Cytokines and Brain Injury: Invited Review (original) (raw)
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Production of cytokines following brain injury: beneficial and deleterious for the damaged tissue
Molecular psychiatry, 1997
A profound inflammatory response is initiated immediately following traumatic brain injury (TBI) and is characterized by the release of several cytokines with pro- and anti-inflammatory functions. In order to elucidate which cytokines are released in the human brain in response to injury as well as in the peripheral compartment, IL-1, IL-6, IL-8, IL-10, TNF-alpha and TGF-beta were monitored in CSF and serum of severely brain-injured patients. Furthermore, we investigated the possible modulation of systemic reactions by IL-6 and the ability of IL-6 and IL-8 to promote the synthesis of nerve growth factor.
The Role of Markers of Inflammation in Traumatic Brain Injury
Frontiers in Neurology, 2013
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 subgroups: the archetypal proinflammatory cytokines (Interleukin-1, Tumor Necrosis Factor, Interleukin-6), the antiinflammatory 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. Such mechanisms have been demonstrated in animal models, mostly in rodents, as well as in human brain. Whilst the humoral immune response is particularly pronounced in the acute phase followingTraumatic brain injury (TBI), the activation of glial cells seems to be a rather prolonged effect lasting for several months. The complex interaction of cytokines and cell types installs a network of events, which subsequently intersect with adjacent pathological cascades including oxidative stress, excitotoxicity, or reparative events including angiogenesis, scarring, and neurogenesis. It is well accepted that neuroinflammation is responsible of beneficial and detrimental effects, contributing to secondary brain damage but also facilitating neurorepair. Although such mediators are clear markers of immune activation, to what extent cytokines can be defined as diagnostic factors reflecting brain injury or as predictors of long term outcome needs to be further substantiated. In clinical studies some groups reported a proportional cytokine production in either the cerebrospinal fluid or intraparenchymal tissue with initial brain damage, mortality, or poor outcome scores. However, the validity of cytokines as biomarkers is not broadly accepted. This review article will discuss the evidence from both clinical and laboratory studies exploring the validity of immune markers as a correlate to classification and outcome following TBI.
Advances in experimental medicine and biology, 2002
Lesions in the nervous system induce rapid activation of glial cells and under certain conditions additional recruitment of granulocytes, T-cells and monocytes/macrophages from the blood stream triggered by upregulation of cell adhesion molecules, chemokines and cytokines. Hematogenous cell infiltration is not restricted to infectious or autoimmune disorders of the nervous system, but also occurs in response to cerebral ischemia and traumatic lesions. Neuroinflammation can cause neuronal damage, but also confers neuroprotection. Granulocytes occlude vessels during reperfusion after transient focal ischemia, while the functional role of T-cells and macrophages in stroke development awaits further clarification. After focal cerebral ischemia neurotoxic mediators released by microglia such as the inducible nitric oxide synthase (leading to NO synthesis) and the cytokines interleukin-1beta (IL-1beta) and tumor necrosis factor-alpha (TNF-alpha) are upregulated prior to cellular inflammat...
Roles of Pro- and Anti-inflammatory Cytokines in Traumatic Brain Injury and Acute Ischemic Stroke
Mechanisms of Neuroinflammation, 2017
This chapter will introduce the reader to the pathophysiology of two devastating neurologic events, traumatic brain injury (TBI) and acute ischemic stroke (AIS). Here we focus on the role of key pro-inflammatory and anti-inflammatory cytokines. Several experimental interventions have been found to modulate cytokine production and brain injury after AIS or TBI. Here minocycline, biological response modifiers, hormonal therapies, omega-3 fatty acids, N-acetylcysteine, and cannabinoids will be discussed. In addition, the role of cytokine-induced inflammasomes in both TBI and AIS will be addressed and followed by discussion of pro-inflammatory cytokines (e.g., TNF-α, IL-1β, IL-18, and IFN-γ). Finally, the main anti-inflammatory cytokines, IL-33, IL-10, IL-6, and IL-4, will be discussed in the context of both TBI and AIS. It should be noted that the role of these cytokines is diverse and the dichotomization of classically pro-versus anti-inflammatory cytokines is being reexamined , as many of these cytokines have been found to play dual roles in TBI and AIS brain injury.
Role and mechanisms of cytokines in the secondary brain injury after intracerebral hemorrhage
Progress in Neurobiology, 2019
A c c e p t e d M a n u s c r i p t 2 1. The epidemiology of ICH 2. The mechanism of ICH-induced brain injury 2.1. Primary injury in ICH 2.2. Secondary injury in ICH 2.2.1. The neuroendocrine axis can be activated in the early stage of ICH 2.2.2. Hematoma dissolution aggravates brain tissue damage 2.2.3. The hemostasis response system is activated to control bleeding 2.2.4. The release of toxic products aggravates brain tissue damage 2.2.5. Activation of the complement system aggravates damage to surrounding brain tissues 3. Mechanism of inflammatory injury after ICH 3.1. The cellular inflammatory response to ICH 3.1.1. Microglia/macrophages 3.
