Neurons do not work in isolation; they form intricate circuitry, the function of which is directly or indirectly influenced by all other cellular components of the brain tissue. Brain injury affects neuronal circuitry by causing the death of neurons and glial cells and destroying connections between them. This includes the cellular extensions dendrites and axons through which neurons receive and emit signals by means of molecules called neurotransmitters.
Brain injury often leads to excessive accumulation of neurotransmitters in the brain tissue, in particular glutamate, which can overstimulate neurons and cause neuronal death. A specific region in the brain controls the muscles moving the hand, for example, while another group of neurons controls the muscles involved in talking, and yet another region processes the information from our auditory system so we can understand spoken language. This very specific localization of functions within the brain is the reason injuries to different brain regions lead to varied symptoms.
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Importantly, the brain can limit the spread of damage by forming a glial scar that seals off the damaged region. Astrocytes produce glucose and other nutrients, as well as support the viability of the surviving cells. Researchers are giving astrocytes, once considered just the glue filling the space between neurons, ever increasing attention. They have long known the importance of astrocytes in maintaining brain environment stability homeostasis , providing nutrition for neurons, and recycling neurotransmitters.
More recently, researchers showed that astrocytes also control many functional aspects of the brain in health and disease. However, nervous tissue has a remarkable ability to adapt its function rather than to regenerate its structure in response to a changing environment; this ability constitutes the basis for learning. In neurobiological terms, this ability to adapt to and learn from experiences is called neural plasticity.
At the structural level, neural plasticity could be defined by the number and complexity of dendrites and axons, the density of synapses connections between neurons, through which information is transmitted from one neuron to another , and in some brain regions also by the number of neurons. Brain injury leads to increased neural plasticity in the spared regions. This allows the neurons in these regions to take over the sensory or motor functions that had been performed by the damaged areas. This remapping of function indeed similar to drawing a new map is critical in the recovery of function.
Astrocytes are important regulators, controlling the number of neurotransmitter molecules present in the space between neuronal and astroglial cells. A large change in the size of this space leads to the development of brain swelling.
Recent findings show that the capacity of astrocytes to take up the inhibitory neurotransmitter gamma-aminobutyric acid GABA is reduced in the zone surrounding brain cells killed by stroke. Such a treatment, if provided at the right time after stroke, results in a faster recovery of function in mouse models. These findings, together with many other reports, demonstrate that the response of brain tissue to injury is complex, that many cellular and biochemical events take place in an orchestrated cascade, and that each phase of the healing process has a specific purpose.
Therefore, the timing of any therapeutic intervention is critically important to the outcome. Neural plasticity peaks within one to three months after injury; this creates a unique window of opportunity. During this window, neurorehabilitation—physical therapy, for example—is most effective. However, significant improvements can occur even at later stages, especially when rehabilitation combines task-specific training with therapies that activate neural plasticity.
Reactive astroglial cells in the glial scar produce molecules that inhibit the growth of neuronal processes and thus limit recovery. At a later stage weeks and months after injury , when the activity of the astroglial cells is no longer needed for limiting the spreading of tissue damage, the immune system signals to the astroglial cells in the scar to reduce their activation. This opens an opportunity for therapeutic interventions. Immune activity in the brain changes with time after injury and needs to be tightly controlled, as its malfunction can aggravate the damage.
Astrocytes contribute to immune regulation through their role in resealing the blood-brain barrier as well as via secretion of factors that directly regulate immune-cell activity. The cells and molecules of the immune system also exert direct effects on brain cells, including neurons, astrocytes, and neural stem cells, and in this way stimulate neural plasticity and promote recovery of brain function. Immune system activity declines as we age, and the resulting imbalance could be one reason for poorer recovery from brain injury in older people and for the age-related decline of perception, motor behavior, cognition, and memory function.
In summary, brain injury affects both neural and nonneural cell populations in the brain and causes cell death as well as cellular dysfunction, the latter not only in the areas directly affected by the primary injury but also in more remote brain regions.
The right timing of any intervention, aligned with the neurobiological processes that take place in the injured brain, is critical to the outcome.
