1. Introduction
The spinal cord is a crucial pathway for the bidirectional transmission of signals between the brain, upper and lower limbs, and trunk. Spinal cord injury (SCI) is defined by a traumatic insult that disrupts the structural and functional integrity of this neural pathway at any spinal level. Individuals with SCI frequently exhibit multiple comorbidities, including locomotor impairment, neurogenic bladder dysfunction, and depression, primarily due to the loss of connectivity between the central nervous system (CNS) and peripheral organs.
The pathophysiology of SCI is highly complex and is broadly categorized into primary and secondary injury phases. The primary injury results from a traumatic insult—such as contusion, compression, or laceration—causing the immediate disruption of the ascending and descending neural tracts within the spinal canal. This is followed by a cascade of biochemical and cellular responses, collectively constituting the secondary injury phase. The hallmarks of this phase include neuroinflammation, excitotoxicity, oxidative stress, and the formation of astroglial scars at the lesion site. This pathological process can persist for months to years post-injury and, if left unaddressed, exacerbate tissue degeneration and functional deficits proportional to the severity of the initial trauma.
The astroglial scar at the injury site, characterized by reactive astrocytes that overexpress glial fibrillary acidic protein (GFAP) [1,2], plays a dual role in the pathophysiology of SCI. While it serves as a protective barrier that limits the spread of secondary damage [3], it also impedes axonal regeneration [2] and inhibits neurogenesis [4]. Notably, both at the lesion epicenter and rostral to the injury site, corticospinal tract axons—which are essential for voluntary motor control—fail to re-establish functional reconnections. Caudally, the loss of supraspinal input disrupts corticospinal circuitry with alpha motoneurons, further compromising motor function. Moreover, progressive gray matter atrophy and motoneuron degeneration—termed transsynaptic degeneration [5,6]—have been observed. This degenerative process exacerbates motor deficits and significantly reduces the repertoire of voluntary movements. Consequently, prolonged disuse following SCI leads to muscle hypotrophy or atrophy, further impairing functional recovery.
Although SCI does not directly inflict physical damage on cortical neurons, evidence suggests that it significantly alters sensorimotor regions functionally connected to the injury site [7]. The primary trauma to spinal neurons can severely disrupt the axonal pathways responsible for transmitting signals between the cortex and spinal cord, thereby impairing communication between supraspinal centers and spinal networks. Research has demonstrated that cortical reorganization initiates soon after the trauma and persists over time [8,9,10].
This reorganization is driven by multiple mechanisms, including the disinhibition of previously suppressed inputs, potentiation of formerly ineffective afferents, axonal and dendritic sprouting, and molecular plasticity. In parallel, systemic inflammation triggered by experimental SCI has been shown to induce deficits in emotional behavior in animal models [11], with elevated levels of pro-inflammatory cytokines detected in brain regions associated with psychological well-being [12]. Furthermore, individuals with SCI exhibit an increased susceptibility to neuropsychological morbidity, highlighting the broader impact of SCI beyond motor dysfunction [13].
Resident immune cells of the CNS, such as astrocytes and microglia, can transition from a quiescent to an activated state in response to environmental changes induced by various conditions, including traumatic brain injury and SCI. Pathogenic effectors can infiltrate the injury site, triggering glial cell reactivity and the subsequent release of diverse inflammatory mediators. Notably, accumulating evidence suggests that astrocytes and microglia exhibit distinct reactive phenotypes, displaying a dual role in CNS pathology. Depending on the context, glial activation can contribute to either neuroprotection or neurodegeneration by engaging in both detrimental and beneficial signaling pathways. Given these complexities, it is crucial to elucidate the specific roles of glial cells in either promoting tissue repair or exacerbating secondary damage following SCI.
2. Neuroinflammatory Response After SCI
The immune system is broadly classified into two main components, the innate and adaptive immune systems. The innate immune system serves as the body’s first line of defense, consisting of neutrophils, eosinophils, basophils, monocytes, and natural killer cells, along with soluble factors such as acute-phase proteins and enzymes that enhance immune responses in a non-specific manner. In contrast, the adaptive immune system generates highly specific responses to antigens and possesses immunological memory, primarily mediated by T and B lymphocytes and humoral factors such as immunoglobulins. Notably, certain components of the innate immune system also function as effectors within the adaptive immune response, effectively bridging the two arms of immunity [14].
