Neuroinflammation in Stroke and Trauma Patients: Comparison
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Please note this is a comparison between Version 2 by Rita Xu and Version 1 by Ane Larrea.

Neuroinflammation has a significant impact on different pathologies, such as stroke or spinal cord injury, intervening in their pathophysiology: expansion, progression, and resolution. Neuroinflammation involves oxidative stress, damage, and cell death, playing an important role in neuroplasticity and motor dysfunction by affecting the neuronal connection responsible for motor control.

 

  • neuroinflammation
  • stroke
  • traumatic injury

1. Introduction

Neuroinflammation is a highly complex process characterized by the activation of various glial cells and the release of proinflammatory mediators in the central nervous system (CNS) [1]. It develops secondary to a variety of stimuli, including traumatic injuries, infections, and neurodegenerative processes [2]. Thus, neuroinflammation has emerged as a key research focus, given its significant impact on neuronal function and neurological and motor recovery from different conditions due to its close relationship with modulation of cellular responses and neural homeostasis [3].
Spinal cord injury (SCI) involves the physical and/or functional disruption of neuronal connections in the spinal cord, affecting the integrity of electrical and chemical signals necessary for proper motor, sensory, and autonomic function [3]. This anatomical damage also triggers an inflammatory response in the CNS. Activation of microglia and astrocytes initiates a molecular signaling cascade involving the release of proinflammatory cytokines and reactive oxygen species (ROS) [2]. This exacerbated inflammation perpetuates neuronal damage and promotes scarring and fibrous tissue formation, resulting in chronic and persistent disability [4]. Cerebral ischemia also activates glial cells in response to tissue stress, resulting in the release of cytokines and chemokines that amplify the inflammatory response [5]. Like SCI, strokes also result in neuroinflammation as an integral component of pathogenesis due to the sudden interruption of blood flow to a part of the brain, which can result in the sudden loss of cognitive, sensory, and/or motor functions [6]. As brain cells die from a lack of oxygen and nutrients, the release of proinflammatory factors is further increased, exacerbating tissue damage and hindering functional recovery [7].
The multidisciplinary approach to addressing neuroinflammation in the context of SCI and stroke is significantly enhanced by state-of-the-art diagnostic techniques. Neuroimaging techniques have emerged as fundamental tools for the accurate assessment of neuroinflammation. Magnetic resonance imaging (MRI) [8], computed tomography (CT) [9], positron emission tomography (PET) [10], and contrast-enhanced ultrasound (CEUS) [11] offer specific visualization of lesions, providing information about their location, extent, and relationship to surrounding structures. This ability to accurately map damage and identify areas affected by inflammation translates into a more comprehensive understanding of the disease, which in turn guides therapeutic decisions and provides a solid basis for prognosis [12]. On the other hand, biomarkers are highly informative molecules that are released into the bloodstream in response to neuroinflammation [13]. These biological indicators, whose presence and concentration can be detected with specific methods, are emerging as promising diagnostic tools [14]. Their ability to provide a window into the internal state of the CNS, even in the absence of overt clinical manifestations, provides potential for early diagnosis and monitoring of disease progression [15]. By analyzing these biomarkers, detailed information is obtained about the degree of inflammation present, immune system response, and cellular activity in the compromised neural tissue. This information can not only accelerate the diagnostic stage but also allow for continuous and adaptive monitoring of the disease course, which is essential for the development of more effective and personalized therapeutic strategies [14,15,16][14][15][16].
In the therapeutic field, the incorporation of electrostimulation and bionanomaterials has arisen as cutting-edge strategies. Electrostimulation has emerged as a highly promising technique to precisely modulate neuronal activity and mitigate the inflammatory responses characteristically observed in SCI and stroke [17]. This therapeutic modality leverages the fundamental principles of bioelectronics and neuroscience to influence the electrical behavior of nerve cells and glial cells, with results in terms of improved motor function, recovery of mobility, and reduction in inflammation in affected regions [18]. Bionanomaterials have proven to be an innovative option in the search for effective strategies to address the implications of neuroinflammation in SCI and stroke [19,20][19][20]. These materials are designed to interact at the nanometer scale with biological tissues. In addition, they exhibit unique characteristics that allow them to act in versatile and highly specific ways for the controlled delivery of therapeutic agents [21]. This nanotechnological approach has enabled the encapsulation and gradual release of anti-inflammatory molecules and growth factors in areas affected by neuroinflammation, which in turn promotes neuronal regeneration, angiogenesis, and reduction in the local inflammatory response [21]. This approach, targeted to the site of injury or the ischemic area in the case of stroke, has great potential to mitigate the adverse effects of neuroinflammation and promote functional recovery and, consequently, motor function [22]. Both strategies converge in their goal of restoring balance and promoting repair in the affected nerve tissue. The combination of these innovative therapeutic strategies, with the constantly evolving research on the mechanisms of neuroinflammation, offers a comprehensive approach to improving patients’ recovery and quality of life.