Frontiers | The Involvement and Therapy Target of Immune Cells After Ischemic Stroke | Immunology
Box One: Pros and cons of reactive astrocytes in brain injury. Astrocytes become activated after events such as neurotrauma and stroke. This phenomenon, known as reactive gliosis, is accompanied by an altered expression of many genes and profound changes in the properties and function of astrocytes.
The cellular hallmarks of reactive gliosis are the thickening hypertrophy of astrocyte processes, proliferation of astrocytes, and increases in the amount of intermediate filaments also called nanofilaments. Intermediate filaments form a scaffold-like network within the cell cytoplasm, a highly dynamic structure involved in cell signaling, adhesion, and migration that can act as a signaling platform, helping cells and tissues cope with stress in health and injury. By using mouse models that lack intermediate filament proteins, we and other researchers have demonstrated that intermediate filaments play a key role in astrocyte activation, and that astrocyte activation itself is important for the early- and late-stage responses after neurotrauma.
Box Two: The immune response in the healthy brain and after brain injury. Traditionally, the central nervous system CNS , which encompasses the brain, spinal cord, and retina, was viewed as immune-privileged, or sequestered from the immune system. Researchers and medical doctors regarded any immune activity in brain tissue to be harmful.
However, increasing evidence shows that normal development of the CNS, along with its maintenance, repair, and renewal, requires both the innate and adaptive immune responses. The innate immune response is the rapid first line of defense against infection.
It lacks specificity and responds in the same manner to a wide range of triggering events. In contrast, the adaptive immune response is inefficient upon a first encounter with an infectious agent such as a virus or bacteria , but its efficiency increases with time. Both the innate and adaptive immune systems rely on many different immune cell types as well as cell-bound soluble immune molecules. For example, normal neurogenesis in the hippocampus and normal cognitive performance require cells of the adaptive immune response called T lymphocytes; the cells also protect neurons from secondary degeneration after injury.
Innate immune response cells called microglia constantly survey brain tissue for protein aggregates or cell debris, which they efficiently remove. However, their prolonged and excessive activity is associated with release of a range of substances that are toxic to the neurons. Monocytes recruited from the blood are important regulators of the local immune response, including the activity of microglia. The complement system, a group of immune system proteins known for initiating inflammation and eliminating pathogenic bacteria, has multiple roles in the CNS.
Edward A Ganio. Anthony Culos. Mohammad S Ghaemi. Benjamin Choisy. Karim Djebali. Jakob F Einhaus. Basile Bertrand. Athena Tanada. Natalie Stanley. Ramin Fallahzadeh. Quentin Baca. Lisa N Quach. Elizabeth Osborn.
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Lauren Drag. Maarten G Lansberg. Martin S Angst. Brice Gaudilliere. Marion S Buckwalter. Correspondence may also be addressed to: Marion S. Nima Aghaeepour. Cite Citation. Permissions Icon Permissions. Abstract Stroke is a leading cause of cognitive impairment and dementia, but the mechanisms that underlie post-stroke cognitive decline are not well understood.
Excessive stimulation of NMDARs during ischemia contributes to mitochondrial injury, apoptotic, and excitotoxic nerve cell death [ 8 ]. Additionally, ischemia impairs ATP synthesis, thus preventing glutamate clearance, leading to continuous stimulation of glutamate receptors while keeping neuronal depolarization constant, generating reactive oxygen species ROS and mitochondrial dysfunction, stimulating necrotic and apoptotic pathways [ 6 ].
These mediators trigger recruitment of peripheral immune cells in order to clear cell debris and heal the brain. Stroke disrupts the blood—brain barrier BBB , increasing its permeability and the entry of immune cells [ 10 ]. The controversial role of macrophages in infarct development may be explained by the concept of classic or alternative macrophage activation, whereby classically activated M1 macrophages exacerbate damage, while alternatively activated M2 macrophages assist in repair and neurogenesis [ 11 ].
The role of neutrophils in brain damage following stroke is equally controversial.
