Interleukin-13 and its receptor are synaptic proteins involved in plasticity and neuroprotection.

Immune system molecules are expressed by neurons, yet their functions are often unknown. We have identified IL-13 and its receptor IL-13Ra1 as neuronal, synaptic proteins in mouse, rat, and human brains, whose engagement upregulates the phosphorylation of NMDAR and AMPAR subunits and, in turn, increases synaptic activity and CREB-mediated transcription. We demonstrate that increased IL-13 is a hallmark of traumatic brain injury (TBI) in male mice as well as in two distinct cohorts of human patients.

Met/HGFR triggers detrimental reactive microglia in TBI.

The complexity of signaling events and cellular responses unfolding in neuronal, glial, and immune cells upon traumatic brain injury (TBI) constitutes an obstacle in elucidating pathophysiological links and targets for intervention. We use array phosphoproteomics in a murine mild blunt TBI to reconstruct the temporal dynamics of tyrosine-kinase signaling in TBI and then scrutinize the large-scale effects of perturbation of Met/HGFR, VEGFR1, and Btk signaling by small molecules. We show Met/HGFR as a selective modifier of early microglial response and that Met/HGFR blockade prevents the induction of microglial inflammatory mediators, of reactive microglia morphology, and TBI-associated responses in neurons and vasculature.

Neuronal nuclear calcium signaling suppression of microglial reactivity is mediated by osteoprotegerin after traumatic brain injury.

Background: Traumatic brain injury (TBI) is characterized by massive changes in neuronal excitation, from acute excitotoxicity to chronic hyper- or hypoexcitability. Nuclear calcium signaling pathways are involved in translating changes in synaptic inputs and neuronal activity into discrete transcriptional programs which not only affect neuronal survival and synaptic integrity, but also the crosstalk between neurons and glial cells. Here, we report the effects of blunting neuronal nuclear calcium signals in the context of TBI.

EPO treatment does not alter acute serum profiles of GFAP and S100B after TBI: A brief report on the Australian EPO-TBI clinical trial.

Purpose: To determine the diagnostic and prognostic value of glial fibrillary acidic protein (GFAP) and S100B after traumatic brain injury (TBI) in an Erythropoietin (EPO) clinical trial and examine whether EPO therapy reduces biomarker concentrations.

Materials And Methods: Forty-four patients with moderate-to-severe TBI were enrolled to a sub-study of the EPO-TBI trial. Patients were randomized to either Epoetin alfa 40,000 IU or 1 ml sodium chloride 0.

Interferons in Traumatic Brain and Spinal Cord Injury: Current Evidence for Translational Application.

This review article provides a general perspective of the experimental and clinical work surrounding the role of type-I, type-II, and type-III interferons (IFNs) in the pathophysiology of brain and spinal cord injury. Since IFNs are themselves well-known therapeutic targets (as well as pharmacological agents), and anti-IFNs monoclonal antibodies are being tested in clinical trials, it is timely to review the basis for the repurposing of these agents for the treatment of brain and spinal cord traumatic injury. Experimental evidence suggests that IFN-α may play a detrimental role in brain trauma, enhancing the pro-inflammatory response while keeping in check astrocyte proliferation; converging evidence from genetic models and neutralization by monoclonal antibodies suggests that limiting IFN-α actions in acute trauma may be a suitable therapeutic strategy.

Erythropoietin Does Not Alter Serum Profiles of Neuronal and Axonal Biomarkers After Traumatic Brain Injury: Findings From the Australian EPO-TBI Clinical Trial.

Objective: To determine profiles of serum ubiquitin carboxy-terminal hydrolase L1 and phosphorylated neurofilament heavy-chain, examine whether erythropoietin administration reduce their concentrations, and whether biomarkers discriminate between erythropoietin and placebo treatment groups.

Design: Single-center, prospective observational study.

Setting: A sub-study of the erythropoietin-traumatic brain injury clinical trial, conducted at the Alfred Hospital, Melbourne, Australia.

Targeted therapeutic mild hypercapnia after cardiac arrest: A phase II multi-centre randomised controlled trial (the CCC trial).

Background: In intensive care observational studies, hypercapnia after cardiac arrest (CA) is independently associated with improved neurological outcome. However, the safety and feasibility of delivering targeted therapeutic mild hypercapnia (TTMH) for such patients is untested.

Methods: In a phase II safety and feasibility multi-centre, randomised controlled trial, we allocated ICU patients after CA to 24h of targeted normocapnia (TN) (PaCO2 35-45mmHg) or TTMH (PaCO2 50-55mmHg).