2. Neuroinflammation

Neuroinflammation includes several pathological processes, ranging from altered morphology of glial cells to invasion and destruction of tissues by immune cells migrating from the periphery [23,24,25,26][23][24][25][26]. The immune system maintains a close relationship with the nervous system, as central nervous system (CNS) cells can be activated by peripheral inflammatory mediators, and peripheral immune cells can infiltrate into the brain [25]. In fact, chronic neuroinflammation can alter learning, cognitive, and motor functions by altering neurotransmission [27], becoming an important risk factor for the development of neuropsychological diseases such as Schizophrenia, Bipolar Disorder [28], Mayor Depressive Disorder [29[29][30][31],30,31], or Parkinson [32].
Microglia cells are the main recipients of peripheral inflammatory signals reaching the brain. Once activated, an inflammatory cascade is initiated with the release of chemokines, cytokines, and reactive oxygen and nitrogen species (ROS and RNS, respectively), triggering the activation of astrocytes and, thus, amplifying the inflammatory signal within the CNS. Several astrocyte functions will be altered, resulting in the dysregulation of neurotrophic factor production, transporter function, and neurotransmitter synthesis. The toxic effects of overexposure to cytokines also affect oligodendrocytes, with subsequent apoptosis and demyelination of neurons. Thus, excessive release of proinflammatory mediators together with incorrect neurotransmitter reuptake, decreased release of neurotrophic factors, and oxidative stress cause damage to neuronal plasticity, leading to neurodegeneration and apoptosis [24] (Figure 1).
Figure 1. Effects of the CNS inflammatory cascade on neuronal plasticity caused by an uncontrolled peripheral inflammatory response. The production of peripheral proinflammatory mediators originating from ROS and mitochondrial dysfunction in immune cells activates microglia. An inflammatory cascade is triggered in which the release of cytokines and other inflammatory mediators induces astrocyte activation, thus amplifying the inflammatory signal in the CNS. Several astrocyte functions are altered due to continuous exposure to cytokines, inflammatory mediators, and ROS/RNS. Oligodendrocytes, especially sensitive to the toxic effect of TNF-α, induce apoptosis and demyelination. NTs: Neurotransmitters; ROS: reactive oxygen species; RNS: reactive nitrogen species; TNF-α: tumor necrosis factor.

