Traumatic brain injury induces long-lasting changes in immune and regenerative signaling (original) (raw)
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Journal of Neurotrauma, 2003
Much of the functional deficit derives from delayed cell death resulting from induction of neurotoxic factors that overwhelm endogenous neuroprotective responses. To identify the potential molecular mechanisms underlying such delayed responses, we compared gene expression patterns using high-density oligonucleotide arrays at 4, 8, 24, and 72 h after moderate levels of lateral fluid percussion-induced brain injury in rats and lateral controlled cortical impact injury in mice (a total of 47 profiles). Expression of 82 genes in 12 functional categories was significantly changed in both species after trauma. The largest number of gene expression changes were found in the functional groups related to inflammation (17%), transcription regulation (16%), and cell adhesion/extracellular matrix (15%). Fifty percent of genes similarly altered across models had not been previously implicated in traumatic brain injury. Of particular interest were expression changes in genes linked to neurodegeneration, such as ATF3 and lysosomal membrane glycoprotein 2, and to neuroprotection including lipocortin 1, calponin 3, gelsolin, Id-1, and p45 NF-E2. Gene expression profiling across species and models may help identify candidate molecular pathways induced by brain injury, some of which may provide novel targets for therapeutic intervention.
PLOS ONE
The cumulative effect of mild traumatic brain injuries (mTBI) can result in chronic neurological damage, however the molecular mechanisms underpinning this detriment require further investigation. A closed head weight drop model that replicates the biomechanics and head acceleration forces of human mTBI was used to provide an exploration of the acute and chronic outcomes following single and repeated impacts. Adult male C57BL/6J mice were randomly assigned into one of four impact groups (control; one, five and 15 impacts) which were delivered over 23 days. Outcomes were assessed 48 hours and 3 months following the final mTBI. Hippocampal spatial learning and memory assessment revealed impaired performance in the 15-impact group compared with control in the acute phase that persisted at chronic measurement. mRNA analyses were performed on brain tissue samples of the cortex and hippocampus using quantitative RT-PCR. Eight genes were assessed, namely MAPT, GFAP, AIF1, GRIA1, CCL11, TAR...
Journal of Neurotrauma, 2014
Mild traumatic brain injury (mTBI) often has long-term effects on cognitive function and social behavior. Altered gene expression may be predictive of long-term psychological effects of mTBI, even when acute clinical effects are minimal or transient. Controlled cortical impact (CCI), which causes concussive, but nonpenetrant, trauma to underlying (non-cortical) brain, resulting in persistent changes in hippocampal synaptic function, was used as a model of mTBI. The hippocampal transcriptomes of sham-operated or injured male rats at 1, 7, and 30 days postinjury were examined using microarrays comprising a comprehensive set of expressed genes, subsequently confirmed by quantitative reverse-transcriptase polymerase chain reaction. Transcripts encoding the chemokines, chemokine (C-C motif) ligand (Ccl)2 and Ccl7, inflammatory mediators lipocalin-2 (Lcn2) and tissue inhibitor of metalloproteinase 1 (Timp1), immunocyte activators CC chemokine receptor type 5 (Ccr5) and Fc fragment of IgG, low affinity IIb, receptor (CD32) (Fcgr2b), the major histocompatibility complex II immune response-related genes, Cd74 and RT1 class II, locus Da (RT1-Da), the complement component, C3, and the transcription factor, Kruppel-like factor 4 (Klf4), were identified as early (Ccl2, Ccl7, Lcn2, and Timp1), intermediate (Ccr5, Fcgr2b, Cd74, RT1-Da, and C3), and late (Klf4) markers for bilateral hippocampal response to CCI. Ccl2 and Ccl7 transcripts were up-regulated within 24 h after CCI, and their elevation subsided within 1 week of injury. Other transcriptional changes occurred later and were more stable, some persisting for at least 1 month, suggesting that short-term inflammatory responses trigger longer-term alteration in the expression of genes previously associated with injury, aging, and neuronal function in the brain. These transcriptional responses to mTBI may underlie long-term changes in excitatory and inhibitory neuronal imbalance in hippocampus, leading to long-term behavioral consequences of mTBI.
Neurotrauma reports, 2021
Traumatic brain injury (TBI) causes acute and lasting impacts on the brain, driving pathology along anatomical, cellular, and behavioral dimensions. Rodent models offer an opportunity to study the temporal progression of disease from injury to recovery. Transcriptomic and epigenomic analysis were applied to evaluate gene expression in ipsilateral hippocampus at 1 and 14 days after sham (n = 2 and 4, respectively per time point) and moderate lateral fluid percussion injury (n = 4 per time point). This enabled the identification of dynamic changes and differential gene expression (differentially expressed genes; DEGs) modules linked to underlying epigenetic response. We observed acute signatures associated with cell death, astrocytosis, and neurotransmission that largely recovered by 2 weeks. Inflammation and immune signatures segregated into upregulated modules with distinct expression trajectories and functions. Whereas most down-regulated genes recovered by 14 days, two modules with delayed and persistent changes were associated with cholesterol metabolism, amyloid beta clearance, and neurodegeneration. Differential expression was paralleled by changes in histone H3 lysine residue 4 trimethylation at the promoters of DEGs at 1 day post-TBI, with the strongest changes observed for inflammation and immune response genes. These results demonstrate how integrated genomics analysis in the pre-clinical setting has the potential to identify stage-specific biomarkers for injury and/or recovery. Though limited in scope here, our general strategy has the potential to capture pathological signatures over time and evaluate treatment efficacy at the systems level.
