Shamsudheen Moidunny’s research while affiliated with University of Miami and other places

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Publications (13)


Anxiety-like behavior during protracted morphine withdrawal is driven by gut microbial dysbiosis and attenuated with probiotic treatment
  • Preprint

February 2025

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5 Reads

Mark Oppenheimer

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Junyi Tao

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Shamsudheen Moidunny

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The development of anxiety during protracted opioid withdrawal heightens the risk of relapse into the cycle of addiction. Understanding the mechanisms driving anxiety during opioid withdrawal could facilitate the development of therapeutics to prevent negative affect and promote continued abstinence. Our lab has previously established the gut microbiome as a driver of various side effects of opioid use, including analgesic tolerance and somatic withdrawal symptoms. We therefore hypothesized that the gut microbiome contributes to the development of anxiety-like behavior during protracted opioid withdrawal. In this study, we first established a mouse model of protracted morphine withdrawal, characterized by anxiety-like behavior and gut microbial dysbiosis. Next, we used fecal microbiota transplantation (FMT) to show that gut dysbiosis alone is sufficient to induce anxiety-like behavior. We further demonstrate that probiotic therapy during morphine withdrawal attenuates the onset of anxiety-like behavior, highlighting its therapeutic potential. Lastly, we examined transcriptional changes in the amygdala of morphine-withdrawn mice treated with probiotics to explore mechanisms by which the gut-brain axis mediates anxiety-like behavior. Our results support the use of probiotics as a promising therapeutic strategy to prevent gut dysbiosis and associated anxiety during opioid withdrawal, with potential implications for improving treatment outcomes in opioid recovery programs.


Morphine treatment induces taxonomic and functional dysbiosis in small intestinal microbiome. (a) Beta diversity of phylogenic relative abundance of ileal microbiome at species level in control and morphine group calculated as Bray-Curtis dissimilarity matrix. PERMANOVA analysis (p = .026) show significant changes in microbial composition. (b) Cladogram showing the differentially abundant microbial taxa, including bacteria, archaea, virus, fungi identified by LEfSe analysis (P < .05 Krushkal-wallis test, LDA > 2.0). Green represents taxa abundant in morphine group compared to control; blue, represents taxa abundant in control group compared to morphine group. (u_s: unclassified species, u_g: unclassified genus, u_f: unclassified family, u_c: unclassified class, u_o: unclassified order) (c) Principal component analysis based on relative abundance of KOs discriminates the functional signature of control and morphine microbiome. (d) Overview of microbiome functional profile based on KEGG metabolism in control and morphine groups. Bar graph showing enrichment of GO modules involved in (e) LPA and LTA biosynthesis, (f) lipid metabolism, (g) vitamin metabolism, (h) amino acid metabolism, and (i) other biologically important GO modules. n = 5 mice per group. Data (e, f, g, h, and i) were analyzed using moderated t-test (mean± standard error of mean (SEM), *p adj ≤ .05, **p adj ≤ .01, ***p adj ≤ .001, ****p adj ≤ .0001. n = 5 per group.
Morphine use results in broad changes in small intestinal metabolome. (a) Score plot showing Partial Least Squares-discriminant analysis (PLS-DA) of morphine and control ileal metabolite profile (variance is explained by PC1 (55.4%) and PC2 (14.1%)). (b) Volcano plot showing most significant metabolites identified by univariate analysis. 115 out of 243 metabolites were significantly different in morphine compared to control samples. (c) Heat map showing top 50 metabolites significantly altered across control and morphine groups. Box plots showing log2 fold changes in relative abundance (Peak area) of (d) phosphocholines, (e) N-acylethanolamines, and (f) carnitines. n = 5 per group. Data (d, e, and f) were analyzed using moderated t-test; the box-and-whisker plot indicates the minimum and maximum distribution (whiskers) and the upper and lower quartile limits (box), with the median value shown as a line. *p adj ≤ .05, **p adj ≤ .01, ***p adj ≤ .001, ****p adj ≤ .0001.
Global overview of small intestine transcriptome changes in morphine treated mice. (a) Volcano plot of the 5140 differentially expressed genes between morphine and control group (Log2 (fold change) > 1; Padj <.005). Functional annotation enrichment analyses of (b) 2606 upregulated and (c) 2534 downregulated genes after morphine using ClueGO charts. Detailed functional annotation enrichment analyses of the (d) 2606 upregulated and (e) 2534 downregulated core genes using ToppGene, ToppCluster, and Cytoscape are shown. GO: biological process (teal), cellular component (brown), and molecular function (blue gray), disease (green). The full list of gene set enrichment results and P values are in Supplementary file 3.
Morphine mediated changes in murine intestinal transcriptome profiles are influenced by gut microbiota. (a) Volcano plot of the 1371 differentially expressed genes between morphine and AM group (Log2 (fold change) > 1; Padj <.005). Functional annotation enrichment analyses of the (b) 667 upregulated and (c) 704 downregulated genes after morphine using ClueGO charts. Detailed functional annotation enrichment analyses of the (d) 667 upregulated and (e) 704 downregulated core genes using ToppGene, ToppCluster, and Cytoscape are shown. GO: biological process (teal), cellular component (brown), and molecular function (blue gray), disease (green). The full list of gene set enrichment results and P values are in Supplementary file 4.
Systematic molecular correlations across multi-omes integrating morphine mediated changes in microbiome, metabolome, and host transcriptome. Host microbiome interaction network (Spearman coefficient ≥ ± 0.7) showing significant correlations between microbiome, metabolites and DEGs (P adj ≤ 0.05). Microbial species, metabolites, and DEGs are represented as nodes; microbiome (blue square), metabolite (orange circle), DEGs (gray triangle). Lines represent statistically significant correlations and are colored red for positive and blue for negative correlations.
Multi-omics analysis revealing the interplay between gut microbiome and the host following opioid use
  • Article
  • Full-text available

