Spinal cord injury (SCI) is a devastating condition of the central nervous system that often results in severe autonomic dysfunction and permanent motor deficits. A critical contributor to disease progression is secondary injury, characterized by persistent inflammation and immune dysregulation, which exacerbates neural damage and impedes recovery. Consequently, modulating post-injury inflammatory responses and optimizing the local immune microenvironment have emerged as key therapeutic priorities. While current SCI treatments – including surgical decompression, pharmacotherapy, and cellular transplantation – offer some benefits, their clinical effectiveness remain suboptimal. Recent advances have underscored the pivotal roles of immune cells in SCI pathophysiology, revealing their dynamic and temporal involvement in secondary injury processes. Following SCI, diverse immune cell populations infiltrate the lesion site and engage in complex neuroinflammatory cascades through cytokine and chemokine signaling. These immune responses exhibit dualistic potential – either exacerbating tissue damage or facilitating repair – depending on cellular phenotypes and microenvironmental cues. Targeting these immunomodulatory mechanisms presents a promising avenue for enhancing neural recovery. This review examines the contributions of major immune cell subsets – macrophages/microglia, neutrophils, T cells, B cells, and dendritic cells – in regulating post-SCI inflammation, tissue remodeling, and immune microenvironment restoration. We highlight emerging combination immunotherapies that leverage synergistic interactions between multiple immune cell types to optimize therapeutic outcomes. Additionally, we discuss current translational challenges and future research directions in immune-based interventions for SCI, providing both conceptual frameworks and practical considerations to guide the development of effective immunotherapeutic strategies.
The interaction between astrocytes, microglia, and regulatory T cells (Tregs) is essential for maintaining immune homeostasis in the central nervous system (CNS). During neuroinflammation, communication between astrocytes and reactive microglia promotes the upregulation of chemokines that induce T cell infiltration and differentiation into Th17 cells through RORγt activation in response to IL-1β. Effector Th17 cells secrete IL-17 A and IL-17 F, which act on astrocytes and reactive microglia to induce the secondary release of TNF-α and IL-6. This establishes a paracrine feed-forward loop in which glia-derived IL-6 promotes further polarization of T cells toward the Th17 phenotype. In turn, TNF-α acts synergistically with IL-17 to promote the expansion of neurotoxic reactive astrocytes and contributes to disease progression. In contrast, sustained pro-inflammatory cytokine signaling induces CD69 expression on T cells, which, upon interaction with the S100A8/A9 complex secreted by reactive astrocytes, suppresses RORγt and promotes the generation of immunoregulatory Tregs. These CD69⁺ Tregs secrete IL-10 and amphiregulin (Areg), attenuating astrogliosis by inhibiting the STAT3–IL-6 pathway and helping to restore cerebral homeostasis. The persistence and dynamic regulation of Tregs underscore their homeostatic and therapeutic relevance. Additionally, communication between the gut microbiota (GM) and the aryl hydrocarbon receptor (AhR) is a key modulator of the Th17/Treg axis. Although its role in T cell differentiation within the CNS still requires further investigation, it represents a promising therapeutic strategy to modulate glial activation in chronic neuroinflammatory diseases. Astrocytes and regulatory T cells physiologically cooperate to sustain an immunosuppressive brain microenvironment, crucial for neuronal protection. The balance between Th17 cells and regulatory T cells is essential to maintain immune homeostasis in the central nervous system. Astrocyte-regulatory T cell interactions modulate neuroinflammation through key pathways such as IL-2/STAT5, IL-6/STAT3, CD69, and AhR.
The high incidence of depression and anxiety disorders worldwide, with figures of depression > 300 million and anxiety > 264 million, poses a serious challenge to health and wellness. Treatment is still limited by existing pharmacotherapies with delayed onset, adverse side effects, poor entry into the blood–brain barrier (BBB), and resistance in approximately 30
Therapeutic for Alzheimer’s disease (AD) remains a pressing medical challenge in the field of neuroscience. Natural compounds with structural diversity and multi-target regulatory properties have attracted increasing attention for the treatment of complex neurodegenerative disorders. Fraxetin, previously identified through computer-aided virtual screening, C. elegans assays, and in vitro cellular models as a potential anti-AD natural compound, was further investigated in this study using established in vivo and in vitro systems to evaluate its efficacy in ameliorating cognitive function and elucidate underlying mechanisms. A sporadic AD mouse model was established by intracerebroventricular injection of STZ (3 mg/kg). Fraxetin (3, 10, and 30 mg/kg/day, po.) was administered until the mouse sacrifices. Cognitive performance was evaluated using the novel object recognition, passive avoidance, and Morris water maze tests. STZ induced cerebral energy metabolism disturbances accompanied by mitochondrial dysfunction, neuroinflammation, oxidative stress, neuronal and synaptic loss, and cholinergic system impairment. Behavioral tests confirmed that fraxetin ameliorated cognitive deficits in STZ-induced mice. Further studies revealed that fraxetin preserved mitochondrial structural integrity and enhanced mitochondrial biogenesis, accompanied by upregulation of the Sirt1/PGC-1α/Nrf1/TFAM pathway. In parallel, fraxetin attenuated microglial overactivation and neuroinflammatory responses. Consistently, in LPS-stimulated BV2 microglial cells, fraxetin inhibited nitric oxide and inflammatory mediator release, which was associated with modulation of the TLR2/MYD88/NF-κB signaling pathway, while restoring cellular bioenergetic status, indicating coordinated regulation of inflammation-associated metabolic dysfunction. Importantly, fraxetin attenuated neurodegenerative alterations in STZ-treated mice, as evidenced by reduced neuronal loss and synaptic degeneration. These effects were associated with activation of the BDNF/TrkB/ERK/CREB neurotrophic pathway and inhibition of acetylcholinesterase activity, supporting preservation of synaptic and cholinergic function. This study provides experimental evidence supporting fraxetin as a promising natural multi-target candidate for the intervention of AD.
In recent years, opioid abuse has become a major public health crisis affecting millions of individuals throughout the world. This widespread abuse of prescription opioids and dramatic increase in their availability have created the opioid epidemic. Further, oxycodone (oxy), which is prescribed for multiple types of pain, is gaining momentum as a pain reliever in pregnant women. Whilst successful in inducing analgesia, oxy freely passes through the placenta and can impact the overall development of the fetus in major ways. Currently, mechanisms that lead to impairment in the exposed offspring, including identification of biomarkers, are not well described. To fill this gap, our study utilizes a preclinical rodent model to test the therapeutic efficacy of omega-3 fatty acids (O3FA) in attenuating neurodevelopmental deficits in offspring exposed to chronic stress (CS) and oxy in utero which mirrors real-world cases of opioid use during pregnancy co-occurring with chronic psychosocial stress. Our results show that O3FA supplementation partially rescues phenotypic, biochemical, molecular, and behavioral endpoints. Notably, our proteomic study identified distinct key synaptic signatures, including functional pathways impacted in different treatment groups. Furthermore, RT-qPCR results identified key inflammatory markers whose expression was ameliorated by O3FA supplementation. Together, this study bridges an important knowledge gap pertinent to maternal–fetal health that reflects a combined exposure of oxy and CS that is clinically relevant and enumerates the therapeutic efficacy of O3FA in mitigating neurodevelopmental deficits in offspring exposed to in utero oxy and CS. Dietary supplementation with Omega-3 fatty acids rescues neurodevelopmental deficits in offspring exposed to in utero maternal oxycodone and chronic stress.
