Browsing by Subject "neuroinflammation"
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Item Ablation of GSDMD Improves Outcome of Ischemic Stroke Through Blocking Canonical and Non-canonical Inflammasomes Dependent Pyroptosis in Microglia(Frontiers Media S.A., 2020-11-23) Wang, Kankai; Sun, Zhezhe; Ru, Junnan; Wang, Simin; Huang, Lijie; Ruan, Linhui; Lin, Xiao; Jin, Kunlin; Zhuge, Qichuan; Yang, SuIschemia/reperfusion (I/R) injury is a significant cause of mortality and long-term disability worldwide. Recent evidence has proved that pyroptosis, a novel cell death form, contributes to inflammation-induced neuron death and neurological function impairment following ischemic stroke. Gasdermin D (GSDMD) is a newly discovered key molecule of cell pyroptosis, but its biological function and precise role in ischemic stroke are still unclear. The present study investigates the cleavage activity of GSDMD, localization of pyroptotic cells, and global neuroinflammation in gsdmd (-/-) mice after I/R. The level of cell pyroptosis around the infarcted area was significantly increased in the acute phase of cerebral I/R injury. The ablation of GSDMD reduced the infraction volume and improved neurological function against cerebral I/R injury. Furthermore, we confirmed I/R injury induced cell pyroptosis mainly in microglia. Knockdown of GSDMD effectively inhibited the secretion of mature IL-1beta and IL-18 from microglia cells but did not affect the expression of caspase-1/11 in vitro and in vivo. In summary, blocking GSDMD expression might serve as a potential therapeutic strategy for ischemic stroke.Item Aging impairs regulatory T cells to affect the mouse model of late-onset multiple sclerosis(2022-08) Wang, Weikan; Su, Dong-Ming; Berg, Rance E.; Bunnell, Bruce A.; Yang, Shaohua; Jones, Harlan P.; Zode, Gulab S.Although multiple sclerosis (MS) primarily onsets in young adults, it can also develop in the elderly, which is termed late-onset (aged) MS. CD4+ Foxp3 + regulatory T (Treg) cells play an ameliorative role in severity of MS or its animal model experimental autoimmune encephalomyelitis (EAE), and the aged immune system accumulates peripheral Treg (pTreg) cells. However, late-onset MS in the aged patients presents a more progressive disease course. We investigated why the accumulated pTreg cells fail to ameliorate the MS severity in the aged individuals by using an aged EAE mouse model to recapitulate late-onset MS in patients. We observed that the onset of EAE is delayed in aged mice, but disease severity is increased compared to young EAE mice. We found that the distribution of Treg cells in aged EAE mice exhibited an increased proportion of polyclonal (pan-) pTreg cells and a decreased proportion of antigen specific-pTreg cells in the periphery, but decreased proportions of both pan- and antigen specificTreg cells in the central nervous system (CNS). Transiently inhibiting Foxp3 or depleting pTreg cells partially corrected Treg distribution and restored the balance of effector T cells (Teff) and Treg cells in the aged inflamed CNS, thereby ameliorating the disease in the aged EAE mice. Furthermore, in the aged inflamed CNS, CNS-Treg cells exhibited a high plasticity and T effector (CNS-Teff) cells presented a great clonal expansion, disrupting the Treg/Teff balance. These results provide evidence and mechanism that accumulated aged pTreg cells play a detrimental role in neuronal inflammation of aged MS.Item Are aged pTreg cells "the more the better?"