August 2023

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44 Reads

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22 Citations

Udhghatri Kolli

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Richa Jalodia

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Shamsudheen Moidunny

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[...]

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Opioid crisis is an ongoing epidemic since the past several decades in the United States. Opioid use-associated microbial dysbiosis is emerging as a key regulator of intestinal homeostasis and behavioral responses to opioid. However, the mechanistic insight into the role of microbial community in modulating host response is unavailable. To uncover the role of opioid-induced dysbiosis in disrupting intestinal homeostasis we utilized whole genome sequencing, untargeted metabolomics, and mRNA sequencing to identify changes in microbiome, metabolome, and host transcriptome respectively. Morphine treatment resulted in significant expansion of Parasuterella excrementihominis, Burkholderiales bacterium 1_1_47, Enterococcus faecalis, Enterorhabdus caecimuris and depletion of Lactobacillus johnsonii. These changes correlated with alterations in lipid metabolites and flavonoids. Significant alteration in microbial metabolism (metabolism of lipids, amino acids, vitamins and cofactors) and increased expression of virulence factors and biosynthesis of lipopolysaccharides (LPS) and lipoteichoic acid (LTA) were observed in microbiome of morphine-treated animals. In concurrence with changes in microbiome and metabolome extensive changes in innate and adaptive immune response, lipid metabolism, and gut barrier dysfunction were observed in the host transcriptome. Microbiome depleted mice displayed lower levels of inflammation, immune response and tissue destruction compared to mice harboring a dysbiotic microbiome in response to morphine treatment, thus establishing dysbiotic microbiome as mediator of morphine gut pathophysiology. Integrative analysis of multi-omics data highlighted the associations between Parasutterella excrementihominis, Burkholderiales bacterium 1_1_47, Enterococcus faecalis, Enterorhabdus caecimuris and altered levels of riboflavin, flavonoids, and lipid metabolites including phosphocholines, carnitines, bile acids, and ethanolamines with host gene expression changes involved in inflammation and barrier integrity of intestine. Omic analysis also highlighted the role of probiotic bacteria Lactobacillus johnsonii, metabolites flavonoids and riboflavin that were depleted with morphine as important factors for intestinal homeostasis. This study presents for the first time ever an interactive view of morphine-induced changes in microbial metabolism, strain level gut microbiome analysis and comprehensive view of changes in gut transcriptome. We also identified areas of potential therapeutic interventions to limit microbial dysbiosis and present a unique resource to the opioid research community.