Over the past decades, both preclinical and clinical studies have elucidated the role of inflammation in secondary injury responses following SCI. In a previous study conducted by our group, we demonstrated that elevated levels of pro-inflammatory cytokines in the spinal cord and bloodstream, from one hour to twenty-eight days post-injury, correlated with locomotor impairment and depression-like behavior in rats subjected to compression-induced SCI [11]. Notably, our findings revealed that IL-1β levels at the injury site peaked at forty-eight hours post-SCI, followed by a gradual decline until day twenty-eight [11].
Inflammation plays a pivotal role in secondary injury mechanisms, significantly impacting neurological recovery and overall health outcomes in individuals with SCI. Immediately after injury, the immune response is rapidly activated, triggering the release of pro-inflammatory cytokines [15]. These cytokines reach elevated levels in the blood and cerebrospinal fluid (CSF) within the first few hours to days post-injury [16]. Studies have shown that activated microglia and macrophages are detectable in the spinal cord as early as one hour after SCI, with their numbers peaking between five and ten days post-injury and persisting for months [17]. Neutrophils infiltrate the lesion site within hours, while T cells arrive weeks later, further shaping the inflammatory microenvironment [17].
Systemic inflammation remains persistently elevated in individuals with chronic SCI, often lasting for months to years after the initial trauma [18]. Elevated levels of C-reactive protein (CRP), a key marker of systemic inflammation, along with sustained increases in cytokines such as IL-6 and TNF-α, are commonly observed in this population [19]. A meta-analysis involving over 250 individuals with chronic SCI reported a mean CRP level of 4.8 mg/dL, with 76% of participants classified as having a moderate to high risk of cardiovascular dysmetabolic syndrome [20]. Notably, individuals with SCI at levels above thoracic 6 (T6) exhibit the most pronounced inflammatory responses, and those who use motorized wheelchairs show even higher levels of systemic inflammatory markers [15,21,22].
In this context, inflammation following SCI is a dynamic and prolonged process that profoundly influences recovery and long-term health outcomes. Understanding the response of innate immune cells, such as astrocytes and microglia, to injury is critical for developing effective therapeutic strategies and enhancing our comprehension of cytokine responses post-injury. Future research should prioritize personalized interventions aimed at modulating inflammation to improve clinical outcomes in SCI patients.
3. Astrocytes: Guardians and Barriers
Astrocytes, the most abundant type of glial cells, play a vital role in maintaining the functionality of the CNS. Beyond providing essential support to neurons, astrocytes facilitate the uptake and recycling of neurotransmitters and contribute to the maintenance of the blood–brain barrier, thereby supporting various critical neuronal processes [23]. Additionally, astrocytes are involved in the formation and elimination of synapses during brain development. Given their wide-ranging functions, it is unsurprising that disruptions in astrocyte activity are linked to numerous neurodegenerative conditions, including aging, dementia, Alzheimer’s disease, and amyotrophic lateral sclerosis [24,25].
Although astrocyte proliferation is typically associated with a pro-inflammatory environment following many CNS lesions, studies suggest that the proliferation and survival of oligodendrocytes depend on astrocytes in demyelinating and neurodegenerative diseases [26]. However, the role of astrocytes remains controversial. For instance, in multiple sclerosis, astrocytes can either contribute to myelin degradation or promote repair [27,28]. Following SCI, astrocytes exhibit a dual role. Upon injury, they become reactive, characterized by hypertrophy and the upregulation of GFAP. This reactive state leads to the formation of a glial scar, which serves to physically isolate the lesion site, preventing the spread of inflammatory mediators to surrounding healthy tissue. While this barrier function is protective, it also hinders axonal regeneration, thus presenting a double-edged sword.
