Hyperthermia and Mild Traumatic Brain Injury: Effects on Inflammation and the Cerebral Vasculature

Mild traumatic brain injury (mTBI) or concussion represents the majority of brain trauma in the United States. The pathophysiology of mTBI is complex and may include both focal and diffuse injury patterns. In addition to altered circuit dysfunction and traumatic axonal injury (TAI), chronic neuroinflammation has also been implicated in the pathophysiology of mTBI. Recently, our laboratory has reported the detrimental effects of mild hyperthermic mTBI in terms of worsening histopathological and behavioral outcomes. To clarify the role of temperature-sensitive neuroinflammatory processes on these consequences, we evaluated the effects of elevated brain temperature (39°C) on altered microglia/macrophage phenotype patterns after mTBI, changes in leukocyte recruitment, and TAI. Sprague-Dawley male rats underwent mild parasagittal fluid-percussion injury under normothermic (37°C) or hyperthermic (39°C) conditions. Cortical and hippocampal regions were analyzed using several cellular and molecular outcome measures. At 24 h, the ratio of iNOS-positive (M1 type phenotype) to arginase-positive (M2 type phenotype) cells after hyperthermic mTBI showed an increase compared with normothermia by flow cytometry. Inflammatory response gene arrays also demonstrated a significant increase in several classes of pro-inflammatory genes with hyperthermia treatment over normothermia. The injury-induced expression of chemokine ligand 2 (Ccl2) and alpha-2-macroglobulin were also increased with hyperthermic mTBI. With western blot analysis, an increase in CD18 and intercellular cell adhesion molecule-1 (ICAM-1) with hyperthermia and a significant increase in Iba1 reactive microglia are reported in the cerebral cortex. Together, these results demonstrate significant differences in the cellular and molecular consequences of raised brain temperature at the time of mTBI. The observed polarization toward a M1-phenotype with mild hyperthermia would be expected to augment chronic inflammatory cascades, sustained functional deficits, and increased vulnerability to secondary insults. Mild elevations in brain temperature may contribute to the more severe and longer lasting consequences of mTBI or concussion reported in some patients.