The cytokine temporal profile in rat cortex after controlled cortical impact

Abstract

Cerebral inflammatory responses may initiate secondary cascades following traumatic brain injury (TBI). Changes in the expression of both cytokines and chemokines may activate, regulate, and recruit innate and adaptive immune cells associated with secondary degeneration, as well as alter a host of other cellular processes. In this study, we quantified the temporal expression of a large set of inflammatory mediators in rat cortical tissue after brain injury. Following a controlled cortical impact (CCI) on young adult male rats, cortical and hippocampal tissue of the injured hemisphere and matching contralateral material was harvested at early (4, 12, and 24 hours) and extended (3 and 7 days) time points post-procedure. Naïve rats that received only anesthesia were used as controls. Processed brain homogenates were assayed for chemokine and cytokine levels utilizing an electrochemiluminescence-based multiplex ELISA platform. The temporal profile of cortical tissue samples revealed a multi-phasic injury response following brain injury. CXCL1, IFN-γ, TNF-α levels significantly peaked at four hours post-injury compared to levels found in naïve or contralateral tissue. CXCL1, IFN-γ, and TNF-α levels were then observed to decrease at least 3-fold by 12 hours post-injury. IL-1β, IL-4, and IL-13 levels were also significantly elevated at four hours post-injury although their expression did not decrease more than 3-fold for up to 24 hours post-injury. Additionally, IL-1β and IL-4 levels displayed a biphasic temporal profile in response to injury, which may suggest their involvement in adaptive immune responses. Interestingly, peak levels of CCL2 and CCL20 were not observed until after four hours post-injury. CCL2 levels in injured cortical tissue were significantly higher than peak levels of any other inflammatory mediator measured, thus suggesting a possible use as a biomarker. Fully elucidating chemokine and cytokine signaling properties after brain injury may provide increased insight into a number of secondary cascade events that are initiated or regulated by inflammatory responses.

Chemokines in CNS injury and repair

“…In head trauma and in cortical stab wound injury, CCL2, produced by activated astrocytes (Glabinski et al 1996), macrophages and endothelial cells (Berman et al 1996), is the most strongly transcribed chemokine in the brain (Stefini et al 2008) and is also found in extracellular fluid (Helmy et al 2011). The protein, which is expressed at a high basal level, is further elevated ∼90-fold (to 1333 pg/mg) following TBI (Dalgard et al 2012). However, when only fold changes are considered, then the ∼236-fold induction of CXCL1 (to 170 pg/mg) is even stronger.…”

Beneficial Effect of Erythropoietin Short Peptide on Acute Traumatic Brain Injury

“…Interestingly, on day 2, the composite SNAP scores of the JM4-and PBS-treated groups fell dramatically, only to increase again on day 3. TBI has been associated with delayed activation of CCL2 and CCL20, as well as secondary delayed activation of interleukin (IL)-1β and IL-4 in a rat CCI model, suggesting a temporal relationship between the cytokine profile, their targeted cellular infiltrates, and observed clinical deficits [28]. Exploration of EPO as an immunomodulatory agent has revealed that EPO reduces levels of the proinflammatory cytokines tumor necrosis factor (TNF)-α, IL-1β, interferon (IFN)-γ, IL-6, and intracellular adhesion molecule 1 following EPO treatment in TBI and EAE [29][30][31].…”

“…In this study we designed a novel small, cyclical, EPOderived peptide based on a nonhematopoietic domain within the early sequence [amino acids (AA) [28][29][30][31][32][33][34][35][36][37][38][39][40][41][42][43][44][45][46] of the fulllength EPO molecule that we have named JM4. We evaluated its neuroprotective capabilities on a controlled cortical impact (CCI) model of TBI in mice.…”

In Vivo Microdialysis Sampling of Cytokines from Rat Hippocampus: Comparison of Cannula Implantation Procedures

“…45 CXCL1 protein has been quantified from tissue samples from rat brain after a TBI. 46 In this study, CXCL1, was detected in nearly all dialysates which would be expected given the mechanical injury induced by the implantation of the microdialysis probe. This mechanical injury could cause release from the different cells that release CXCL1.…”