(Impact Journals, LLC, 2022-12-25) Wang, Weikan; Thomas, Rachel; Su, Dong-MingItem Astrocyte Elevated Gene-1, a Novel Modulator of Astrocyte Function: Implications for neuroAIDS, aging and glioblastoma(2013-12-01) Vartak, Neha; Ghorpade, AnujaVartak-Sharma, Neha N., Astrocyte elevated gene-1, a novel modulator of astrocyte function: Implications for NeuroAIDS, aging and glioblastoma. Doctor of Philosophy (Biomedical Sciences), Nov, 2013, 180 pp., 1 table, 40 illustrations, 336 bibliographies. Recent attempts to analyze human immunodeficiency virus (HIV)-1-induced gene expression changes in astrocyte identified a multifunctional oncogene, astrocyte elevated gene-1 (AEG-1), as an HIV-1 and tumor necrosis factor-inducible transcript. Subsequently, due to its homology to mouse breast cancer metastasis protein, metadherin, AEG-1 was largely implicated in carcinogenesis of diverse cancer types. However, the role of AEG-1 in astrocytes, the original cell type in which AEG-1 was first identified, still remains to be investigated. In the present study, we identified AEG-1 as a novel modulator of astrocyte function during reactive astrogliosis, neuroinflammation and neurodegeneration, and elucidated its implications in NeuroAIDS, aging and cancer. Our in vitro and in vivo studies recognized AEG-1 modulation of astrocyte migration and proliferation towards the wound site, thereby regulating astrocyte wound healing, a fundamental homeostatic function of astrocytes. Further, AEG-1 expression analyses in HIV-1+ and HIV-1 encephalitic human brain tissues provided the necessary physiological evidence for AEG-1 induction upon HIV-1 neuroinvasion. Herein, we identified AEG-1 as an inflammatory response gene and as an important upstream regulator of NF-κB signaling in astrocytes. Our results demonstrated AEG-1 cytoplasmic and nuclear interaction with NF-κB p65 subunit, which was crucial for NF-κB nuclear translocation, thereby regulating astrocyte neuroinflammation. In the same study, we also identified AEG-1 as a novel regulator of astrocyte glutamate clearance, an important determinant of neurocognitive CNS function, by modulating the expression of the key glutamate transporter, excitatory amino acid transporter 2. Analyses of AEG-1 expression in the cognitive centers of the brain of aging individuals demonstrated AEG-1 age-dependent expression in the human brain, which further proposed a role for AEG-1 in cellular oxidative stress responses. Herein, we identified a novel antioxidant cytoprotective role of AEG-1 in astrocytes and astrocytoma cells. Cellular localization studies by confocal microscopy revealed AEG-1 localization to the dense fibrillar components of the nucleolus in response to injury or oxidative stress, suggesting AEG-1 implication in ribosomal RNA processing. Our results demonstrated AEG-1 regulation of catalase activation and Nrf2 stabilization in response to oxidative stress and further elucidated AEG-1 modulation of Nrf2 nuclear translocation, the first step in antioxidant cellular defense mechanisms. The results presented in this thesis provide insight into the role of oncogene AEG-1 in human astrocytes and ameliorates our understanding of astrocyte-mediated processes in normal and disease-relevant pathologies, ranging from HIV-1-associated neurocognitive disorders and traumatic CNS injuries to primary neoplasms of the brain.Item Astrocyte HIV-1 Tat Differentially Modulates Behavior and Brain MMP/TIMP Balance During Short and Prolonged Induction in Transgenic Mice(Frontiers Media S.A., 2020-12-15) Joshi, Chaitanya R.; Stacy, Satomi; Sumien, Nathalie; Ghorpade, Anuja; Borgmann, KathleenDespite effective antiretroviral therapy (ART), mild forms of HIV-associated neurocognitive disorders (HAND) continue to afflict approximately half of all people living with HIV (PLWH). As PLWH age, HIV-associated inflammation perturbs the balance between brain matrix metalloproteinases (MMPs) and their tissue inhibitors of metalloproteinases (TIMPs), likely contributing to neuropathogenesis. The MMP/TIMP balance is associated with cognition, learning, and memory, with TIMPs eliciting neuroprotective effects. Dysregulation of the MMP/TIMP balance was evident in the brains of PLWH where levels of TIMP-1, the inducible family member, were significantly lower than non-infected controls, and MMPs were elevated. Here, we evaluated the MMP/TIMP levels in the doxycycline (DOX)-induced glial fibrillary acidic protein promoter-driven HIV-1 transactivator