Following injury to the central nervous system (CNS), astrocytes, normally supportive glial cells, undergo a transformation into a reactive state. Among these, a distinct subset known as proliferative reactive astrocytes emerges and plays a critical role in both injury response and tissue repair. This topic explores the complex functions of these astrocytes beyond glial scar formation, highlighting their involvement in neuroprotection, synaptic remodeling, and the restoration of CNS homeostasis. Proliferative reactive astrocytes are regulated by signaling pathways such as JAK/STAT3, Notch, and YAP/TAZ, which control their activation, proliferation, and interaction with other cell types. These astrocytes engage closely with neurons, microglia, and the extracellular matrix, influencing inflammatory responses, axon regeneration, and synaptic plasticity. Their behavior is not uniform; rather, it shows significant regional and temporal heterogeneity, suggesting that their function is finely tuned to the injury context. Understanding the roles of proliferative astrocytes is essential for developing targeted therapies for CNS injuries and neurodegenerative diseases. Instead of being solely seen as barriers to regeneration, these cells are now recognized as potential agents of repair. Emerging strategies aim to modulate their behavior to enhance recovery while minimizing harmful effects. This topic brings attention to the evolving view of astrocytes as dynamic and influential players in CNS repair. By harnessing their regenerative potential, future therapeutic interventions may better support functional recovery after trauma or disease.

Spinal cord injury (SCI) causes progressive secondary damage, yet translation of hypothermia, one of the few preclinical neuroprotectants, has been limited by slow, equipment-dependent cooling that rarely meets the therapeutic window. We tested whether repurposing dexmedetomidine (Dex), an FDA-approved α2-agonist that blocks shivering and has intrinsic neuroprotection, could provide early pharmacological hypothermia to enhance recovery after SCI. Adult mice received moderate thoracic contusive SCI followed by intraperitoneal Dex (100 µg/kg) at 1 h postinjury. Core temperature, vital signs, and ECG were monitored for 24 h. Locomotor recovery, bladder function, tissue preservation, neuronal and axonal sparing, serotonergic circuitry, raphe activation, cytokine profiles, and ERK and RIPK1 signaling were assessed. Comparator groups included untreated injury, conventional surface cooling, hypothermia-prevention by heating, and ERK inhibition. At ambient room temperature (∼24°C), Dex induced rapid, stable moderate hypothermia (∼29-32°C for ∼16 h) without respiratory compromise or arrhythmia. This pharmacological hypothermia, combined with Dex's intrinsic actions, produced greater locomotor and bladder recovery than untreated injury or conventional cooling. Dex preserved perilesional tissue, neuronal survival, axonal integrity, and descending serotonergic input while restoring raphe activation. Mechanistically, Dex plus hypothermia synergistically suppressed acute proinflammatory cytokines, increased IL-10 at Days 7 and 14, activated early ERK-dependent survival signaling, and reduced acute RIPK1-associated injury; blocking hypothermia or ERK signaling attenuated these benefits. The neuroprotective effects of Dex were similar in both sexes. A single clinically relevant Dex dose provides dual-action therapy-pharmacological hypothermia plus intrinsic neuroprotection-offering an immediately translatable, equipment-free strategy for acute SCI and other neurotrauma.

Astrocytes undergo pronounced reactivity during traumatic brain injury (TBI); however, the temporal dynamics of this response and the signaling mechanisms regulating astrocyte proliferation remain incompletely defined. In this study, we characterized the spatiotemporal profile of astrocyte reactivity and proliferation in the hippocampus during TBI and investigated the involvement of mammalian target of rapamycin complex 1 (mTORC1) signaling in these processes. Using a mouse model of TBI, we found that injury triggered a rapid astrocytic response in the hippocampus, characterized by increased glial fibrillary acidic protein (GFAP) expression and morphological hypertrophy as early as 4 h post-injury. Astrocyte proliferation emerged subsequently, peaked during the acute phase (48 and 72 h), and declined to baseline levels at 7 days post-trauma, indicating a transient proliferative response during TBI. Concurrently, mTORC1 signaling was robustly activated in reactive astrocytes in the hippocampus and was specifically associated with proliferative reactive astrocytes during injury. Pharmacological inhibition of mTORC1 signaling with rapamycin significantly reduced reactive astrocyte proliferation during TBI without altering astrocytic hypertrophy. Together, these findings demonstrate that TBI induces a rapid but transient astrocyte activation and proliferation response in the hippocampus and that mTORC1 activation is required for the proliferation, but not the hypertrophic activation, of reactive astrocytes during traumatic brain injury.