Preventing neutrophil migration into cerebral ischemic tissue has been shown to reduce infarct size and improve neurological outcomes in mice [ 13 ]; however, neutrophil depletion has not been found to reduce brain damage after stroke [ 14 ]. Influx of lymphocytes usually occurs 2—3 days after stroke. Regulatory T-cells T regs also have controversial effects in stroke. T regs can be strong promoters of ischemia or may lead to protective effects, mitigating infarct development. The local and systemic immune response to ischemic stroke appears to differ from that mounted after injury to other organs or systems.
Although the precise reasons remain unclear, several hypotheses could explain these putative differences. During homeostasis, the brain is considered an immune-privileged tissue protected by a specific vessel structure, the BBB. During ischemic stroke, the BBB is breached and various immune cells including both resident and peripheral cells are recruited to the affected area.
Ischemic stroke is also thought to influence immune cells in the circulation, possibly through increased activation of the sympathetic nervous system and the hypothalamic—pituitary—adrenal HPA axis. This may lead to a reduction in circulating immune cell counts and increase the risk of infectious complications [ 18 ].
During ischemic stroke, self-epitopes protected by the systemic immune system through different mechanisms may become open to adaptive immunity. This, in turn, may modulate the immune system to respond to self-antigens in the central nervous system CNS , thus leading to autoimmunity. Therefore, stroke-induced immunosuppression helps prevent post-injury autoimmunity against CNS antigens [ 19 ].
Further studies are required to better elucidate the timing of inflammatory and anti-inflammatory responses in the brain. Ischemic stroke without systemic inflammation may lead to active depression of peripheral immunity by the brain. In the absence of systemic inflammation but in the presence of local inflammatory cytokines after brain injury, an anti-inflammatory response may be triggered that is detrimental, because it shuts down defense mechanisms, rendering the body susceptible to infection.
Under these conditions, the response could in fact be considered maladaptive or inefficient [ 4 , 20 ]. Finally, unlike brain damage, other types of organ injury induce a potent stimulus of anti-inflammatory signaling by the CNS. Pro-inflammatory cytokines released during inflammation play a central role in wound healing. To control inflammation, the CNS sets up a homeostatic, counter-regulatory anti-inflammatory response, and the brain—immune interaction helps maintain homeostasis [ 21 ].
As noted above, stroke is associated with immune consequences, including local autoimmunity and peripheral immunosuppression. Local autoimmunity contributes to lesion formation. In experimental stroke, inhibition of this response has been shown to be beneficial. However, severe peripheral immunosuppression predisposes patients to subsequent bacterial infections, which have a negative effect on clinical outcome. The immune and molecular mechanisms responsible for this systemic immune activation have yet to be elucidated.
Post-stroke immunosuppression has been considered an adaptive response, which prevents autoimmunity against CNS antigens. However, the mechanisms associated with stroke-related autoimmunity to brain antigens require elucidation. Reaction to stroke injury appears to involve a maladaptive response. During stroke, self-epitopes, protected by the systemic immune system through different mechanisms [ 23 ], could become open to adaptive immunity, which may modulate the immune system to respond to self-antigens in CNS, thus leading to autoimmunity.
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Therefore, stroke-induced immunosuppression helps prevent post-injury autoimmunity. Post-stroke infections result in systemic inflammation, making patients more prone to autoimmunity against brain antigens [ 20 ]. However, immune responses against self-antigens may happen as a collateral effect. Post-stroke infection after endotoxin administration in rats increases both T helper Th 1-mediated immune response and mortality rates [ 24 ].
Furthermore, stroke patients with acquired infection appeared to present immune responses against myelin basic protein and glial fibrillary acidic protein, and have worse outcomes compared to stroke patients with no infection [ 25 ]. This may emphasize the need to decrease the incidence of post-stroke infection. Central nervous system damage affects the immune response, as demonstrated in humans after neurosurgery, acute traumatic brain injury, and spinal cord injury [ 21 ].