of transcription (Tat) transgenic mouse model. The HIV-1 protein Tat is constitutively expressed by most infected cells, even during ART suppression of viral replication. Many studies have demonstrated indirect and direct mechanisms of short-term Tat-associated neurodegeneration, including gliosis, blood-brain barrier disruption, elevated inflammatory mediators and neurotoxicity. However, the effects of acute vs. prolonged exposure on Tat-induced dysregulation remain to be seen. This is especially relevant for TIMP-1 as expression was previously shown to be differentially regulated in human astrocytes during acute vs. chronic inflammation. In this context, acute Tat expression was induced with DOX intraperitoneal injections over 3 weeks, while DOX-containing diet was used to achieve long-term Tat expression over 6 months. First, a series of behavior tests evaluating arousal, ambulation, anxiety, and cognition was performed to examine impairments analogous to those observed in HAND. Next, gene expression of components of the MMP/TIMP axis and known HAND-relevant inflammatory mediators were assessed. Altered anxiety-like, motor and/or cognitive behaviors were observed in Tat-induced (iTat) mice. Gene expression of MMPs and TIMPs was altered depending on the duration of Tat expression, which was independent of the HIV-associated neuroinflammation typically implicated in MMP/TIMP regulation. Collectively, we infer that HIV-1 Tat-mediated dysregulation of MMP/TIMP axis and behavioral changes are dependent on duration of exposure. Further, prolonged Tat expression demonstrates a phenotype comparable to asymptomatic to mild HAND manifestation in patients.Item Blood Inflammatory Exosomes with Age Prime Microglia through Complement Signaling for Negative Stroke Outcomes(2020-05) Zhang, Hongxia; Jin, Kunlin; Forster, Michael J.; Yang, Shaohua; Shi, Xiangrong; Cunningham, J. ThomasThe systemic inflammatory milieu plays an important role in the age-related decline of functional integrity, but its contribution to age-related disease (e.g., stroke) remains largely unknown. Here, we found that activated complement molecules (C1q, C3a, C3b) in serum exosomes increased with age, whereas CD46, a C3b/C4b-inactivating factor, was higher in serum exosomes from young rats. These serum inflammatory exosomes passed the blood-brain barrier and primed the microglial response that led to exacerbation of synaptic loss and motor deficits after ischemic stroke via microglial C3a receptor (C3aR). When aged rats were exposed to serum exosomes from young rats, microglia-mediated synaptic loss was reduced and motor deficits after stroke were improved. Administration of C3aR inhibitor or microglial depletion attenuated synaptic loss associated with the treatment of serum exosome from aged rats, in parallel with improved post-stroke outcome. Our data suggest that peripheral circulating old exosomes act as inflammatory mediators and influence ischemic stroke outcome through a complement-microglia axis.Item Editorial: The NLRP3 inflammasome-mediated neuroinflammation and its related mitochondrial impairment in neurodegeneration(Frontiers Media S.A., 2023-01-31) Deng, Chao; Cai, Xiang; Wang, Qing; Jin, KunlinItem Healthy Human Fecal Microbiota Transplantation into Mice Attenuates MPTP-Induced Neurotoxicity via AMPK/SOD2 Pathway(Aging and Disease, 2023-05-18) Xie, Zhencao; Zhang, Mahui; Luo, Yuqi; Jin, Dana; Guo, Xingfang; Yang, Wanlin; Zheng, Jialing; Zhang, Hongfei; Zhang, Lu; Deng, Chao; Zheng, Wenhua; Tan, Eng-King; Jin, Kunlin; Zhu, Shuzhen; Wang, QingIncreasing evidence has shown that gut dysbacteriosis may play a crucial role in neuroinflammation in Parkinson's disease (PD). However, the specific mechanisms that link gut microbiota to PD remain unexplored. Given the critical roles of blood-brain barrier (BBB) dysfunction and mitochondrial dysfunction in the development of PD, we aimed to evaluate the interactions among the gut microbiota, BBB, and mitochondrial resistance