Studies have identified distinct subtypes of reactive astrocytes, termed “A1” (neurotoxic) and “A2” (neuroprotective) [29]. A1 astrocytes, induced by inflammatory cytokines, exacerbate neuronal death, while A2 astrocytes, triggered by ischemia, promote tissue repair and regeneration [29]. Targeting the modulation of astrocytic phenotypes represents a promising therapeutic strategy for improving outcomes following SCI. Table 1 provides a comparative summary of the roles of normal astrocytes, A1, and A2 subtypes.
3.1. Phenotype A1 Astrocytes and Neurotoxicity
Following CNS injury, astrocytes can undergo phenotypic changes, resulting in increased GFAP expression at the injury site [1] or morphological alterations in adjacent regions [46,47]. Hypertrophic reactive astrogliosis, a hallmark of pro-inflammatory astrocytic morphology, includes changes in cellular structure, the release of various molecules, and altered function [48]. It can be hypothesized that reactive astrocytes following certain CNS injuries are of the A1 subtype, as many behavioral deficits correlate with elevated GFAP expression and morphological changes [46,47]. Indeed, neurotoxin-induced neuronal and oligodendrocyte loss are associated with pain symptoms linked to A1 astrocytes [49]. These morphological and genotypic changes in astrocytes, along with the observed dysfunctions, strongly suggest that A1 astrocytes are present at the site of SCI.
In this context, SCI is recognized for inducing cell death primarily through apoptosis, a process involving multiple steps from oxygen–glucose deprivation and reperfusion to the loss of critical proteins. It has been demonstrated that A1 astrocytes can exacerbate apoptosis of healthy cortical neurons following oxygen–glucose deprivation and reperfusion, leading to a reduction in key signaling proteins such as calmodulin-dependent kinase II (CaMK II), synapsin I, and synaptophysin. Conversely, inhibiting the neurotoxic polarization of astrocytes has been shown to enhance functional recovery [50]. It has been proposed that the polarization of A1 astrocytes is influenced by microglia, which secrete pro-inflammatory factors such as interleukin-1 alpha (IL-1α), tumor necrosis factor (TNF), and complement component 1 subcomponent q (C1q) [25]. Notably, the use of the non-specific microglial inhibitor minocycline has demonstrated the protection of CXCR7, a non-classical G-protein-coupled receptor of CXCL12 that regulates cell cycle progression and proliferation, as well as the activation of the phosphoinositide 3-kinase/Akt (PI3K/Akt) signaling pathway after skin and muscle injury in rats [51]. The PI3K/Akt pathway plays a crucial role in inhibiting nuclear factor-κB (NF-κB) activation and suppressing A1 astrocyte proliferation [52]. Therefore, strategies aimed at reducing the A1 astrocyte population while promoting the A2 subtype could hold promise for the development of new therapeutic approaches following SCI.
3.2. Phenotype A2 Astrocytes and Neuroprotection
While A1 astrocytes induce the loss of several normal astrocytic functions, including the upregulation of various genes and the maintenance of synapses, A2 astrocytes play a crucial role in promoting tissue repair and neuronal survival [25]. A2 astrocytes, in particular, have garnered significant attention for their neuroprotective roles in the context of SCI. These astrocytes foster neuronal survival and tissue repair by releasing neurotrophic factors and mitigating inflammation. Anderson et al. (2016) were among the first to distinguish A1 and A2 astrocytes using transcriptomic profiling in mouse models of CNS injury [53]. Following SCI, A2 astrocytes are upregulated in response to IL-6 family cytokines, particularly Leukemia Inhibitory Factor (LIF). Experimental studies have shown that A2 astrocytes express neurotrophic factors such as brain-derived neurotrophic factor (BDNF) and glial cell line-derived neurotrophic factor (GDNF) [43,54]. These molecules support neuronal survival and axonal regeneration, as demonstrated by increased neuronal viability and functional recovery in mice with enhanced A2 astrocyte activity [43,55].