In an experimental mouse model, it was demonstrated that stroke induces rapid and long-lasting suppression of cellular immune responses [ 18 ]. In humans, alterations in cell-mediated immunity, including decreased peripheral blood lymphocyte counts and impaired mitogenic T cell responses, have been reported after acute ischemic stroke [ 26 ]. In ischemic stroke, impairment of respiratory burst caused by circulating neutrophils and monocytes has also been observed. Additionally, stroke-induced neutrophil alterations are associated with the catecholamine response [ 27 ].
By linking the innate and adaptive immunity, macrophages interact with T-cells to trigger specific immune responses.
New Directions in Research and Therapies in Traumatic Brain Injury
After stroke, a reduction in the expression of major histocompatibility complexes MHC class II or HLA-DR in humans and in co-stimulation efficacy occurs, with production of pro-inflammatory cytokines [ 28 ]. In short, stroke affects immune system function, impairing bactericidal immunity and thus predisposing the host to bacterial infection. Moreover, immune organ size is reduced after stroke, which suggests immunosuppression [ 18 ].
In this line, stroke has been shown to decrease spleen size due to splenocyte death, which decreases production of T cell mitogenic factors, preventing T cell proliferation and production of pro-inflammatory cytokines [ 18 ], and migration of cells from the spleen to the cerebral parenchyma [ 29 ].
Immunological Mechanisms and Therapies in Brain Injuries and Stroke
In the post-stroke phase, a T cell shift from a cell-mediated inflammatory Th1-type response to a humoral mediated anti-inflammatory Th2-type response occurs, probably to protect the brain from additional inflammatory injury, and to stimulate tissue repair and neuronal regeneration [ 30 ]. On the other hand, this shift results in immunosuppression of the host, resulting in increased post-stroke infection susceptibility. Experimental and clinical studies show that monocytes, dendritic cells, and T regs greatly increase secretion of IL after stroke [ 31 , 32 ], averting a pro-inflammatory response.
Based on the foregoing, innate immune cells become a desirable target for the treatment of stroke. Clarifying the complex crosstalk between immune responses and the nervous system is important to developing new therapies capable of reducing inflammation and improving recovery from stroke. The sympathetic nervous system SNS has a critical role in the communication between neural and immune structures Fig.
Overactivation of the adrenergic nerve terminals is regarded as an advanced post-stroke immunosuppression mechanism, which induces activation of the SNS and leads to catecholamine secretion by the adrenal medulla and nerve terminals in peripheral organs [ 34 ]. Although increased catecholamine blood levels have been reported after experimental and clinical stroke [ 4 , 35 ], their correlation with lymphopenia, humoral immunosuppression, or bacterial infection has not been confirmed in stroke patients [ 36 ].
Ischemic stroke induces systemic immunosuppression mediated by several factors. This contributes to the overall immunosuppressive state after stroke, which is the main explanation for post-stroke susceptibility to infection. Blue arrows represent the systemic effects of stroke. Green lines represent possible therapeutic targets to prevent systemic immunosuppression and stroke-associated pneumonia.
Dopamine is another catecholamine that can be released after stroke. Even though the immunomodulatory effects of noradrenaline and adrenaline are well-established, the influence of dopamine on inflammatory responses remains unclear. However, dopamine might be a promising target in stroke therapy. Alpha-adrenergic receptors are also expressed by most inflammatory cells and located in the CNS.
Thus, after stroke, modulation of sympathetic activity may influence brain and lung damage differentially. These complex interactions still need to be clarified. Briefly, the HPA axis is a set of CNS and endocrine structures that co-regulates bodily functions through the release of corticotropin-releasing hormone CRH by the hypothalamus in response to stress [ 41 ].
Stroke induces production of these pro-inflammatory cytokines, which in turn can be sensed by the hypothalamus, resulting in excessive glucocorticoid secretion [ 43 ]. These effects may explain the lymphocyte apoptosis and lymphopenia observed after stroke [ 18 ]. Both low and high levels of cortisol are clinically associated with higher mortality after stroke [ 44 ], and the role of this hormone in the modulation of post-stroke inflammation is still unclear.