Lesion Size Is Exacerbated in Hypoxic Rats Whereas Hypoxia-Inducible Factor-1 Alpha and Vascular Endothelial Growth Factor Increase in Injured Normoxic Rats: A Prospective Cohort Study of Secondary Hypoxia in Focal Traumatic Brain Injury.

Background: Hypoxia following traumatic brain injury (TBI) is a severe insult shown to exacerbate the pathophysiology, resulting in worse outcome. The aim of this study was to investigate the effects of a hypoxic insult in a focal TBI model by monitoring brain edema, lesion volume, serum biomarker levels, immune cell infiltration, as well as the expression of hypoxia-inducible factor-1 alpha (HIF-1α) and vascular endothelial growth factor (VEGF).

Materials And Methods: Female Sprague-Dawley rats (n = 73, including sham and naive) were used.

Therapies negating neuroinflammation after brain trauma.

Traumatic brain injury (TBI) elicits a complex secondary injury response, with neuroinflammation as a crucial central component. Long thought to be solely a deleterious factor, the neuroinflammatory response has recently been shown to be far more intricate, with both beneficial and detrimental consequences depending on the timing, magnitude and specific immune composition of the response post-injury. Despite extensive preclinical and clinical research into mechanisms of secondary injury after TBI, no effective neuroprotective therapy has been identified, with potential candidates repeatedly proving disappointing in the clinic.

Environmental Enrichment Attenuates Traumatic Brain Injury: Induced Neuronal Hyperexcitability in Supragranular Layers of Sensory Cortex.

We have previously demonstrated that traumatic brain injury (TBI) induces significant long-term neuronal hyperexcitability in supragranular layers of sensory cortex, coupled with persistent sensory deficits. Hence, we aimed to investigate whether brain plasticity induced by environmental enrichment (EE) could attenuate abnormal neuronal and sensory function post-TBI. TBI (n = 22) and sham control (n = 21) animals were randomly assigned housing in either single or enriched conditions for 7-9 weeks.

Activation of the kynurenine pathway and increased production of the excitotoxin quinolinic acid following traumatic brain injury in humans.

Unlabelled: During inflammation, the kynurenine pathway (KP) metabolises the essential amino acid tryptophan (TRP) potentially contributing to excitotoxicity via the release of quinolinic acid (QUIN) and 3-hydroxykynurenine (3HK). Despite the importance of excitotoxicity in the development of secondary brain damage, investigations on the KP in TBI are scarce. In this study, we comprehensively characterised changes in KP activation by measuring numerous metabolites in cerebrospinal fluid (CSF) from TBI patients and assessing the expression of key KP enzymes in brain tissue from TBI victims.

Measurement of serum melatonin in intensive care unit patients: changes in traumatic brain injury, trauma, and medical conditions.

Melatonin is an endogenous hormone mainly produced by the pineal gland whose dysfunction leads to abnormal sleeping patterns. Changes in melatonin have been reported in acute traumatic brain injury (TBI); however, the impact of environmental conditions typical of the intensive care unit (ICU) has not been assessed. The aim of this study was to compare daily melatonin production in three patient populations treated at the ICU to differentiate the role of TBI versus ICU conditions.

Anti-lysophosphatidic acid antibodies improve traumatic brain injury outcomes.

Background: Lysophosphatidic acid (LPA) is a bioactive phospholipid with a potentially causative role in neurotrauma. Blocking LPA signaling with the LPA-directed monoclonal antibody B3/Lpathomab is neuroprotective in the mouse spinal cord following injury.

Findings: Here we investigated the use of this agent in treatment of secondary brain damage consequent to traumatic brain injury (TBI).

Post-traumatic hypoxia is associated with prolonged cerebral cytokine production, higher serum biomarker levels, and poor outcome in patients with severe traumatic brain injury.

Secondary hypoxia is a known contributor to adverse outcomes in patients with traumatic brain injury (TBI). Based on the evidence that hypoxia and TBI in isolation induce neuroinflammation, we investigated whether TBI combined with hypoxia enhances cerebral cytokine production. We also explored whether increased concentrations of injury biomarkers discriminate between hypoxic (Hx) and normoxic (Nx) patients, correlate to worse outcome, and depend on blood-brain barrier (BBB) dysfunction.

The role of markers of inflammation in traumatic brain injury.