to oxidation and inflammation in PD. We investigated the effects of fecal microbiota transplantation (FMT) on the physiopathology of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated mice. The aim was to explore the role of fecal microbiota from PD patients and healthy human controls in neuroinflammation, BBB components, and mitochondrial antioxidative capacity via the AMPK/SOD2 pathway. Compared to control mice, MPTP-treated mice exhibited elevated levels of Desulfovibrio, whereas mice given FMT from PD patients exhibited enriched levels of Akkermansia and mice given FMT from healthy humans showed no significant alterations in gut microbiota. Strikingly, FMT from PD patients to MPTP-treated mice significantly aggravated motor impairments, dopaminergic neurodegeneration, nigrostriatal glial activation and colonic inflammation, and inhibited the AMPK/SOD2 signaling pathway. However, FMT from healthy human controls greatly improved the aforementioned MPTP-caused effects. Surprisingly, the MPTP-treated mice displayed a significant loss in nigrostriatal pericytes, which was restored by FMT from healthy human controls. Our findings demonstrate that FMT from healthy human controls can correct gut dysbacteriosis and ameliorate neurodegeneration in the MPTP-induced PD mouse model by suppressing microgliosis and astrogliosis, ameliorating mitochondrial impairments via the AMPK/SOD2 pathway, and restoring the loss of nigrostriatal pericytes and BBB integrity. These findings raise the possibility that the alteration in the human gut microbiota may be a risk factor for PD and provide evidence for potential application of FMT in PD preclinical treatment.Item Mechanisms by which 17β-Estradiol (E2) suppress neuronal cox-2 expression(2015-12-01) Stacey, Winfred; Rosalie M. Uht; Rebecca L. Cunningham; Eric B. GonzalesData from animal models indicate that 17β-estradiol (E2) deprivation increases susceptibility to neurodegenerative diseases. E2 attenuates inflammatory response by suppressing expression of pro-inflammatory genes; however, the mechanisms by which E2 suppress neuronal pro-inflammatory genes are not well established. Histological analyses of postmortem human brains suggest that neuronal cyclooxygenase-2 (COX-2) is upregulated in early stages of Alzheimer’s disease (AD) and in Parkinson’s disease (PD). Given that COX-2 is selectively expressed in a subset of neurons in the hippocampus, cerebral cortex, and amygdala, we investigated mechanisms by which E2 could down-regulate cox-2 expression in a neuronal system. To characterize the effect of E2 on cox 2 in a neuronal system, we used the AR-5 and N27 rat neuronal cell line models. Our data indicate that E2 and ERβ agonist diarylpropionitrile (DPN) suppress COX-2 pre-mRNA and mRNA levels to the same extent in AR-5 but not in N27. Furthermore, PHTPP, a selective ERβ antagonist, reversed the effect of both E2 and DPN in AR-5. Because the cox-2 promoter lacks palindromic estrogen response elements (EREs), we targeted a proximal promoter region with a nuclear factor- ĸB (NF-ĸB) response element implicated in cox-2 regulation. E2 and DPN failed to increase ERβ occupancy at the cox-2 promoter. Rather, DPN decreased promoter occupancy of p65 NF-κB subunit and acetylation of histone 4 (Ac-H4). Treatment with the non-specific HDAC inhibitor Trichostatin A (TSA) counteracted DPN’s repressive effects on cox-2 expression. In keeping with the effect of TSA, E2 and DPN increase HDAC1 promoter occupancy; however recruitment of HDAC3 was unchanged. HDAC1 is known to form a complex with Swi-independent A (Sin3A); E2 and DPN increased Sin3A occupancy. The recruitment of HDAC1 seems to correlate with decreased acetylation of histone 4 (H4) and not histone 3 (H3). Furthermore E2 alone increased methylation status in the cox-2 proximal promoter. Taken together, these data suggest that E2 suppresses neuronal cox-2 expression through ERβ-mediated recruitment of HDAC1, Sin3A and a concomitant reduction of p65 