2.1. Stroke

Strokes are those disorders that produce functional and structural neuronal alterations in different areas of the brain due to maintained hypoxia, a consequence of an abrupt variation (interruption or reduction) in cerebral circulation in such regions [33]. Thus, stroke causes transitory or definitive deficits in their functioning, causing sensory, motor, and cognitive alterations [34].
Strokes can be classified into two subtypes based on the cause that determines the presence of the pathology:
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Ischemic stroke (80%): Occurs because of a decrease and insufficiency of blood supply to the CNS, causing a circumscribed area of cerebral infarction. Depending on their etiology, strokes can be subclassified as thrombotic due to the formation of a blood clot in an area of the brain and embolic because of the formation of a blood clot in another cerebral artery that subsequently travels to the brain. When the symptoms last less than 24 h, it is called a transient ischemic attack (TIA [35,36][35][36]).
-
Hemorrhagic stroke (20%): Is due to parenchymal and/or subarachnoid bleeding. Generally, they are caused by arterial hypertension (AHT), aneurysm ruptures, and or arteriovenous malformations [37].
Depending on the affected area, the altered functions will vary, although it is very common that the stroke involves the pyramidal system, causing a first motor neuron or upper motor neuron syndrome [35]. The clinical manifestations can be classified depending on whether they refer to a loss or decrease in functions (negative clinical manifestations) or the appearance of new or abnormal functions (positive clinical manifestations) [37,38][37][38]. On the one hand, the negative clinical manifestations include abolition of superficial reflexes, as well as paralysis or paralytic of muscles. On the other hand, the positive clinical manifestations include muscle spasticity (in antigravitational musculature) and hyperreflexia of the musculature, whose centers are in the intralesional area, appearing pathological reflexes and clonus [37].

Neuroinflammation and Stroke

Following ischemia, a neuropathological cascade of mechanisms is activated that triggers innate and potentially adaptive inflammatory and immune responses in the central and peripheral nervous systems. This activation leads to the extension and deterioration of the brain injury [6].
The progression and increase in neuroinflammation are directly linked to the immune system, as reflected by the increase in damage-associated molecular patterns (DAMPs) to nuclear or cytosolic proteins observed after stroke [39]. Thus, cells of the innate immune system, such as neutrophils, macrophages/microglia, and astrocytes, are activated [12]. In turn, there is also activation of T cells, regulatory T cells, and B cells of the adaptive immune system, which are able to specifically recognize antigens presented in the context of major histocompatibility complex molecules on antigen-presenting cells [40]. In CNS, infiltrating T cells are mainly CD4+ T cells (helper) [41] and CD8+ T cells (cytotoxic) [42].
Importantly, in the acute phase, immediately after stroke, neuroinflammation may play an endogenous neuroprotective role by phagocytizing leukocytes brain cells and increasing immune cell signaling [43]. This action increases the expression of anti-inflammatory cytokines that facilitate axonal recovery and repair [39]. T-helper cells may have a dual role in neuroinflammation, as, on the one hand, they can secrete anti-inflammatory cytokines that can limit the inflammatory response and protect brain tissue [40]. However, on the other hand, they trigger the release of potent proinflammatory cytokines into cerebrospinal fluid and blood, increasing infarction and cell apoptosis (Figure 2) [39,40,43][39][40][43].
Figure 2. Neuroinflammation process in stroke. After a stroke, cell damage and neuronal death occur, triggering the increased release of chemokines and proinflammatory cytokines that lead to blood–brain barrier (BBB) disruption and immune cell infiltration. This causes brain neurotoxicity and neuroinflammation.
Moreover, it is necessary to highlight the role that neuroinflammation plays in the integrity of the blood–brain barrier (BBB) and vice versa [44]. Disruption of the BBB allows immune cells, inflammatory molecules, and serum proteins to penetrate the brain parenchyma from the periphery [45]. This causes the migration of prostaglandins, proinflammatory cytokines, and other mediators to the site of injury, which increases the number of immune cells and microglia [44]. Thus, the inflammatory response and brain damage are aggravated in the ischemic penumbra, the region surrounding the infarct area at high risk of further damage [46]. Neuroinflammation in the ischemic penumbra can be particularly detrimental, as it can contribute to cell death in this area, which enlarges the size of the cerebral infarct and aggravates the clinical consequences of stroke. Disruption of the BBB may also have long-term consequences after stroke [12]. The influx of immune cells and inflammatory molecules can perpetuate neuroinflammation, which may contribute to the progression of brain damage and scar formation in the affected tissue [45]. In addition, BBB dysfunction may affect the regulation of cerebral blood flow and homeostasis of the brain environment, which may influence functional recovery and brain plasticity after stroke [44]. Likewise, neuronal antigen response may be induced, and chronic cell death may be increased, perpetuating long-term neuroinflammation [12,44,45][12][44][45].