Within minutes of a traumatic impact, a robust inflammatory response is elicited in the injured brain. The complexity of this post-traumatic squeal involves a cellular component, comprising the activation of resident glial cells, microglia, and astrocytes, and the infiltration of blood leukocytes. The second component regards the secretion immune mediators, which can be divided into the following sub-groups: the archetypal pro-inflammatory cytokines (Interleukin-1, Tumor Necrosis Factor, Interleukin-6), the anti-inflammatory cytokines (IL-4, Interleukin-10, and TGF-beta), and the chemotactic cytokines or chemokines, which specifically drive the accumulation of parenchymal and peripheral immune cells in the injured brain region.

Guilty molecules, guilty minds? The conflicting roles of the innate immune response to traumatic brain injury.

Traumatic brain injury (TBI) is a complex disease in the most complex organ of the body, whose victims endure lifelong debilitating physical, emotional, and psychosocial consequences. Despite advances in clinical care, there is no effective neuroprotective therapy for TBI, with almost every compound showing promise experimentally having disappointing results in the clinic. The complex and highly interrelated innate immune responses govern both the beneficial and deleterious molecular consequences of TBI and are present as an attractive therapeutic target.

Attenuated neurological deficit, cell death and lesion volume in Fas-mutant mice is associated with altered neuroinflammation following traumatic brain injury.

Progressive neurodegeneration following traumatic brain injury (TBI) involves the Fas and TNF-receptor1 protein systems which have been implicated in mediating delayed cell death. In this study, we used two approaches to assess whether inhibition of these pathways reduced secondary brain damage and neurological deficits after TBI. Firstly, we investigated whether the expression of non-functional Fas in lpr mice subjected to TBI altered tissue damage and neurological outcome.

Involvement of pro- and anti-inflammatory cytokines and chemokines in the pathophysiology of traumatic brain injury.

Despite dramatic improvements in the management of traumatic brain injury (TBI), to date there is no effective treatment available to patients, and morbidity and mortality remain high. The damage to the brain occurs in two phases, the initial primary phase being the injury itself, which is irreversible and amenable only to preventive measures to minimize the extent of damage, followed by an ongoing secondary phase, which begins at the time of injury and continues in the ensuing days to weeks. This delayed phase leads to a variety of physiological, cellular, and molecular responses aimed at restoring the homeostasis of the damaged tissue, which, if not controlled, will lead to secondary insults.

In situ detection of inflammatory mediators in post mortem human brain tissue after traumatic injury.

Little is known about the molecular events following severe traumatic brain injury (TBI) in humans and to date there are no efficient therapies for the treatment of patients. In this study, the first of its kind in human tissue, a total of 21 post mortem trauma brain samples were analyzed. The inflammatory response within the brain tissue was explored by measuring the expression of various inflammatory cytokines at the mRNA and protein levels.

Role of chemokines in CNS health and pathology: a focus on the CCL2/CCR2 and CXCL8/CXCR2 networks.

Chemokines and their receptors have crucial roles in the trafficking of leukocytes, and are of particular interest in the context of the unique immune responses elicited in the central nervous system (CNS). The chemokine system CC ligand 2 (CCL2) with its receptor CC receptor 2 (CCR2), as well as the receptor CXCR2 and its multiple ligands CXCL1, CXCL2 and CXCL8, have been implicated in a wide range of neuropathologies, including trauma, ischemic injury and multiple sclerosis. This review aims to overview the current understanding of chemokines as mediators of leukocyte migration into the CNS under neuroinflammatory conditions.

Modulation of immune response by head injury.

Despite the fact that traumatic brain injury (TBI) is a silently growing epidemic, we are yet to understand its multifaceted pathogenesis, where various cellular pathways are initiated in response to both the primary mechanical insult and secondary physiologically mediated injury. Although the brain has traditionally been considered an immunologically privileged site, evidence to the contrary exists in studies of central nervous system (CNS) pathology, in particular TBI. Transmigration of leukocytes following blood brain barrier (BBB) disruption results in activation of resident cells of the CNS, such as microglia and astrocytes, to possess immunological function.

Activin a release into cerebrospinal fluid in a subset of patients with severe traumatic brain injury.

Activin A is a member of the transforming growth factor-beta superfamily and has been demonstrated to be elevated during inflammation and to have neuroprotective properties following neural insults. In this study, we examined whether traumatic brain injury (TBI) induced a response in activin A or in the concentrations of its binding protein, follistatin. Thirty-nine patients with severe TBI had daily, matched cerebrospinal fluid (CSF) and serum samples collected post-TBI and these were assayed for activin A and follistatin using specific immunoassays.