and H4 levels. Here we conclude that E2 suppresses neuronal cox-2 expression through a mechanism that involves a combination of decreasing activator and increasing repressor recruitment to the cox-2 promoter.Item Modulation of Astrocyte Phenotype in Response to T-cell Interaction(2021-05) Hersh, Jessica M.; Yang, Shaohua; Smith, Michael L.; Jin, Kunlin; Hodge, Lisa M.We determined that T-cell astrocyte interaction modulates interleukin-10 (IL-10) production from both cell types. The impact of IL-10 on astrocytes was compared to IL-10 generated from T-cell-astrocyte interactions in vitro. We demonstrated that T-cells directly interact with astrocytes to upregulate gene expression and secretion of IL-10, confirmed by elevated STAT3p/STAT3 expression in astrocytes. IL-10 increased astrocytes proliferation. In addition, IL-10 treatment and CD4+ co-culture shifts primary astrocytes toward a more energetic phenotype. These findings indicate that direct interaction of CD4+ T-cells with astrocytes, activated the IL-10 anti-inflammatory pathway, altering astrocyte phenotype, metabolism, and proliferation.Item Pathological Mechanisms of Retinal Ischemia/Reperfusion Injury and Potential Targets of Neuroprotection(2015-12-01) Silverman, Sean M.; Clark, Abbot F.; Pang, Iok-Hou; Krishnamoorthy, Raghu R.Neurodegenerative diseases trigger a cascade of pathological mediators including significant accumulation of reactive oxygen species (ROS) and chronic neuroinflammation resulting in widespread neuronal loss. We can effectively mimic these changes in a mouse model of retinal ischemia/reperfusion (I/R) injury. Herein we demonstrate retinal I/R leads to chronic upregulation of C1q expression accompanied by similar long-term activation of microglia and astrocytes, as well as a significant increase in retinal ROS. These changes resulted in morphological and functional degeneration. In addition, we identified the neuroprotective potential of modulating changes in C1q and superoxide by genetic and pharmacological methods. In the retina I/R injury resulted in significant increases in C1q expression, glial activation and cell density by day 3 compared to controls. These changes continued to increase and were sustained through our entire 28 day time course. Similar effects from injury were observed in the superior colliculus (SC), one of the primary visual centers in the brain of rodents. Surprisingly, hemispheres corresponding to both injured and noninjured eyes displayed signs of chronic neuroinflammation by day 21. Using the chemilluminescent compound L-012 we demonstrated a novel method for non-invasive in vivo detection of superoxide in the eye as early as 24 hours post injury. These findings were confirmed with dihydroethidium (DHE) in the retina. Our previous work has characterized inner retinal thinning, loss of retinal ganglion cells (RGCs), and suppression of b-wave amplitudes due to I/R injury. Using C1qa-deficient mice, we show complete morphological protection and ablation of reactive microgliosis. However, astrocytes were unaffected by deletion of C1q, and retinal function was only partially preserved. Two superoxide inhibitors, Apocynin and Tempol, significantly reduced L-012 chemilluminescence 24 and 48 hours after injury. Further, Apocynin treatment completely protected against morphological degeneration in the retina and significantly rescued functional deficits. In conclusion, this study demonstrates the therapeutic potential of modulating either C1q or superoxide for neuroprotection following injury or diseases where they are implicated in pathological loss.Item Pyruvate Intervention for Brain Injury Inflicted by Cardiac Arrest-Resuscitation(2016-05) Nguyen, Anh Q.; Mallet, Robert T.; Olivencia-Yurvati, Albert H.; Raven, Peter B.; Yang, Shaohua; Rickards, Caroline A.Fewer than 10% of the 360,000 people who suffer out-of-hospital cardiac arrest annually in the U.S. survive to hospital discharge. Many suffer brain injuries that greatly affect their