2.2. Spinal Cord Injury

SCI is a pathological process of any etiology that affects the spinal cord and causes transitory or permanent impairment of motor, sensory, and autonomic function [3]. The annual incidence of SCI is approximately 11.4 to 53.4 per million population worldwide, and its etiology may be due to traumatic (80%) or non-traumatic causes (congenital or secondary to disease). SCI can be classified according to [47]:
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Cause: Traumatic or non-traumatic.
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Mechanism of injury: Hyperflexion, flexion with rotation, hyperextension, or compression.
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Level of injury: Cervical, dorsal, or/and lumbosacral.
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Extension: Complete or incomplete.
The assessment of motor and sensory functions is performed according to international standards via the American Spinal Injury Association (ASIA) Impairment Scale [47]. The prognostic factor is determined by the evaluation of the ASIA scale 72 h after the injury, with the maximum risk of mortality in the first year [47].
It is important to know the extension of the SCI since incomplete SCI causes specific syndromes: Scheiner´s syndrome, anterior spinal artery syndrome [48], spinal cord hemisection [49], posterior cord [50], and cauda equina syndrome [51]. All of these syndromes preserve some spinal cord function below the level of the lesion. However, in the case of complete SCI, all functions below the lesion are abolished [52].
SCI shows different clinical phases. The first is the spinal shock phase, immediately after the injury, which extends up to the second and eighth weeks [53,54][53][54]. This phase is identified as the most severe since motor, sensory, and vegetative functions of the lesional and infralateral segments are interrupted [53]. At this time, motor disturbances are characteristic of the lower motor neuron [55]. After the spinal shock, the phase of spinal automatism appears, where the spinal reflex center and activities in the intralesional segment are recovered [56] (except in cauda equina lesions [51]), and even the alteration of the injured segment persists. In this case, the typical motor alteration is of the upper motor neuron [56].

Neuroinflammation and Spinal Cord Injury

Following SCI, a range of vascular, cellular, and molecular alterations originate in the CNS and produce imbalances between immune cells and modulatory factors resulting from neuroinflammation secondary to trauma [57]. Although these may have a dual effect in helping to regulate axonal homeostasis and healing, the imbalance in production results in increased axonal and tissue damage and cell death, aggravating the initial situation, course, and prognosis of SCI [2,58][2][58].
Acute neuroinflammation develops in several stages (Figure 3). In the first stage, the release of proinflammatory cytokines, chemokines, and ROS by microglia, astrocytes, and peripheral immune cells is induced [58]. In this way, a cascade activation of inflammatory and immune pathways is caused, attracting the presence of a greater number of immune cells to the site of the lesion [59]. In the second stage, macrophage and T-cell infiltration occurs [60], increasing pro-inflammatory cytokine and pro-inflammatory chemokine proliferation. Finally, in the third stage, BBB injury occurs, resulting in the migration of leukocytes to the area of the lesion [61].
Figure 3. Stages of neuroinflammation in SCI.
BBB is a highly specialized structure that separates the peripheral blood from the CNS and protects the brain from the entry of potentially harmful substances and immune cells [62]. The BBB is composed mainly of endothelial cells with tight junctions that form a highly selective barrier to the passage of molecules [62,63][62][63]. It is also surrounded by glial cells that contribute to maintaining the integrity of the barrier [64]. BBB injury results in increased permeability and migration of immune molecules and cells into neuronal tissue [65]. The injury is produced by the activation of microglia and astrocytes and the release of proinflammatory cytokines and chemokines that induce the expression of adhesion molecules on endothelial cells [2]. These cells are also damaged by increased production of ROS and by the action of proteolytic enzymes that lead to the disruption of endothelial cell junctions [63]. Moreover, the expression of endothelial cell transporters and proteins is also modified during neuroinflammation [66], thus altering the regulation of the flow of molecules. All these processes lead to the amplification of the inflammatory response.
The close relationship between neuroplasticity and neuroinflammation in the context of SCI should be emphasized. The presence of edema and an increase in BBB permeability, as well as the release of proinflammatory cytokines, chemokines, and ROS, affect neuronal reorganization in the area of the lesion [67]. Likewise, after SCI, the unaffected areas also undergo changes in connections and functions in an attempt to compensate for the functional loss secondary to the injury [68]. Consequently, neuronal circuits, synaptic plasticity, and activation of non-injured motor areas are reorganized to compensate for lost functions [69]. The neuroplasticity of uninjured areas can be affected by neuroinflammation since inflammatory mediators can positively alter synaptic signaling and, thus, neuronal plasticity [69,70][69][70]. Additionally, neurotrophic mediators affect the survival and growth of neurons after SCI growth of neurons after SCI, attenuating part of the deleterious effects triggered by mitochondrial dysfunction and oxidative stress [71].