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Morphine treatment compromises intestinal epithelial barrier function in mice. (a) Representative H&E stained small intestinal sections from control, morphine, naltrexone and naltrexone + morphine treated mice. (Scale bar: 50 μm). (b) Scoring guide for histopathological damage scoring from H&E stained intestinal sections. (c) Graph showing histopathological damage score in intestinal sections in different mice groups. (d) Representative image of Claudin-1 (green) organization in distal small intestine of control, morphine, naltrexone and naltrexone + morphine treated mice. (Scale bar: 50 μm). (e) Representative image for ZO-1 and F-actin staining from frozen ileum sections in control and morphine mice groups. White arrow indicates co-localization of ZO-1 with F-actin in control mice. Data represented as bar plots with Standard error of mean (SEM). Data were analyzed by one-way ANOVA with post-hoc Tukey’s test. ****P ≤ 0.0001.
Morphine treatment increases neutrophil recruitment to intestinal tissue by regulating tissue chemokine expression. (a) Gating strategy for neutrophils isolated from lamina propria from mouse small intestine of control and morphine treated mice group with representative dot plot graphs for control and morphine group. (b) Graph showing CD11b+ Ly6G+ neutrophil cells, as a percentage of viable CD45 cell subset. (c) Heat map of chemokine levels in distal small intestinal homogenate from control and morphine group as determined by qPCR array. (d) Relevant chemokines differentially produced in distal small intestine in control and morphine group. Data represented as bar plots with SEM. (b,d)Data were analyzed by student’s t-test (n = 8–10). *P ≤ 0.05; **P ≤ 0.01; ****P ≤ 0.0001.
Gut microbiome regulates morphine-induced neutrophil infiltration and changes in chemokine expression. (a) Representative dot plot graphs showing flow cytometry for neutrophil population in different treatment groups. (b) Graph showing CD11b+ Ly6G+ neutrophil cells, as a percentage of viable CD45 cell subset in different treatment groups. (c) Relevant chemokines differentially produced in distal small intestine in different treatment groups. (d) Representative H&E stained small intestinal sections from control, morphine, Abx and Abx+morphine treated mice groups. (Scale bar: 50 μm). (e) Representative image of Claudin-1 (green) organization in distal small intestine of control, morphine, Abx and Abx+morphine treated mice. (Scale bar: 50 μm). Data represented as bar plots with SEM. Data were analyzed by one-way ANOVA with post-hoc Tukey’s test. *P ≤ 0.05; ***P ≤ 0.001.
Morphine-induced tissue neutrophil infiltrates cause tissue disruption and disrupt tight junction organization. (a) Experimental scheme for neutrophil depletion in C57 mice with anti-Ly6G or anti-isotype antibody treatment for 3 days prior to morphine treatment (n = 5). (b) Flow cytometry analysis of CD45+ CD11b+Ly6G+ neutrophils in blood of mice treated with either anti-isotype or anti-Ly6G antibody. (c) Representative H&E stained small intestinal sections from control, morphine, anti-Isotype+morphine, and anti-Ly6G+morphine treated mice groups. (Scale bar: 50 μm). (d) Graph showing histopathological damage score in intestinal sections in different mice groups. (e) Representative image of Claudin-1 (green) organization in distal small intestine of control, morphine, anti-Isotype+morphine, and anti-Ly6G+morphine treated mice groups. (Scale bar: 50 μm). Data represented as bar plots with SEM. Data were analyzed by one-way ANOVA with post-hoc Tukey’s test. *P ≤ 0.05; ****P ≤ 0.0001.
Morphine-induced tissue neutrophil infiltrates mediates gut microbial dysbiosis. 16S rRNA sequencing was performed from DNA sample extracted from small intestinal luminal sample from treated or untreated mice groups (n = 5) (a) Alpha diversity analysis using Shannon index shows increased alpha diversity in morphine and anti-isotype + morphine group compared to control and anti-Ly6G+morphine group. (b) Principal coordinates analysis (PCoA) of control samples shows distinct clustering of control group compared to morphine group using Unifrac metric (p = 0.008) and Bray-Curtis (p = 0.014). Comparison between OUT level showed distinct clustering between anti-Ly6G+morphine and morphine group using Unifrac (p = 0.041) and Bray-Curtis (p =0 .011) . Cladogram plotted from LEfSe analysis showing taxonomic comparison between (c) morphine and control treated mice, and (d) morphine and anti-Ly6G+morphine treated mice. (c,d) Morphine enriched taxa are green and control/anti-Ly6G+morphine enriched taxa are red. (e) Microbial composition in different treatment groups at the family level. (f) Tukey’s box plots showing relative abundance of bacterial genus significantly changing among different treatment groups. Data represented as bar plots with SEM. Data were analyzed by one-way ANOVA with post-hoc Tukey’s test. (n = 5). *P ≤ 0.05; **P ≤ 0.01; ***P ≤ 0.001; ****P ≤ 0.0001.
Morphine mediated neutrophil infiltration in intestinal tissue play essential role in histological damage and microbial dysbiosis