Another pivotal study by Zamanian et al. (2012) utilized transcriptomic analysis to demonstrate that A2 astrocytes are induced by ischemic injury and exhibit a gene expression profile distinct from that of A1 astrocytes, which are linked to neurotoxic effects [29]. They identified key markers of A2 astrocytes, such as S100A10 and Tgm1, which are involved in tissue repair and extracellular matrix remodeling. These markers were significantly upregulated in the perilesional regions of the spinal cord following injury, highlighting the potential role of A2 astrocytes in promoting recovery [29].
In vivo experiments using conditional knockout models have further emphasized the importance of A2 astrocytes. The targeted deletion of signal transducer and activator of transcription (STAT3), a transcription factor essential for astrocyte reactivity, impaired A2 astrocyte activation and exacerbated neuronal death, as demonstrated by Sofroniew et al. (2015) [35]. In contrast, the pharmacological activation of STAT3 signaling enhanced A2 astrocyte responses and improved recovery outcomes in SCI models, suggesting that STAT3 acts as a master regulator of A2 astrocyte functions. The differentiation of A2 astrocytes is primarily regulated by the Janus kinase 2 (JAK2)/STAT3 signaling pathway [56]. Following SCI, cytokines such as IL-6 activate the JAK/STAT3 pathway in astrocytes, prompting the transcription of genes associated with the A2 phenotype [57]. Notably, STAT3 phosphorylation is a critical event that facilitates its nuclear translocation and the activation of target genes, including neurotrophic factors and anti-inflammatory mediators [58].
Additional signaling pathways also modulate A2 astrocyte functions. The PI3K/Akt pathway, activated by growth factors such as insulin-like growth factor 1 (IGF-1), promotes astrocyte survival and enhances their reparative properties. This pathway interacts synergistically with STAT3 signaling to upregulate neurotrophic factors [59]. Moreover, the Notch signaling pathway has been implicated in maintaining the A2 astrocyte phenotype by regulating gliogenic gene expression [60].
The neuroprotective roles of A2 astrocytes make them an attractive therapeutic target for SCI. Pharmacological strategies aimed at enhancing A2 astrocyte activity or mimicking their neurotrophic effects have demonstrated preclinical efficacy. For instance, the administration of IL-6 family cytokines or small-molecule activators of STAT3 signaling has been shown to promote A2 astrocyte responses and improve functional recovery in rodent models of SCI [58].
Furthermore, cell-based therapies utilizing astrocyte precursors engineered to adopt an A2 phenotype represent a novel approach for intervention. These strategies aim to deliver reparative astrocytes directly to the injured spinal cord, where they can exert localized neuroprotective effects [61]. However, further studies are necessary to optimize the safety and efficacy of such approaches in translational settings.
In summary, A2 astrocytes represent a neuroprotective subtype that plays a crucial role in promoting neuronal survival and tissue repair following SCI. Experimental studies have shed light on the molecular and signaling mechanisms driving their activation, particularly the JAK/STAT3 pathway. Therapeutic strategies targeting A2 astrocytes hold significant promise for improving SCI outcomes, and future research should focus on elucidating the precise molecular cues that regulate A2 astrocyte activity and developing clinically viable interventions.
4. Microglia: Responders and Regulators
Microglia, the resident immune cells of the CNS, are among the first responders to SCI. These cells play a pivotal role in the pathophysiology of the injury by transitioning from a surveillant state to an activated state, characterized by morphological changes and the release of pro-inflammatory cytokines such as tumor necrosis factor-alpha (TNF-α) and interleukin 1-beta (IL-1β). This initial activation contributes to secondary injury by exacerbating inflammation and oxidative stress [62].
Conversely, microglia also play a reparative role. Given that microglia are known as the resident macrophages of the CNS and M1 and M2 subtypes may coexist at the spinal cord after injury, it is possible to suggest that microglia/macrophages can assume different phenotypes [63]. Microglia/macrophages possess the capacity to shift functions to maintain tissue homeostasis. Stimulation by lipopolysaccharide (LPS) or interferon gamma (IFN-γ) induces a pro-inflammatory M1 phenotype, leading to the release of additional pro-inflammatory cytokines [64]. On the other hand, microglia/macrophages can adopt an anti-inflammatory M2-like phenotype in response to IL-4/IL-13 stimuli, promoting tissue repair and axonal growth by secreting neurotrophic factors such as BDNF [64]. However, the persistent presence of the pro-inflammatory M1-like phenotype can impede these reparative processes, suggesting the need for therapeutic interventions that shift microglial activation towards a more regenerative profile. Table 2 provides a comparative overview of the M1 and M2 microglial/macrophage phenotypes and their roles in neuroinflammation and tissue repair.