2.3. Neuroinflammation and Mitochondrial Activity

Mitochondria are recognized as powerhouses, present in virtually all eukaryotic cells. They are dynamic organelles that constantly fuse and divide to regulate their shape, size, number, and bioenergetic function [72]. In fact, there is a variable number of mitochondria in the cellular medium, and their number is directly related to the energy needs of the cell [73,74][73][74]. They are responsible for carrying out several functions, such as calcium homeostasis [75], programmed cell death or apoptosis [76], synaptic plasticity, adenosine triphosphate (ATP) synthesis via the tricarboxylic acid cycle (TAC), and OXPHOS and ROS production and elimination [77,78][77][78]. ROS are chemical compounds that are formed after incomplete reduction in oxygen [79]. They are natural metabolites generated in normal cellular activity that participate in cell signaling. However, an imbalance between ROS production and the antioxidant defense system in the organism leads to disruption of cellular function and toxicity. This can occur due to an overproduction of ROS or a decrease in the antioxidant defense mechanism [80].
In this sense, oxidative stress derived from the increase in the ROS production at the neuronal level and in cells of the peripheral system causes a decrease in the generation of ATP that will eventually lead to a lack of energy at times of increased energy demand, for example, in neuronal activity to modulate synaptic connections and neuronal plasticity [77] or under conditions of stress and inflammation [81], factors that have often been related to different neurodegenerative diseases [82,83][82][83]. Inflammation is a physiological response of the immune system that promotes the mobilization of immune cells to the site of infection or damage to eliminate the triggering factor, repair the damaged tissue, and restore the homeostasis of the organism. Cellular energy metabolism is an important part of the machinery that ensures the proper functioning of immune [1]. Without adequate energy, immune function would fail, altering immune responses or triggering uncontrolled activation [81]. This process would end up damaging and fragmenting mitochondrial DNA that will be released first to the cytosol and then to the extracellular medium by various mechanisms, including transport in mitochondria-derived vesicles (MVD) or via mitochondrial permeability transition pores (MPT). This mitochondrial DNA (mtDNA) acts as a potent DAMP (damage-associated molecular patterns), activating the TLR9-mediated signaling pathway that will ultimately lead to increased production of proinflammatory mediators, such as TNF and IL-6 [84]. Taken together, inflammation can impair mitochondrial function, while alterations in mitochondrial activity may promote uncontrolled inflammatory responses, creating a vicious cycle that can ultimately compromise neuronal function at the bioenergetic level [85].

2.4. Cytokines and Chemokines Involved in Neuroinflammation

Cytokines and chemokines are cell signaling molecules that play a crucial role in regulating the immune response and communication between different cell types in the body. However, in the context of SCI and stroke, the interaction of these molecules can have both beneficial and detrimental effects on neuroinflammation (Table 1).
Table 1. Cytokines and chemokines involved in neuroinflammation: Detrimental and beneficial effects related to each molecule.
Cytokines and Chemokines Detrimental Effects Beneficial Effects Secretory Cell Refs.
Interleukin 1β (IL-1β) Increased secondary brain damage

Increased BBB permeability		 Tissue recovery

Apoptosis inhibition		 Microglia

Macrophages		 [86]
Interleukin 1α (IL-1α) Chronic inflammation

Damage of tissue

Autoimmune pathologies		 Tissue recovery

Activation immune system		 Microglia [2,18][2][18]
Interleukin 1F1 (IL-1F1) Increased inflammatory response, hypersensitivity, and autoimmune diseases Regulation of the immune response

Tissue recovery.