HVEM (Herpesvirus Entry Mediator) is an immune checkpoint (ICP) that plays a crucial role in immune regulation, exerting both stimulatory and inhibitory effects depending on the specific ligands or receptors it engages. Although HVEM’s function in modulating immunity is well-recognized in the peripheral immune system and tumor microenvironments, its role and clinical relevance in the central nervous system (CNS) remain largely unexplored. In this study, we measured soluble HVEM (sHVEM) and other ICPs in cerebrospinal fluid (CSF) and plasma samples from people living with HIV (PLWH), both with and without HIV-associated neurocognitive disorders (HAND). We observed that sHVEM levels were elevated in PLWH, particularly in those with HAND, and positively correlated in the CSF with pro-inflammatory cytokines, including IFN-γ, IL-1β, and TNF-α. In vitro, HVEM expression was significantly upregulated in human neural cell lines, including neurons, in response to treatment with IFN-γ, IL-1β, and TNF-α. Additionally, recombinant HVEM-Ig could enhance T cell production of inflammatory cytokines, such as IFN-γ and TNF-α. In rhesus macaques (RMs), HVEM was constitutively expressed in brain neurons and showed marked upregulation in response to SIV infection. These findings suggest that neuronal HVEM may contribute to sHVEM levels and neuroinflammation in the CNS. Therefore, sHVEM holds potential as a biomarker for HAND and as a therapeutic target for neuroinflammatory conditions in PLWH. NIH/NINDS R56NS129438; NIH/NIAAA UH2UH3 AA026218; American Foundation for AIDS Research amfAR-110389 Neuroimmunology (NEUR)

It has been reported both in clinic and rodent models that beyond spinal cord injury directly induced symptoms, such as paralysis, neuropathic pain, bladder/bowel dysfunction, and loss of sexual function, there are a variety of secondary complications, including memory loss, cognitive decline, depression, and Alzheimer’s disease. The large-scale longitudinal population-based studies indicate that post-trauma depression is highly prevalent in spinal cord injury patients. Yet, few basic studies have been conducted to address the potential molecular mechanisms. One of possible factors underlying the depression is the reduction of adult hippocampal neurogenesis which may come from less physical activity, social isolation, chronic pain, and elevated neuroinflammation after spinal cord injury. However, there is no clear consensus yet. In this review, we will first summarize the alteration of hippocampal neurogenesis post-spinal cord injury. Then, we will discuss possible mechanisms underlie this important spinal cord injury consequence. Finally, we will outline the potential therapeutic options aimed at enhancing hippocampal neurogenesis to ameliorate depression.