Following SCI, microglia/macrophages swiftly respond to tissue damage by undergoing both morphological and functional changes, which result in a combination of beneficial and detrimental effects on neuronal survival and recovery. Understanding the signaling pathways that regulate microglial/macrophage activation and function is essential for the development of targeted therapies aimed at promoting recovery and mitigating secondary injury in SCI.
Microglia/macrophages respond to SCI within minutes to hours by adopting a reactive phenotype, characterized by changes in gene expression, proliferation, and the secretion of inflammatory mediators [67]. Rice et al. (2007) utilized a mouse model of compressive SCI to demonstrate that microglia/macrophages are among the earliest responders, with a marked increase in the expression of IBA1 and IL-1β, which serve as markers of microglial/macrophage activation and inflammatory mediator release, respectively [67]. Additionally, cytokines such as IL-1β, IL-1α, and TNF-α, along with chemokines, are elevated within 15 min post-injury in mice. Immunohistochemical analysis confirmed a rapid peak in microglia/macrophage activation within 3 h, followed by a secondary wave of chemokine expression 24 h later [67]. Persistent microglia/macrophage activation, lasting from one to twelve weeks after contusion injury at the T12 level, was observed up to 5 mm rostral to the injury site [73]. Notably, the activation patterns of glial cells vary across different SCI models. Ischemic injuries typically result in transient increases in activation that persist for less than 2 weeks, whereas spinal contusion damage induces longer-lasting glial activation, which can persist for over a month post-injury [74].
Microglia/macrophage activation following SCI is mediated by multiple signaling pathways, with key contributions from NF-κB, JAK/STAT, and PI3K/Akt signaling. At the molecular level, SCI induces the rapid activation of the NF-κB pathway in microglia/macrophages, leading to the transcription of pro-inflammatory cytokines such as TNF-α, IL-6, and IL-1β. The pharmacological inhibition of NF-κB activation, using compounds like BAY 11-7082, a NLRP3 inflammasome inhibitor, has been shown to reduce neuroinflammation by attenuating microglia/macrophage activation, neutrophil infiltration, and reactive gliosis, ultimately promoting recovery in animal models of compressive SCI [65].
As with astrocytes, the JAK/STAT pathway plays a crucial role in modulating microglia/macrophage phenotypes following SCI. After injury, an increase in the expression of SH3 domain-binding protein 2 (SH3BP2) regulates JAK/STAT signaling, leading to neurological deficits and the induction of M1-like microglia/macrophages by LPS. Conversely, blocking SH3BP2 has been shown to improve neurological outcomes and functional recovery in injured rats by attenuating neuroinflammation and microglia/macrophage polarization [66]. Additionally, a recent study demonstrated that the pan-JAK inhibitor tofacitinib can improve motor dysfunction in SCI models, inhibit neuronal apoptosis, reduce scar tissue formation, and promote the axonal repair and recovery of nerve fibers [69]. The JAK/STAT activation following SCI is likely driven by increased IL-6 levels, leading to the upregulation of the IL-6 receptor (IL-6R) and JAK-STAT signaling in the spinal cord [75]. Notably, elevated IL-6 expression in the injured spinal cords of mice was associated with JAK1/STAT3 activation in the neurons of the anterior horns within 12 h post-injury. However, administration of the JAK inhibitor AG-490 has been shown to hinder recovery, indicating the complex role of JAK/STAT signaling in post-SCI recovery [76]. Thus, a more comprehensive understanding of microglia/macrophage polarization remains essential for developing effective therapeutic strategies following SCI.