November 2022

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83 Reads

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8 Citations

The gut microbial ecosystem exhibits a complex bidirectional communication with the host and is one of the key contributing factors in determining mucosal immune homeostasis or an inflammatory state. Opioid use has been established to induce gut microbial dysbiosis consistent with increased intestinal tissue inflammation. In this study, we investigated the role of infiltrated immune cells in morphine-induced intestinal tissue damage and gut microbial dysbiosis in mice. Results reveal a significant increase in chemokine expression in intestinal tissues followed by increased neutrophil infiltration post morphine treatment which is direct consequence of a dysbiotic microbiome since the effect is attenuated in antibiotics treated animals and in germ-free mice. Neutrophil neutralization using anti-Ly6G monoclonal antibody showed a significant decrease in tissue damage and an increase in tight junction protein organization. 16S rRNA sequencing on intestinal samples highlighted the role of infiltrated neutrophils in modulating microbial community structure by providing a growth benefit for pathogenic bacteria, such as Enterococcus, and simultaneously causing a significant depletion of commensal bacteria, such as Lactobacillus. Taken together, we provide the first direct evidence that neutrophil infiltration contributes to morphine-induced intestinal tissue damage and gut microbial dysbiosis. Our findings implicate that inhibition of neutrophil infiltration may provide therapeutic benefits against gastrointestinal dysfunctions associated with opioid use.


Morphine treatment upregulates TLR expression in intestinal tissue. Increased TLR signaling in intestinal epithelial cells leads to MLCK induced tight junction redistribution and increase intestinal permeability. (Adapted and modified from Meng et al. 2013). (IEC, Intestinal epithelial cell)
Opioid use and gut-brain axis: opioid induced gut dysbiosis leads to mucosal, systemic, and neuroinflammation which contributes to opioid associated comorbidities such as tolerance, dependence and withdrawal. (GDNF, glia derived neurotropic factor; SCFA, short-chain fatty acid; BA, bile acid; ACh, Acetylcholine; VIP, vasoactive intestinal polypeptide; NO, nitric oxide; ENS, enteric nervous system; MOR, μ opioid receptor; LP, lamina propria; ILC3, innate lymphoid cells 3; BBB, blood brain barrier)
Opioid Use, Gut Dysbiosis, Inflammation, and the Nervous System

