Early inflammatory mediator gene expression in two models of traumatic brain injury: ex vivo cortical slice in mice and in vivo cortical impact in piglets

Abstract

BackgroundThe immunological response during the first 24 hours after traumatic brain injury (TBI) may be a critical therapeutic interval for limiting the secondary neuronal damage that is influenced by enhanced inflammatory mediator expression.MethodsTo gain further insight of the early injury response, we examined the expression of several inflammatory genes by real-time qPCR as a function of time or distance from injury in two distinct mammalian models: an ex vivo mouse cortical slice injury system and an in vivo piglet model of brain injury.ResultsInterleukin-1β (IL-1β), tumor necrosis factor-α (TNF-α), chemokine ligands 2 (CCL2), 3 (CCL3), 4 (CCL4), and prostaglandin-endoperoxide synthase 2 (PTGS2) mRNAs increased within 5 h after injury in mouse cortical slices. Chemokine and PTGS2 mRNAs remained elevated in slices at 24 h, whereas IL-1β and TNF-α expressions decreased from earlier peak levels. At 24 h after cortical injury in 1-month-old piglets, the expression of CCL2 mRNA was significantly increased in the lesion core and in the penumbra region. The expression of PTGS2, IL-1β, and TNF-α was variable among the piglets.ConclusionsThese in vitro and large animal models of cortical injury expand our understanding of the early timing and spread of the immunological response and can serve as preclinical systems to facilitate the discovery of therapeutic agents for TBI aimed at regulating inflammatory mediator expression.

Microglial cell‐derived interleukin‐6 influences behavior and inflammatory response in the brain following traumatic brain injury

“…TBI is a major health problem with high rates of mortality and morbidity worldwide (Dewan et al, ). It involves dynamic processes in which the inflammatory brain response is coordinated by several cells, such as astrocytes, phagocytic cells and microglia, and different cytokines, with IL‐6 being an important mediator of the inflammatory cascade (Chhor et al, ; Frugier et al, ; Graber, Costine, & Hickey, ; A. Kumar, Alvarez‐Croda, Stoica, Faden, & Loane, ; Lenzlinger, Morganti‐Kossmann, Laurer, & Mclntosh, ; Penkowa et al, ; Penkowa, Moos, et al, ). Since microglia are one of the major sources and targets of IL‐6, we have examined the role of microglia‐derived IL‐6 by analyzing the transcriptome of the brain cortex following a cryolesion (Figures and ).…”

“…Regarding body weight, no significant differences were observed between 5-10-week-old Il6 lox/lox and Il6 ΔMic male and female mice either 1-2 (Figure 3b 3.3 | Microglial Il6 deficiency impairs the transcriptome elicited by a cryolesion of the cortex TBI is a major health problem with high rates of mortality and morbidity worldwide (Dewan et al, 2018). It involves dynamic processes in which the inflammatory brain response is coordinated by several cells, such as astrocytes, phagocytic cells and microglia, and different cytokines, with IL-6 being an important mediator of the inflammatory cascade (Chhor et al, 2017;Frugier et al, 2010;Graber, Costine, & Hickey, 2015;A. Kumar, Alvarez-Croda, Stoica, Faden, & Loane, 2015;Lenzlinger, Morganti-Kossmann, Laurer, & Mclntosh, 2001;Penkowa et al, 2003;.…”

MUC1‐ and Survivin‐based DNA Vaccine Combining Immunoadjuvants CpG and interleukin‐2 in a Bicistronic Expression Plasmid Generates Specific Immune Responses and Antitumour Effects in a Murine Colorectal Carcinoma Model

“…The detected transcripts encoded chemokines ( CCL‐3, CCL‐4, CCL‐5, CCL‐19, CCL‐20 and CCL‐21 ), cytokines ( IL‐2, IFN‐γ, TNF‐α and GM‐CSF ) and immune modulating factors in the tumour microenvironment (VEG‐F, SDF‐1, FAP, MMP‐9, IL‐10 and PDL‐1) . Primers and other details have been described in previously published reports by our group and others . qRT‐PCR data were analysed using the comparative Ct method, and expression levels of target genes were normalized to β‐actin levels in each tissue sample.…”

Neuroimmunology of Traumatic Brain Injury: Time for a Paradigm Shift

“…Inflammatory profiles that are initially neuroprotective may change over time to become maladaptive (or, vice versa) in some models, but not others. Recent studies indicate that inflammatory gene expression does indeed change over time, and differences have been noted between the site of injury and distal brain regions (Almeida-Suhett et al, 2014; Graber et al, 2015; Lagraoui et al, 2012). There is evidence supporting that a unilateral brain injury resulting in deformation of the cortex can cause inflammation in ipsilateral and contralateral hippocampus (Almeida-Suhett et al, 2014).…”