Tissue damage resulting from a spinal cord injury (SCI) is primarily driven by a robust neuroimmune/neuroinflammatory response. This intricate process is mainly governed by a multitude of cytokines and cell surface proteins in the central nervous system (CNS). However, the critical components of the neuroimmune/neuroinflammatory response during SCI are still not well-defined. In this study, we investigated the impact of CD1d, an MHC class I-like molecule mostly known for presenting lipid antigens to natural killer T (NKT) cells and regulating immune/inflammatory responses, on neuroimmune/neuroinflammatory responses induced by SCI. We observed an increased expression of CD1d on various cell types within the spinal cord, including microglia/macrophages, oligodendrocytes (ODCs), and endothelial cells (DCs), but not on neurons or astrocytes post-SCI. In comparison to wildtype (WT) mice, a T10 contusive SCI in CD1d knockout (CD1dKO or Cd1d -/- ) mice resulted in markedly reduced proinflammatory cytokine release, microglia/macrophage activation and proliferation. Following SCI, the levels of inflammatory cytokines and activation/proliferation of microglia/macrophages were dramatically reduced, while anti-inflammatory cytokines such as IL-4 and growth factors like VEGF were substantially increased in the spinal cord tissues of CD1dKO mice when compared to WT mice. In the post-acute phase of SCI (day 7 post-SCI), CD1dKO mice had a significantly higher frequency of tissue-repairing macrophages, but not other types of immune cells, in the injured spinal cord tissues compared to WT mice. Moreover, CD1d-deficiency protected spinal cord neuronal cells and tissue, promoting functional recovery after a SCI. However, the neuroinflammation in WT mouse spinal cords was independent of the canonical CD1d/NKT cell axis. Finally, treatment of injured mice with a CD1d-specific monoclonal antibody significantly enhanced neuroprotection and improved functional recovery. Therefore, CD1d promotes the proinflammatory response following a SCI and represents a potential therapeutic target for spinal cord repair. Significance Statement The cell surface molecule, CD1d, is known to be recognized by cells of the immune system. To our knowledge, this is the first observation that the CD1d molecule significantly contributes to neuroinflammation following a spinal cord injury (SCI) in a manner independent of the CD1d/NKT cell axis. This is important, because this work reveals CD1d as a potential therapeutic target following an acute SCI for which there are currently no effective treatments.

L- menthol (LM) is a safe and bioactive monoterpenoid from Mentha haplocalyxBriq., with which an acute treatment has shown significant antidepressant-like effects potentially mediated by the modification of monoamine system in mice. Nonetheless, the above conclusions were all based on the forced swimming test. The antidepressant-like effects of acute and subchronic administrations with LM on other depression models have never been illuminated, and its potential mechanisms require further explorations. In this study, the antidepressant-like effects and potential mechanisms of an acute treatment with LM were validated through behavioral despair tests, reserpine-induced ptosis, akinesia and hypothermia test, and 5-hydroxytryptophan-induced head-twitch test in mice. The antidepressant-like effects of subchronic treatments with LM were evaluated in a modified lipopolysaccharide (LPS)-induced depression model. Furthermore, the effects of subchronic treatments with LM on the microglial activation, hippocampal neurogenesis and brain-derived neurotrophic factor (BDNF)/tropomyosin-related kinase B (TrkB) signaling pathway in LPSinduced mice were detected through immunofluorescence assay, enzyme-linked immunosorbent assay and western blotting analysis. Our results showed that acute and subchronic administrations with LM exerted significant antidepressant-like effects in different depression models, which might be mediated by modulating the monoamine system, alleviating neuroinflammation and upregulating the BDNF/TrkB signaling pathway in mice. Taken together, the current study systematically explored the potential of LM as a new candidate for depression therapy, and provided a modified LPS-induced depression model with better apparent and predictive validity.

Abstract Background Tissue damage and cellular destruction are the major events in traumatic brain injury (TBI), which trigger sterile neuroimmune and neuroinflammatory responses in the brain. While appropriate acute and transient neuroimmune and neuroinflammatory responses facilitate the repair and adaptation of injured brain tissues, prolonged and excessive neuroimmune and neuroinflammatory responses exacerbate brain damage. The mechanisms that control the intensity and duration of neuroimmune and neuroinflammatory responses in TBI largely remain elusive. Methods We used the controlled cortical impact (CCI) model of TBI to study the role of immune checkpoints (ICPs), key regulators of immune homeostasis, in the regulation of neuroimmune and neuroinflammatory responses in the brain in vivo. Results We found that de novo expression of PD-L1, a potent inhibitory ICP, was robustly and transiently induced in reactive astrocytes, but not in microglia, neurons, or oligodendrocyte progenitor cells (OPCs). These PD-L1+ reactive astrocytes were highly enriched to form a dense zone around the TBI lesion. Blockade of PD-L1 signaling enlarged brain tissue cavity size, increased infiltration of inflammatory Ly-6CHigh monocytes/macrophages (M/Mɸ) but not tissue-repairing Ly-6CLowF4/80+ M/Mɸ, and worsened TBI outcomes in mice. PD-L1 gene knockout enhanced production of CCL2 that is best known for its ability to interact with its cognate receptor CCR2 on Ly-6CHigh M/Mϕ to chemotactically recruit these cells into inflammatory sites. Mechanically, PD-L1 signaling in astrocytes likely exhibits dual inhibitory activities for the prevention of excessive neuroimmune and neuroinflammatory responses to TBI through (1) the PD-1/PD-L1 axis to suppress the activity of brain-infiltrating PD-1+ immune cells, such as PD-1+ T cells, and (2) PD-L1 intrinsic signaling to regulate the timing and intensity of astrocyte reactions to TBI. Conclusions PD-L1+ astrocytes act as a gatekeeper to the brain to control TBI-related neuroimmune and neuroinflammatory responses, thereby opening a novel avenue to study the role of ICP–neuroimmune axes in the pathophysiology of TBI and other neurological disorders.