January 2022

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185 Reads

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20 Citations

Journal of Neuroimmune Pharmacology

Opioid use disorder (OUD) is defined as the chronic use or misuse of prescribed or illicitly obtained opioids and is characterized by clinically significant impairment. The etiology of OUD is multifactorial as it is influenced by genetics, environmental factors, stress response and behavior. Given the profound role of the gut microbiome in health and disease states, in recent years there has been a growing interest to explore interactions between the gut microbiome and the central nervous system as a causal link and potential therapeutic source for OUD. This review describes the role of the gut microbiome and opioid-induced immunopathological disturbances at the gut epithelial surface, which collectively contribute to OUD and perpetuate the vicious cycle of addiction and relapse. Graphical Abstract


HIV Tat-Mediated Induction of Monocyte Transmigration Across the Blood–Brain Barrier: Role of Chemokine Receptor CXCR3

August 2021

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88 Reads

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11 Citations

HIV trans-activator of transcription (Tat), one of the cytotoxic proteins secreted from HIV-infected cells, is also known to facilitate chemokine-mediated transmigration of monocytes into the brain leading, in turn, to neuroinflammation and thereby contributing to the development of HIV-associated neurocognitive disorders (HAND). The mechanism(s) underlying HIV Tat-mediated enhancement of monocyte transmigration, however, remain largely unknown. CXC chemokine receptor 3 (CXCR3) that is expressed by the peripheral monocytes is known to play a role in the monocyte influx and accumulation. In the present study, we demonstrate for the first time that exposure of human monocytes to HIV Tat protein resulted in upregulated expression of CXCR3 leading, in turn, to increased monocyte transmigration across the blood–brain barrier (BBB) both in the in vitro and in vivo model systems. This process involved activation of toll-like receptor 4 (TLR4), with downstream phosphorylation and activation of TANK-binding kinase 1 (TBK1), and subsequent phosphorylation and nuclear translocation of interferon regulatory factor 3 (IRF3), ultimately leading to enhanced expression of CXCR3 in human monocytes. These findings imply a novel molecular mechanism underlying HIV Tat-mediated increase of monocyte transmigration across the BBB, while also implicating a novel role of CXCR3-dependent monocyte transmigration in HIV Tat-mediated neuroinflammation.


Glycogen synthase kinase‐3 inhibition rescues sex‐dependent contextual fear memory deficit in human immunodeficiency virus‐1 transgenic mice

November 2020

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38 Reads

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4 Citations

Background and Purpose A significant number of HIV‐1 patients on antiretroviral therapy develop HIV‐associated neurocognitive disorders (HAND). Evidence indicate that biological sex may regulate HAND pathogenesis, but the mechanisms remain unknown. We investigated synaptic mechanisms associated with sex differences in HAND, using the HIV‐1‐transgenic 26 (Tg26) mouse model. Experimental Approach Contextual‐ and cue‐dependent memories of male and female Tg26 mice and littermate wild type mice were assessed in a fear conditioning paradigm. Hippocampal electrophysiology, immunohistochemistry, western blot, qRT‐PCR and ELISA techniques were used to investigate cellular, synaptic and molecular impairments. Key Results Cue‐dependent memory was unaltered in male and female Tg26 mice, when compared to wild type mice. Male, but not female, Tg26 mice showed deficits in contextual fear memory. Consistently, only male Tg26 mice showed depressed hippocampal basal synaptic transmission and impaired LTP induction in area CA1. These deficits in male Tg26 mice were independent of hippocampal neuronal loss and microglial activation but were associated with increased HIV‐1 long terminal repeat mRNA expression, reduced hippocampal synapsin‐1 protein, reduced BDNF mRNA and protein, reduced AMPA glutamate receptor (GluA1) phosphorylation levels and increased glycogen synthase kinase 3 (GSK3) activity. Importantly, selective GSK3 inhibition using 4‐benzyl‐2‐methyl‐1,2,4‐thiadiazolidine‐3,5‐dione increased levels of synapsin‐1, BDNF and phosphorylated‐GluA1 proteins, restored hippocampal basal synaptic transmission and LTP, and improved contextual fear memory in male Tg26 mice. Conclusion and Implications Sex‐dependent impairments in contextual fear memory and synaptic plasticity in Tg26 mice are associated with increased GSK3 activity. This implicates GSK3 inhibition as a potential therapeutic strategy to improve cognition in HIV‐1 patients.