Journal of Neurotrauma, 2014
Secondary insults, such as hemorrhagic shock (HS), worsen outcome from traumatic brain injury (TBI). Both TBI and HS modulate levels of inflammatory mediators. We evaluated the addition of HS on the inflammatory response to TBI. Adult male C57BL6J mice were randomized into five groups (n = 4 [naïve] or 8/group): naïve; sham; TBI (through mild-tomoderate controlled cortical impact [CCI] at 5 m/sec, 1-mm depth), HS; and CCI + HS. All non-naïve mice underwent identical monitoring and anesthesia. HS and CCI + HS underwent a 35-min period of pressure-controlled hemorrhage (target mean arterial pressure, 25-27 mm Hg) and a 90-min resuscitation with lactated Ringer's injection and autologous blood transfusion. Mice were sacrificed at 2 or 24 h after injury. Levels of 13 cytokines, six chemokines, and three growth factors were measured in serum and in five brain tissue regions. Serum levels of several proinflammatory mediators (eotaxin, interferon-inducible protein 10 [IP-10], keratinocyte chemoattractant [KC], monocyte chemoattractant protein 1 [MCP-1], macrophage inflammatory protein 1alpha [MIP-1a], interleukin [IL]-5, IL-6, tumor necrosis factor alpha, and granulocyte colony-stimulating factor [G-CSF]) were increased after CCI alone. Serum levels of fewer proinflammatory mediators (IL-5, IL-6, regulated upon activation, normal T-cell expressed, and secreted, and G-CSF) were increased after CCI + HS. Serum level of anti-inflammatory IL-10 was significantly increased after CCI + HS versus CCI alone. Brain tissue levels of eotaxin, IP-10, KC, MCP-1, MIP-1a, IL-6, and G-CSF were increased after both CCI and CCI + HS. There were no significant differences between levels after CCI alone and CCI + HS in any mediator. Addition of HS to experimental TBI led to a shift toward an anti-inflammatory serum profile-specifically, a marked increase in IL-10 levels. The brain cytokine and chemokine profile after TBI was minimally affected by the addition of HS.
Journal of Cerebral Blood Flow & Metabolism, 2010
The role of neuroinflammation is increasingly being recognised in a diverse range of cerebral pathologies, including traumatic brain injury (TBI). We used cerebral microdialysis and paired arterial and jugular bulb plasma sampling to characterise the production of 42 cytokines after severe TBI in 12 patients over 5 days. We compared two microdialysis perfusates in six patients: central nervous system perfusion fluid and 3.5% human albumin solution (HAS); 3.5% HAS has a superior fluid recovery (95.8 versus 83.3%), a superior relative recovery in 18 of 42 cytokines (versus 8 of 42), and a qualitatively superior recovery profile. All 42 cytokines were recovered from the human brain. Sixteen cytokines showed a stereotyped temporal peak, at least twice the median value for that cytokine over the monitoring period; day 1: tumour necrosis factor, interleukin (IL)7, IL8, macrophage inflammatory protein (MIP)1α, soluble CD40 ligand, GRO, IL1β, platelet derived growth factor (PDGF)-AA, MIP1β,...
The Duality of the Inflammatory Response to Traumatic Brain Injury
Molecular Neurobiology, 2001
One and a half to two million people sustain a traumatic brain injury (TBI) in the US each year, of which approx 70,000-90,000 will suffer from long-term disability with dramatic impacts on their own and their families' lives and enormous socioeconomic costs. Brain damage following traumatic injury is a result of direct (immediate mechanical disruption of brain tissue, or primary injury) and indirect (secondary or delayed) mechanisms. These secondary mechanisms involve the initiation of an acute inflammatory response, including breakdown of the blood-brain barrier (BBB), edema formation and swelling, infiltration of peripheral blood cells and activation of resident immunocompetent cells, as well as the intrathecal release of numerous immune mediators such as interleukins and chemotactic factors. An overview over the inflammatory response to trauma as observed in clinical and in experimental TBI is presented in this review. The possibly harmful/beneficial sequelae of post-traumatic inflammation in the central nervous system (CNS) are discussed using three model mediators of inflammation in the brain, tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and transforming growth factor-β (TGF-β). While the former two may act as important mediators for the initiation and the support of post-traumatic inflammation, thus causing additional cell death and neurologic dysfunction, they may also pave the way for reparative processes. TGF-β, on the other hand, is a potent anti-inflammatory agent, which may also have some deleterious long-term effects in the injured brain. The implications of this duality of the post-traumatic inflammatory response for the treatment of brain-injured patients using anti-inflammatory strategies are discussed.
Cytokines in inflammatory brain lesions: helpful and harmful
Trends in Neurosciences, 1996
Multiplesclerosis (MS) isthoughtto bean autoimmunedisease. [n healthyindividuals, theT cells of the immune system, when activatedby an infectious agent,regularlytraffic acrossan intact blood-brainbarrier,surveythe CNS andthenleave. In MS,for reasons thatareonlygraduallybeing understood,certain eventsin the peripheral immune responseand in the brain causesome autoreactiveT cellsto stayinthe CNS.Their presence initiates infiltrationbyother leukocytes and activation and recruitmentof endogenous gliato the inflammatoryprocess, ultimatelyleadingto the destructionof myelinandthe myelin-producing cell, the oligodendrocyte, andthe dysfunction of axons. The keymediatorsinthe subsequent cycles of histological damageandrepair, andclinical relapseand remissionare thoughtto be adhesionmolecules, chemokines andcytokines.