The PI3K/Akt pathway plays a vital role in promoting cell survival, proliferation, and angiogenesis in response to extracellular signals. The pharmacological enhancement of PI3K/Akt signaling has been shown to mitigate secondary injury and promote neuronal survival [70]. For instance, Hu et al. (2023) demonstrated that, using an anti-inflammatory and antioxidative agent, it is possible to alleviate neuroinflammation and reduce microglia/macrophage activation through the PI3K/Akt signaling pathway after SCI [70].
Given the dual nature of microglia/macrophage responses, therapeutic strategies aim to modulate their activation states. Small-molecule inhibitors targeting NF-κB via Toll-like receptor 4 (TLR4) have shown promising results in preclinical studies, effectively reducing excessive inflammation [71]. However, it is crucial to emphasize the complexity of microglia/macrophage functions in SCI, as these cells contribute to both neuroinflammation and tissue repair. Experimental studies have identified key signaling pathways, such as NF-κB, JAK/STAT, and PI3K/Akt, which regulate microglia/macrophage activity following injury. Therapeutic interventions targeting these pathways provide promising strategies for modulating microglia/macrophage activity and improving outcomes after SCI. Future research should focus on optimizing microglia/macrophage-based therapies to enhance their clinical applicability.
5. Altered Inflammation in the Brain–Spinal Axis After SCI
The effects of SCI extend beyond the spinal cord, impacting glial cells in supraspinal regions such as the brain. Astrocytes and microglia/macrophages in these areas undergo significant changes that influence motor recovery and contribute to chronic pain. Notably, the prolonged activation of microglia/macrophages in the thalamus has been implicated in central neuropathic pain, underscoring the importance of targeting glial cells in therapeutic strategies [77]. Recent experimental studies have revealed numerous cellular and molecular alterations in brain regions following SCI, which are associated with emotional and cognitive deficits [12,78]. Specifically, the chronic activation of microglia/macrophages in the hippocampus and cerebral cortex results in hypertrophic morphology and a predominance of the pro-inflammatory M1 phenotype [79]. Moreover, the severity of SCI is positively correlated with increased brain inflammation in rodent models [80]. These findings highlight the need for interventions that target glial cell activation to address both the physical and neuropsychological consequences of SCI.
From a clinical perspective, epidemiological data show that approximately 22% of individuals with SCI experience significant symptoms of depression [81], while the prevalence of anxiety ranges from 15% to 32% [82]. Furthermore, a study using functional magnetic resonance imaging (fMRI) in SCI patients revealed that spinal cord and cortical atrophy, particularly in the primary motor and sensory cortices, occur following injury. This suggests a cortical reorganization of the sensorimotor system [83]. Brain atrophy after SCI is likely linked to axonal degeneration, as demonstrated by the microstructural changes in white matter and demyelination in the brain structures of individuals with SCI [84]. These findings highlight the profound impact of SCI not only on the spinal cord but also on the brain, contributing to both physical and psychological challenges.
Although the precise mechanisms underlying brain changes following SCI remain unclear, experimental studies suggest that systemic inflammation may play a key role in affecting brain neurons. In fact, spinal and systemic pro-inflammatory cytokines, including TNF-α, IFN-γ, IL-1β, and IL-6, along with a reduction in the anti-inflammatory cytokine IL-10, have been observed in a compression SCI model in female rats. Notably, IL-1β and IL-6 levels persisted for up to 28 days post-injury [11]. These animals displayed depressive-like behavior, which was linked to systemic inflammation, suggesting that pro-inflammatory molecules contribute to neuropsychiatric symptoms [11]. Additionally, after SCI, the blood–spinal cord barrier is compromised, and increased permeability persists for up to seven days after injury [85], potentially allowing pro-inflammatory molecules to reach the brain. Preclinical studies further highlight the connection between brain inflammation, neurodegeneration, and cognitive and affective disorders in SCI models [79]. These findings underscore the intricate relationship between spinal injury, systemic inflammation, and brain function.