In summary, the marked anti-inflammatory responses that occur with sympathetic system and HPA axis activation result in strong glucocorticoid secretion. This dysregulation of the corticosteroid system induces immunosuppression, and might be associated with secondary infections and poor outcomes after stroke. The main function of the vagus nerve is to regulate the parasympathetic nervous system PNS , which is also involved in the control of inflammation [ 45 ].
This peripheral immune stimulation can reduce inflammation in the lungs [ 50 ], but can also causes sickness behavior, acting as a negative feedback loop to prevent a potentially harmful overreaction of the immune system during inflammatory conditions such as bacterial infections by suppressing production of pro-inflammatory cytokines by activated macrophages, thus impairing host defense [ 51 ]. After stroke, neuronal, glial, and vascular compartments are damaged, and this can trigger inflammasome and innate immune activation through the release of DAMPs [ 34 ].
After stroke, cells in the hypoperfused territory become necrotic, release HMGB1, induce expansion of a monocyte subpopulation, and contribute to the immunosuppressive state in the subacute phase of stroke, predisposing patients to pneumonia [ 52 ]. A recent experimental study showed that genetic or pharmacological blockade of pattern recognition receptor signaling via HMGB1 and receptor for advanced glycation end products RAGE abrogated cellular immunosuppression and restored lymphocyte activation in the subacute phase after stroke [ 53 ].
In short, activation of the DAMP system after stroke induces a key mechanism of the intricate local and peripheral immune response that has profound consequences on clinical outcome. Given this high incidence, recent studies have sought to investigate the mechanisms involved in development of pneumonia after stroke.
Traditionally, SAP was considered secondary to the aspiration and dysphagia that result from impaired swallowing function and involved a variety of aspects, including decreased level of consciousness, body positioning in bed, mechanical ventilation, and patient immobility [ 57 ]. However, the high incidence of pneumonia in post-stroke patients when compared to that observed in patients with only dysphagia or impaired consciousness suggests that other immunological mechanisms are implicated in the pathogenesis of SAP [ 4 , 58 ].
Many stroke patients do have impaired swallowing function, which can be related to inadequate dopamine transmission [ 58 ]. In this line, D1 dopamine receptor blockade has been shown to inhibit the swallow reflex and reduce substance P secretion by the glossopharyngeal nerve in distal organs [ 59 ].
Low sputum levels of substance P, which is responsible for the coughing and swallowing reflex, have been observed in elderly patients who developed pneumonia after aspiration [ 58 ]. Accordingly, an increase in serum levels of substance P after treatment with an angiotensin-converting enzyme inhibitor was associated with a reduction of aspiration, suggesting an additional role of lower substance P levels in broncho-aspiration [ 58 ].
Aspiration is not the only cause of SAP as it has been shown to occur in healthy individuals to a similar extent as that observed in stroke patients, though pneumonia does not develop [ 60 ]. The oral flora change rapidly after stroke and colonization by Gram-negative bacteria occurs more frequently than in non-stroke patients [ 61 ]. Different bacterial species have been isolated from the sputum of stroke patients, including Streptococcus pneumoniae , Staphylococcus aureus , Klebsiella pneumoniae , Pseudomonas aeruginosa, Escherichia coli and Enterobacter cloacae [ 62 ].
Even though E. It is important to elucidate the mechanisms and identify the causative agents of SAP in order to develop specifically targeted therapies to mitigate post-stroke bacterial complications. Due to its narrow therapeutic time window and concerns about hemorrhagic complications, thrombolysis is still not used regularly [ 64 ].
Stroke yields complex changes in the immune system through different mechanisms resulting in immunosuppression, which leaves the host susceptible to infections. Targeting these different pathways to prevent the immune shift that usually follows stroke may provide an avenue for adjunctive therapy to prevent and address post-stroke infections. In this context, experimental models of ischemic stroke have shown that stem cells can lead to decreased post-ischemic inflammatory damage and functional improvement [ 65 ]. Further studies at both bench and bedside are needed to understand the mechanisms underlying stem cell therapy, and improve its therapeutic efficacy in patients with stroke.