daily activities and quality of life. Despite improvements in clinical outcomes from cardiac arrest as a result of therapeutic hypothermia, survival rates are still dismal. Additional interventions to be used alone or in combination with therapeutic hypothermia could potentially save many lives. The intermediate metabolite pyruvate has been proven to be neuroprotective when given acutely. The goal of this investigation is to examine the neuroprotective capabilities and mechanisms of pyruvate in a large animal model of cardiac arrest, closed-chest cardiopulmonary resuscitation (CPR) and countershock induced defibrillation. The central hypothesis is that pyruvate therapy suppresses matrix metalloproteinase (MMP) activity and thereby preserves blood-brain barrier (BBB) integrity, increases expression and content of the cytoprotective cytokine erythropoietin (EPO), and dampens inflammation following cardiac arrest, and, thus, improves neurobehavioral recovery from cardiac arrest. Experiments were conducted in Yorkshire swine, subjected to cardiac arrest, closed-chest cardiocerebral resuscitation (CCR), defibrillation by trans-thoracic countershock, and recovery. The project was divided into two studies with different durations of cardiac arrest, producing different intensities of brain damage. In the first study, swine were subjected to 6 min of untreated cardiac arrest and 4 min of CCR, following by defibrillation and recovery of spontaneous circulation (ROSC). In the second study, untreated cardiac arrest was extended to 10 min before 4 min CCR. Animals were euthanized at 1, 4, and 72 h ROSC, and the brain was biopsied for histological and biochemical analyses. For animals in 72 h ROSC groups, neurological assessment and testing were performed at 24, 48, and 72 h ROSC. At 3 d ROSC, the number of viable cerebellar Purkinje cells fell by 30% vs. Sham control, but pyruvate infusion during CCR and the first 60 min ROSC preserved these neurons. EPO mRNA abundance was sharply increased at 4 h ROSC and in the non-arrest Sham, indicating the surgical protocol, hyperoxic ventilation and anesthesia induced neuroprotective EPO, which may have limited brain injury. There were no differences in neurological scores among Sham, CPR, and CPR+Pyruvate, prompting study of more prolonged cardiac arrest to intensify brain injury. At 4 h ROSC in 10 min untreated cardiac arrest group, cardiac arrest unexpectedly decreased hippocampal and cerebellar MMP-2 activities and cerebellar EPO content, regardless of treatment. 72 h survival rate fell from 100% in study one (6 min pretreatment arrest) to only 2 of 6 pigs in study two (10 min pretreatment arrest), which wide disparity in neurological function among the 2 survivors. Collectively, these results indicate the prolonging pre-intervention arrest from 6 to 10 min sharply intensified brain injury, depleted cytoprotective EPO, and inactivated oxyradical-sensitive enzymes. Pyruvate treatment did not exert favorable effects on these variables, indicating that pyruvate may have had limited ability to traverse the blood brain barrier and protect the brain parenchyma in this large animal model of cardiac arrest and CCR.Item Transcriptome and functional profiles of R/G-HIV+ human astrocytes: Implications for shock or lock therapies in the brain(2020-05) Edara, Venkata Viswanadh; Borgmann, Kathleen; Berg, Rance E.; Krishnamoorthy, Raghu R.; Mathew, Porunelloor A.; Yang, Shaohua; Patterson, Rita M.A significant number of people living with human immunodeficiency virus (HIV) suffer from HIV-associated neurocognitive disorders (HAND). Many previous studies investigating HIV in astrocytes as a heterogenous population have established the relevance of astrocytes to HIV-associated neuropathogenesis. However, these studies were unable to differentiate the state of infection, i.e. active or restricted, or to evaluate how this affects astrocyte biology. In this study a pseudotyped doubly labelled fluorescent reporter R/G-HIV-1 