Graphene oxide (GO) has been unveiled to exhibit high proton conductivity in a humidified or aqueous environment, making it a promising candidate to construct proton conduction nanochannels. In this work, we systematically investigate how the confinement effect and surface chemistry influence the proton transportation behavior in graphene-based nanochannels via extensive ReaxFF MD simulations. Graphene (GE), graphane (GA), and hydroxygraphane (HG) sheets were employed to mimic the graphitic and functionalized region of GO and construct nanochannels with different interlayer distances. We find that confined water molecules are stratified and their orientation is influenced by the surface chemistry, thus impacting the distribution of protons. Surface chemistry makes the compression of the hydrogen-bond network induced by the confinement effect more variable. The hydrogen-bond network between GE slabs is crushed by extreme confinement and ultrafast proton transportation behavior mainly achieved via vehicle mechanism. Meanwhile, the hydrogen-bond network and solvation structure can be kept more complete with the existence of functional groups. The hydrogen bonds formed with surface functional groups impede the transportation of water molecules but allow more Grotthuss hopping of protons to different extents. Our work clarified the proton transportation mechanism in graphene-based nanochannels with different interlayer distances and surface chemistry and can guide the future design of proton conduction devices such as proton exchange membranes.

BackgroundSoluble programmed cell death-ligand 1 (sPD-L1) has been well documented to activate immunosuppression and is considered an essential predictor of negative clinical outcomes for several malignances and inflammatory conditions. However, the clinical significance of sPD-L1 in the peripheral blood of patients with coronary artery disease (CAD) remains unclear. The aim of this study was to assess the correlations of sPD-L1 with clinical features in CAD patients and evaluate the diagnostic value of this protein in CAD.MethodsA total of 111 CAD patients and 97 healthy volunteers who served as healthy controls (HCs) were consecutively enrolled. Plasma levels of sPD-L1 were measured with an amplified enzyme-linked immunosorbent assay (ELISA), and hs-CRP was measured with a C-reactive protein assay kit. The levels of other inflammatory cytokines were assessed in 88 CAD patients and 47 HCs by a multiparameter immunoluminescence flow cytometry detection technique. A logistic regression model was used to assess the independent association of sPD-L1 with acute coronary syndrome (ACS). The correlation between sPD-L1 and inflammatory cytokines in ACS was also assessed.ResultsPlasma levels of sPD-L1 were significantly increased in CAD patients, especially those with ACS. Univariate logistic regression analysis revealed that sPD-L1 (OR: 3.382, 95% CI: 2.249–5.084, p < 0.001), BMI, hypertension, diabetes, dyslipidemia, previous MI, and the levels of HDL-C, LDL-C and hs-CRP were significantly associated with ACS. sPD-L1 (OR: 3.336, 95% CI: 1.084–6.167, p = 0.001) was found to be independently and significantly associated with ACS in the subsequent multivariable logistic regression analysis. Additionally, elevated plasma sPD-L1 levels were associated with increased interleukin-6 and interleukin-8 levels in ACS patients. Receiver operating characteristic (ROC) analysis showed that the AUC of sPD-L1 for diagnosing ACS was 0.778, with a sensitivity of 73.9% and a specificity of 73.4%, which was comparable with that of the inflammatory biomarker hs-CRP.ConclusionThe plasma sPD-L1 level reflects the severity of CAD, is associated with inflammatory responses and is a potential new biomarker for the diagnosis of ACS.