Opioids Impair Intestinal Epithelial Repair in HIV-Infected Humanized Mice

January 2020

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127 Reads

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52 Citations

Intestinal barrier dysfunction and subsequent microbial translocation play crucial roles in persistent immune activation leading to HIV disease progression. Opioid use is associated with worse outcome in HIV-infected patients. The exacerbated disease progression by opioids is mainly driven by excessive intestinal inflammation and increased gut permeability. The objective of this study is to investigate how opioids potentiate HIV disease progression by compromising intestinal barrier function and impairing intestinal epithelial self-repair mechanism. In the present study, abnormal intestinal morphology and reduced epithelial proliferation were observed in bone marrow-liver-thymus humanized mice and in HIV-infected patients who were exposed to opioids. In bone marrow-liver-thymus mice, HIV, and morphine independently, and additively induced gut dysbiosis, especially depletion of Lachnospiraceae, Ruminococcaceae, and Muribaculaceae. We also observed that the abundance of Lachnospiraceae, Ruminococcaceae, and Muribaculaceae negatively correlated with apoptosis of epithelial cells, and intestinal IL-6 levels. Previous studies have shown that these bacterial families play crucial roles in maintaining intestinal homeostasis because they include most short-chain fatty acid-producing members. Short-chain fatty acids have been shown to maintain stem cell populations and suppress inflammation in the gut by inhibiting histone deacetylases (HDAC). In addition, we demonstrate that morphine exposure inhibited growth of intestinal organoids derived from HIV transgenic mice by suppressing Notch signaling in an HDAC-dependent manner. These studies implicate an important role for HDAC in intestinal homeostasis and supports HDAC modulation as a therapeutic intervention in improving care of HIV patients, especially in opioid-abusing population.


Oncostatin M promotes excitotoxicity by inhibiting glutamate uptake in astrocytes: Implications in HIV-associated neurotoxicity

June 2016

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214 Reads

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34 Citations

Journal of Neuroinflammation

Background: Elevated levels of oncostatin M (OSM), an interleukin-6 cytokine family member, have been observed in HIV-1-associated neurocognitive disorders (HAND) and Alzheimer's disease. However, the function of OSM in these disease conditions is unclear. Since deficient glutamate uptake by astrocytes is instrumental in HAND-associated neurotoxicity, we hypothesized that OSM impairs glutamate uptake in astrocytes and thereby promotes neuronal excitotoxicity. Methods: Primary cultures of mouse cortical astrocytes, neurons, microglia, and BV2 cell line were used. The expression of glutamate transporters (GLAST/EAAT1 and GLT-1/EAAT2) was investigated using real-time PCR and Western blot, and their activity was assessed by measuring (3)H-D-aspartate uptake. Neuronal toxicity was measured using the colorimetric MTT (3-(4,5-dimethylthiazol-2-yl-) 2,5-diphenyltetrazolium bromide) assay and immunocytochemistry. A chimeric HIV-1 that infects murine cells (EcoHIV/NL4-3-GFP virus (EcoHIV)) was used to investigate whether the virus induces OSM, OSM receptor (OSMR)-β, glycoprotein 130 (gp130), GLT-1, GLAST (mRNA and protein), and OSM release (ELISA) in cultured BV2 cells, primary microglia, or astrocytes. Statistical analyses of the data were performed using one-way ANOVA (to allow multiple comparisons) and two-tailed Student's t test. Results: OSM treatment (10 ng/mL) time-dependently reduced GLAST and GLT-1 expression and inhibited (3)H-D-aspartate uptake in cultured astrocytes in a concentration-dependent manner, an effect prevented by the Janus kinase (JAK)/signal transducers and activators of transcription (STAT)3 inhibitor AG490. Down-regulation of astrocytic glutamate transport by OSM resulted in NMDA receptor-dependent excitotoxicity in cortical neurons. Infection with EcoHIV induced OSM gene expression and protein release in BV2 cells and microglia, but not in astrocytes. Conversely, EcoHIV caused a fivefold increase in OSMR-β mRNA (but not gp130) and protein in astrocytes, but not in microglia, which did not express OSMR-β protein. Finally, astrocytic expression of GLAST gene was unaffected by EcoHIV, whereas GLT-1 mRNA was increased by twofold. Conclusions: We provide first evidence that activation of JAK/STAT3 signaling by OSM inhibits glutamate uptake in astrocytes, which results in neuronal excitotoxicity. Our findings with EcoHIV suggest that targeting OSMR-β signaling in astrocytes might alleviate HIV-1-associated excitotoxicity.