bioRxiv (Cold Spring Harbor Laboratory), 2021
Traumatic brain injury (TBI) causes acute and lasting impacts on the brain, driving pathology along anatomical, cellular, and behavioral dimensions. Rodent models offer the opportunity to study TBI in a controlled setting, and enable analysis of the temporal progression that occurs from injury to recovery. We applied transcriptomic and epigenomic analysis, characterize gene expression and in ipsilateral hippocampus at 1 and 14 days following moderate lateral fluid percussion (LFP) injury. This approach enabled us to identify differential gene expression (DEG) modules with distinct expression trajectories across the two time points. The major DEG modules represented genes that were up-or downregulated acutely, but largely recovered by 14 days. As expected, DEG modules with acute upregulation were associated with cell death and astrocytosis. Interestingly, acutely downregulated DEGs related to neurotransmission mostly recovered by two weeks. Upregulated DEG modules related to inflammation were not necessarily elevated acutely, but were strongly upregulated after two weeks. We identified a smaller DEG module with delayed downregulation at 14 days including genes related to cholesterol metabolism and amyloid beta clearance. Finally, differential expression was paralleled by changes in H3K4me3 at the promoters of differentially expressed genes at one day following TBI. Following TBI, changes in cell viability, function and ultimately behavior are dynamic processes. Our results show how transcriptomics in the preclinical setting has the potential to identify biomarkers for injury severity and/or recovery, to identify potential therapeutic targets, and, in the future, to evaluate efficacy of an intervention beyond measures of cell death or spatial learning.
Journal of neuroinflammation, 2015
The 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. To 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. Interleukin-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 increa...
Divergent age-dependent peripheral immune transcriptomic profile following traumatic brain injury
Scientific Reports, 2019
The peripheral immune system is a major regulator of the pathophysiology associated with traumatic brain injury (TBI). While age-at-injury influences recovery from TBI, the differential effects on the peripheral immune response remain unknown. Here, we investigated the effects of TBI on gene expression changes in murine whole blood using RNAseq analysis, gene ontology and network topology-based key driver analysis. Genome-wide comparison of CCI-injured peripheral whole blood showed a significant increase in genes involved in proteolysis and oxidative-reduction processes in juvenile compared to adult. Conversely, a greater number of genes, involved in migration, cytokinemediated signaling and adhesion, were found reduced in CCI-injured juvenile compared to CCI-injured adult immune cells. Key driver analysis also identified G-protein coupled and novel pattern recognition receptor (PRR), P2RY10, as a central regulator of these genes. Lastly, we found Dectin-1, a c-type lectin PRR to be reduced at the protein level in both naïve neutrophils and on infiltrating immune cells in the CCI-injured juvenile cortex. These findings demonstrate a distinct peripheral inflammatory profile in juvenile mice, which may impact the injury and repair response to brain trauma.
Journal of Neuroinflammation, 2011
Background Traumatic brain injury (TBI) causes acute inflammatory responses that result in an enduring cascade of secondary neuronal loss and behavioral impairments. It has been reported that progesterone (PROG) can inhibit the increase of some inflammatory cytokines and inflammation-related factors induced by TBI. Toll-like receptors (TLRs) play a critical role in the induction and regulation of immune/inflammatory responses. Therefore, in the present study, we examined the genomic profiles of TLR-mediated pathways in traumatically injured brain and PROG's effects on these genes. Methods Bilateral cortical impact injury to the medial frontal cortex was induced in C57BL/6J mice. PROG was injected (i.p., 16 mg/kg body weight) at 1 and 6 h after surgery. Twenty-four hours post-surgery, mice were killed and peri-contusional brain tissue was harvested for genomic detection and protein measurement. RT-PCR arrays were used to measure the mRNA of 84 genes in TLR-mediated pathways. Western blot, ELISA and immunohistochemistry were used to confirm the protein expression of genes of interest. Results We found that 2 TLRs (TLR1 and 2), 5 adaptor/interacting proteins (CD14, MD-1, HSPA1a, PGRP and Ticam2) and 13 target genes (Ccl2, Csf3, IL1a, IL1b, IL1r1, IL6, IL-10, TNFa, Tnfrsf1a, Cebpb, Clec4e, Ptgs2 and Cxcl10) were significantly up-regulated after injury. Administration of PROG significantly down-regulated three of the 13 increased target genes after TBI (Ccl-2, IL-1b and Cxcl-10), but did not inhibit the expression of any of the detected TLRs and adaptor/interacting proteins. Rather, PROG up-regulated the expression of one TLR (TLR9), 5 adaptor/interacting proteins, 5 effectors and 10 downstream target genes. We confirmed that Ccl-2, Cxcl-10, TLR2 and TLR9 proteins were expressed in brain tissue, a finding consistent with our observations of mRNA expression. Conclusion The results demonstrate that TBI can increase gene expression in TLR-mediated pathways. PROG does not down-regulate the increased TLRs or their adaptor proteins in traumatically injured brain. Reduction of the observed inflammatory cytokines by PROG does not appear to be the result of inhibiting TLRs or their adaptors in the acute stage of TBI.