was used to identify and enrich restricted and active populations of HIV+ astrocytes based on the viral promoter activity. Here we report, the majority of human astrocytes restricted R/G-HIV-1 gene expression early during infection and were resistant to reactivation by vorinostat and interleukin-1β. However, actively infected astrocytes were inducible, leading to increased expression of viral proteins upon reactivation. R/G-HIV-1 infection also significantly decreased cell proliferation and glutamate clearance ability of astrocytes, which may contribute to excitotoxicity. Moreover, transcriptome analyses to compare gene expression patterns of astrocytes harboring active vs restricted long terminal repeats revealed that the gene expression patterns were similar, and the active population demonstrated more widespread and robust changes. Our data suggest that harboring the HIV genome profoundly alters astrocyte biology and strategies that keep the virus latent (e.g. Block and Lock), or those that reactivate the latent virus (e.g. Shock and Kill) may be detrimental to astrocyte function and possibly augment their deleterious contributions to HAND.Item β-Catenin Regulates Wound Healing and IL-6 Expression in Activated Human Astrocytes(MDPI, 2020-11-06) Edara, Venkata Viswanadh; Nooka, Shruthi; Proulx, Jessica; Stacy, Satomi; Ghorpade, Anuja; Borgmann, KathleenReactive astrogliosis is prominent in most neurodegenerative disorders and is often associated with neuroinflammation. The molecular mechanisms regulating astrocyte-linked neuropathogenesis during injury, aging and human immunodeficiency virus (HIV)-associated neurocognitive disorders (HAND) are not fully understood. In this study, we investigated the implications of the wingless type (Wnt)/beta-catenin signaling pathway in regulating astrocyte function during gliosis. First, we identified that HIV-associated inflammatory cytokines, interleukin (IL)-1beta and tumor necrosis factor (TNF)-alpha induced mediators of the Wnt/beta-catenin pathway including beta-catenin and lymphoid enhancer-binding factor (LEF)-1 expression in astrocytes. Next, we investigated the regulatory role of beta-catenin on primary aspects of reactive astrogliosis, including proliferation, migration and proinflammatory responses, such as IL-6. Knockdown of beta-catenin impaired astrocyte proliferation and migration as shown by reduced cyclin-D1 levels, bromodeoxyuridine incorporation and wound healing. HIV-associated cytokines, IL-1beta alone and in combination with TNF-alpha, strongly induced the expression of proinflammatory cytokines including C-C motif chemokine ligand (CCL)2, C-X-C motif chemokine ligand (CXCL)8 and IL-6; however, only IL-6 levels were regulated by beta-catenin as demonstrated by knockdown and pharmacological stabilization. In this context, IL-6 levels were negatively regulated by beta-catenin. To better understand this relationship, we examined the crossroads between beta-catenin and nuclear factor (NF)-kappaB pathways. While NF-kappaB expression was significantly increased by IL-1beta and TNF-alpha, NF-kappaB levels were not affected by beta-catenin knockdown. IL-1beta treatment significantly increased glycogen synthase kinase (GSK)-3beta phosphorylation, which inhibits beta-catenin degradation. Further, pharmacological inhibition of GSK-3beta increased nuclear translocation of both beta-catenin and NF-kappaB p65 into the nucleus in the absence of any other inflammatory stimuli. HIV+ human astrocytes show increased IL-6, beta-catenin and NF-kappaB expression levels and are interconnected by regulatory associations during HAND. In summary, our study demonstrates that HIV-associated inflammation increases beta-catenin pathway mediators to augment activated astrocyte responses including migration and proliferation, while mitigating IL-6 expression. These findings suggest that beta-catenin plays an anti-inflammatory role in activated human astrocytes during neuroinflammatory pathologies, such as HAND.