL-10 at 6h post injury. Results suggest that the M1 response rises rapidly after injury and overpowers the initial, comparatively smaller, or transient M2 response. A treatment that can modulate inflammation, reduce SIC, and improve recovery should be initiated early (within 10h) after TBI.


M1 and M2 responses; Neuroinflammation; Neurotrauma; Pro- and anti-inflammatory cytokines; Secondary injury cascades; Traumatic brain injury

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