Neuroprotective function.		 Neutrophils [87]
Interleukin 1F2 (IL-1F2) Increased prostaglandins, cyclooxygenase 2, and phospholipase A2 Regulation of the immune response.

Tissue recovery		 Dendritic cells, macrophages, endothelial, and T cells [87]
Interleukin 12 (IL-12) Increased immune response

Difficulty axonal regeneration		 Activation immune system

Elimination death cells		 Dendritic cells, macrophages, monocytes, neutrophils, microglia, and T-cells. [88]
Interleukin 17 (IL-17) Damage of BBB

Increased immune response		 Antipathogenic response

Decontrol immune cells		 T helper, dendritic cells, and macrophages [89,90][89][90]
Tumor Necrosis Factor α (TNF-α) Neurotoxicity

Increased BBB permeability		 Tissue recovery

Antipathogenic response		 Microglia, neurons, astrocytes, monocytes, and oligodendrocytes [2,18,91][2][18][91]
Interferon γ (IFN-γ) Neurotoxicity

Difficulty neuroplasticity		 Antipathogenic response

Tissue recovery		 γδ T-cells [2]
Interleukin 5 (IL-5) Allergic response

Decreased immune response		 Regulation of allergic pathologies

Antipathogenic response		 Hematopoietic and non-hematopoietic cells, granulocytes, T, and natural helper cells [88,92][88][92]
Interleukin 10 (IL-10) Neurotoxicity

Increased inflammatory response		 Inhibition TNF-α; IL-1; IL-6

Limitation inflammatory response		 T and B cells, monocytes, dendritic, and natural killer cells [92]
Interleukin 4 (IL-4) Immunosuppression Inhibition TNF-α; IL-1; IL-6

Limitation inflammatory response		 T helper cells, eosinophils, and eosinophils [93,94][93][94]
Interleukin 6 (IL-6) Neurotoxicity

Increased inflammatory response		 Antipathogenic response

Increased axonal regeneration		 Astrocytes, microglia, and neurons [95,96][95][96]
Interleukin 8 (IL-8) Chronic inflammation

Cardiovascular and pulmonary diseases		 Tissue recovery

Neutrophills quimiotaxis		 Monocytes, endothelial cells, macrophages, and T cells. [15]
C-C Motif Chemokine Ligand 2 (CCL 2) Chronic inflammation

Autoimmune diseases

Increased cancer cell migration		 Regulation of immune response

Angiogenesis

Monocyte chemoattraction		 Activated T cells, astrocytes, microglia, and monocytes [2,[297]][97]
C-C Motif Chemokine Ligand 3 (CCL 3) Increased production of proinflammatory cytokines Regulation of inflammatory response Monocytes, macrophages, and dendritic cells [98,99,100][98][99][100]
C-C Motif Chemokine Ligand 5 (CCL 5) Chronic inflammation

Cardiovascular diseases

Neurological disorders		 Immune cells quimiotaxis

Regulation of immune response

Antiviral response		 IL-1 and macrophage migration inhibitory factor [98,101][98][101]
In certain situations, cytokines and chemokines can be beneficial in the response to SCI and stroke. They can recruit immune system cells and migrate to the site, which is essential to eliminate damaged tissues and toxic substances, as well as to initiate repair. However, overexpression or dysregulation of certain cytokines and chemokines can have detrimental effects. Excessive cytokine release causes excessive attraction of inflammatory cells to the site of injury and can lead to the formation of a toxic environment and excessive scarring that hinders neuronal regeneration. It also contributes to a chronic inflammatory environment. Thus, if the inflammatory response persists in an uncontrolled manner, it can contribute to secondary neuronal death and worsening damage.
Thus, cytokines and chemokines are molecules with a significant influence on neuroinflammation. Their role is complex and depends on the amount and type of molecules released, as well as their interaction with the cellular environment. Therefore, the balance between cytokines and chemokines is crucial in neuroinflammation associated with SCI and stroke.

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