Background Tissue damage and cellular destruction are the major events in traumatic brain injury (TBI), which trigger sterile neuroimmune and neuroinflammatory responses in the brain. While appropriate acute and transient neuroimmune and neuroinflammatory responses facilitate the repair and adaptation of injured brain tissues, prolonged and excessive neuroimmune and neuroinflammatory responses exacerbate brain damage. The mechanisms that control the intensity and duration of neuroimmune and neuroinflammatory responses in TBI largely remain elusive. Methods We used the controlled cortical impact (CCI) model of TBI to study the role of immune checkpoints (ICPs), key regulators of immune homeostasis, in the regulation of neuroimmune and neuroinflammatory responses in the brain in vivo . Results We found that de novo expression of PD-L1, a potent inhibitory ICP, was robustly and transiently induced in reactive astrocytes, but not in microglial cells, neurons, or oligodendrocyte progenitor cells (OPCs). These PD-L1 + reactive astrocytes were highly enriched to form a dense zone around the TBI lesion. Blockade of PD-L1 signaling enlarged brain tissue cavity size, increased infiltration of inflammatory Ly-6C High monocytes/macrophages (M/M ϕ ) but not tissue-repairing Ly-6C Low/ F4/80 + M/M ϕ , and worsened TBI outcomes in mice. PD-L1 gene knockout enhanced production of CCL2 that interacted with its cognate receptor CCR2 on Ly-6C High M/M ϕ to chemotactically recruit these cells into inflammatory sites. Mechanically, PD-L1 signaling in astrocytes likely exhibits dual inhibitory activities for the prevention of excessive neuroimmune and neuroinflammatory responses to TBI through (1) the PD-1/PD-L1 axis to suppress the activity of brain-infiltrating PD-1 + immune cells such as PD-1 + T cells, and (2) PD-L1 reverse signaling to regulate the timing and intensity of astrocyte reactions to TBI. Conclusions PD-L1 + astrocytes act as a gatekeeper to the brain to control TBI-related neuroimmune and neuroinflammatory responses, thereby opening a novel avenue to study the role of ICP-neuroimmune axes in the pathophysiology of TBI and other neurological disorders.

No FDA approved pharmacological therapy is available that would reduce cell death following traumatic brain injury (TBI). Dexmedetomidine (Dex) is a highly selective agonist of alpha-2 adrenergic receptors and has demonstrated neuroprotective effects in hippocampal slice cultures undergoing direct impact. However, no one has tested whether Dex, in addition to its sedative action, has neuroprotective effects in an animal model of TBI. Thus, in the present study, we investigated the effects of Dex on an animal model of TBI. Mice received different doses of Dex (1, 10, or 100 µg/kg bodyweight, n = 10 each group) or saline as control at 1 hour and 12 hours following TBI. The mice treated with Dex lost less cortical tissue than the control mice. Further analysis found that Dex treatment reduced cell death in the cortex and the hippocampus measured by Fluoro-Jade B (FJB) staining, prevented axonal degeneration detected by immunostaining with antibody against β-amyloid precursor protein (β-APP), and protected synapses from elimination with synaptophysin staining. Taken together, in an in vivo murine model of TBI, Dex at the dose of 100 µg/kg not only prevented tissue lesion and cell death, but also reduced axonal injury and synaptic degeneration caused by TBI.

Symptoms are commonly more severe in pediatric traumatic brain injury (TBI) patients than in young adult TBI patients. To understand the mechanism, juvenile mice received a controlled cortical impact (CCI) injury at moderate level. Tissue lesion and cell death were measured and compared to our previous reports on brain injury in the young adult mice that received same level of impact using same injury device. Tissue lesion and cell death in the cortex was much less in the juvenile mouse brain in the first few hours after injury. However, once the injury occurred, it developed more rapidly, lasted much longer, and eventually led to exaggerated cell death and a 32.7% larger tissue lesion cavity in the cortex of juvenile mouse brain than of young adult mouse brain. Moreover, we found significant cell death in the thalamus of juvenile brains at 72 h, which was not commonly seen in the young adult mice. In summary, cell death in juvenile mice was delayed, lasted longer, and finally resulted in more severe brain injury than in the young adult mice. The results suggest that pediatric TBI patients may have a longer therapeutic window, but they also need longer intensive clinical care after injury.