In this context, Yee and Prendergast (2010) demonstrated that the inflammatory response induced by endotoxins is dependent on increased circulating IL-1β, which is closely associated with a decline in social interactions between adult and juvenile female rats [86]. Furthermore, meta-analyses have established a link between serum levels of IL-6 and TNF-α and major depressive disorders (MDDs) [87,88]. Notably, elevated TNF-α concentrations were most commonly found in studies involving MDDs, where symptoms included depressed mood and/or reduced interest or pleasure [87,89]. Anhedonia, the loss of pleasure, has also been shown to be influenced by a temporal imbalance between pro-inflammatory and anti-inflammatory cytokines in systemic circulation—another condition frequently observed in MDD patients [90]. In this regard, the chronic intrathecal administration of baclofen, a γ-aminobutyric acid B (GABA B) receptor agonist, has been shown to prevent cognitive decline in SCI patients over the course of a year [91]. These findings suggest that inflammation plays a central role in both neuropsychiatric symptoms and cognitive deficits following SCI, highlighting potential therapeutic targets for improving mental and cognitive outcomes.
From a molecular perspective, endoplasmic reticulum (ER) stress has been implicated following SCI in response to secondary damage to the spinal cord [92,93], an organelle crucial for the folding of secreted and membrane proteins [94]. This ER stress is also linked to neurodegeneration and cognitive dysfunction [94,95,96]. In particular, the increase in ER stress in certain brain areas correlates with the severity of SCI [80], suggesting a potential molecular pathway tied to the secondary damage after SCI. Pro-inflammatory molecules and reactive oxygen species have been shown to contribute to ER stress [97,98,99], further implicating this process in SCI-related pathology. Evidence supports the idea that activated microglia/macrophages (M1-type), elevated levels of the microglial activator CCL21, neuronal loss, impaired hippocampal neurogenesis, and increased neuronal ER stress all contribute to the development of depressive-like behaviors in experimental SCI models [80]. Additionally, increased microglial activation leads to impaired neurogenesis in the hippocampus and depressive-like behaviors in mice [100]. From a clinical perspective, a 12-week anti-inflammatory diet has been shown to improve mood in SCI patients, with mechanisms likely involving reduced IL-1β levels and improvements in neuroactive compounds related to the kynurenine pathway [101].
In general, circulating markers of inflammation, such as fibrinogen, CRP, TNF-α, IFN-γ, IL-1β, and IL-6, are often elevated in individuals with anxiety disorders [102,103,104,105]. In animal models, Skurlova et al. (2011) demonstrated that in a chronic inflammatory state, heightened anxiety-like behavior in the elevated plus-maze test was associated with the increased expression of IL-1β and IL-6 mRNA in the hippocampus [106], a brain region critical for emotional regulation [107]. Since anxiety often co-occurs with depression-like behaviors after SCI, it is plausible to suggest that these biological mechanisms contribute to this psychiatric phenotype. Consequently, further research is warranted to explore the role of inflammation in the onset of anxiety, as well as how anxiety may modulate inflammation, particularly in contexts where anxiety-like behavior occurs independently of depression.
6. Conclusions
In conclusion, astrocytes and microglia play central roles in the pathophysiology of SCI, acting as both mediators of damage and facilitators of repair. Their complex responses to injury, including the shift between pro-inflammatory and neuroprotective phenotypes, significantly influence the outcomes of SCI, including neuronal survival, tissue repair, and the development of chronic pain or neuropsychiatric disorders. Recent advances in understanding the molecular pathways governing glial activation, such as NF-κB, JAK/STAT, and PI3K/Akt, have revealed potential targets for therapeutic intervention. Furthermore, the interplay between glial cells in the spinal cord and the brain highlights the widespread impact of SCI, with long-term implications for cognitive, emotional, and sensory functions. Future research should focus on fine-tuning the balance between neurotoxic and neuroprotective glial functions, with the goal of enhancing recovery and improving the quality of life for individuals with SCI. This will require a deeper understanding of the molecular mechanisms that regulate glial activation and a concerted effort to develop targeted therapies that can modulate glial responses in both the spinal cord and the brain.
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Fernando da Silva Fiorin www.mdpi.com
