Early Microglial Activation Following Closed-Head Concussive Injury Is Dominated by Pro-Inflammatory M-1 Type

Abstract

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.

3,6’-dithiopomalidomide reduces neural loss, inflammation, behavioral deficits in brain injury and microglial activation

“…Iba1 is a pan-microglial marker whose expression increases with microglial activation ( Hopperton et al, 2018 ). TBI induced a change in microglial phenotype to an activated M1-like state ( Figure 9 ) in line with the literature ( Madathil et al, 2018 ), as well as an elevation in pro-inflammatory mRNA and protein expression (TNF-α, IL-1β, IL-6, Figure 10 ). These changes were largely mitigated by both DP and Pom, with the former consistently demonstrating greater potency.…”

Radiation Induced Metabolic Alterations Associate With Tumor Aggressiveness and Poor Outcome in Glioblastoma

“…A persistent activation of microglia is the hallmark of a chronic neuroinflamation. Microglial activation and its M1 polarization state is characteristically exhibited in traumatic brain injury; however, the extent to which M1 vs. M2 polarization states relate to radiation-induced changes in microglia remains unclear (8,32,102,103). Upon inflammatory trigger, microglial activation matures with sequential changes in its morphology, from resting ramified state to hyper-ramified, bushy and highly phagocytic ameboid state (101,104,105).…”

Serum Protein Biomarker Findings Reflective of Oxidative Stress and Vascular Abnormalities in Male, but Not Female, Collision Sport Athletes

“…VEGF-A has diverse biological functions including regulation of angiogenesis (i.e., the formation of new blood vessels), and elevated serum VEGF-A levels are indicative of endothelial stress and injury (17). Although some studies have reported increased VEGF-A levels in the blood following TBI, including mTBI (14,15,(18)(19)(20), to the best of our knowledge, no studies have investigated the potential associations with collision sport participation or HoC. We found that VEGF-A concentration was increased in male, but not female, footballers when compared to their relative control athletes, but that this increase did not appear to be related to HoC.…”