All aging individuals will develop some degree of decline in cognitive capacity as time progresses. The molecular and cellular mechanisms leading to age-related cognitive decline are still not fully understood. Through our previous research, we discovered that active neural progenitor cells selectively become more quiescent in response to aging, thus leading to the decline of neurogenesis in the aged hippocampus. Here, we further find that aging impaired dendrite development of newborn neurons. Currently, no effective approach is available to increase neurogenesis or promote dendrite development of newborn neurons in the aging brain. We found that systemically administration of 7, 8-dihydroxyflavone (DHF), a small molecule imitating brain-derived neurotrophic factor (BDNF), significantly enhanced dendrite length in the newborn neurons, while it did not promote survival of immature neurons, in the hippocampus of 12-month-old mice. DHF-promoted dendrite development of newborn neurons in the hippocampus may enhance their function in the aging animal leading to a possible improvement in cognition.

Deficits in the Notch pathway are involved in a number of neurologic diseases associated with mental retardation or/and dementia. The mechanisms by which Notch dysregulation are associated with mental retardation and dementia are poorly understood. We found that Notch1 is highly expressed in the adult-born immature neurons in the hippocampus of mice. Retrovirus mediated knockout of notch1 in single adult-born immature neurons decreases mTOR signaling and compromises their dendrite morphogenesis. In contrast, overexpression of Notch1 intracellular domain (NICD), to constitutively activate Notch signaling in single adult-born immature neurons, promotes mTOR signaling and increases their dendrite arborization. Using a unique genetic approach to conditionally and selectively knockout notch 1 in the postnatally born immature neurons in the hippocampus decreases mTOR signaling, compromises their dendrite morphogenesis, and impairs spatial learning and memory. Conditional overexpression of NICD in the postnatally born immature neurons in the hippocampus increases mTOR signaling and promotes dendrite arborization. These data indicate that Notch signaling plays a critical role in dendrite development of immature neurons in the postnatal brain, and dysregulation of Notch signaling in the postnatally born neurons disrupts their development and thus contributes to the cognitive deficits associated with neurological diseases.

Decoy Receptor 3 (DcR3), also called TNFRSF6β, is a member of the tumor necrosis factor receptor superfamily and is a soluble receptor for FasL. DcR3 is overexpressed in cancers and contributes to tumorigenesis through immune suppression and promotion of angiogenesis. We found that DcR3 is overexpressed in breast infiltrating ductal carcinoma (IDC) cells as compared with normal controls. We also conducted a case-control study analyzing associations of DcR3 polymorphisms with breast IDC risk. Subjects included 531 females with breast IDC and 592 age-matched healthy controls. Four DcR3 single nucleotide polymorphism loci with minor frequencies of more than 5% (rs3208008, rs41309931, rs2297441 and rs1291207) were genotyped using polymerase chain reaction restriction fragment length polymorphism and sequencing. Our results revealed significant differences in rs41309931genotypes and alleles (P < 0.01). Based on Haploview software analysis, the haplotype block Ars3208008 Grs41309931 Grs2297441 Ars1291207 exhibited the highest frequency, but, haplotype blocks Ars3208008 Trs41309931 Grs2297441 Ars1291207 and Crs3208008 Grs41309931 Grs2297441 Ars1291207 were associated with breast IDC risk. This study also detected associations between DcR3 gene polymorphisms and the clinicopathological features of breast IDC, including lymph node metastasis and C-erbB2, P53, estrogen receptor and progesterone receptor status. These data indicate that DcR3 gene polymorphisms are associated with sporadic breast IDC risk in Northeast Chinese females.