Adenosine A2B receptor-mediated leukemia inhibitory factor release from astrocytes protects cortical neurons against excitotoxicity

August 2012

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320 Reads

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51 Citations

Journal of Neuroinflammation

Neuroprotective and neurotrophic properties of leukemia inhibitory factor (LIF) have been widely reported. In the central nervous system (CNS), astrocytes are the major source for LIF, expression of which is enhanced following disturbances leading to neuronal damage. How astrocytic LIF expression is regulated, however, has remained an unanswered question. Since neuronal stress is associated with production of extracellular adenosine, we investigated whether LIF expression in astrocytes was mediated through adenosine receptor signaling. Mouse cortical neuronal and astrocyte cultures from wild-type and adenosine A2B receptor knock-out animals, as well as adenosine receptor agonists/antagonists and various enzymatic inhibitors, were used to study LIF expression and release in astrocytes. When needed, a one-way analysis of variance (ANOVA) followed by Bonferroni post-hoc test was used for statistical analysis. We show here that glutamate-stressed cortical neurons induce LIF expression through activation of adenosine A2B receptor subtype in cultured astrocytes and require signaling of protein kinase C (PKC), mitogen-activated protein kinases (MAPKs: p38 and ERK1/2), and the nuclear transcription factor (NF)-κB. Moreover, LIF concentration in the supernatant in response to 5'-N-ethylcarboxamide (NECA) stimulation was directly correlated to de novo protein synthesis, suggesting that LIF release did not occur through a regulated release pathway. Immunocytochemistry experiments show that LIF-containing vesicles co-localize with clathrin and Rab11, but not with pHogrin, Chromogranin (Cg)A and CgB, suggesting that LIF might be secreted through recycling endosomes. We further show that pre-treatment with supernatants from NECA-treated astrocytes increased survival of cultured cortical neurons against glutamate, which was absent when the supernatants were pre-treated with an anti-LIF neutralizing antibody. Adenosine from glutamate-stressed neurons induces rapid LIF release in astrocytes. This rapid release of LIF promotes the survival of cortical neurons against excitotoxicity.


Citations (11)


... Similarly, the utilization of opioids has been associated with modifications in the microbiota (Kolli et al., 2023). In contrast to HIV-1 infection and microbial dysbiosis, little is known about the effects of opioid use on the gut microbiome and the combinatory effect of HIV and drug use on microbiome structure (Hodder et al., 2021;Lloyd et al., 2021). ...

Reference:

Gut microbiota profiling in injection drug users with and without HIV-1 infection in Puerto Rico
Multi-omics analysis revealing the interplay between gut microbiome and the host following opioid use

... Immunohistochemical analysis was performed as previously described. 58 Sections from the ileum from each treatment group were fixed in 10% formalin and embedded in paraffin wax. For immunostaining, 8 μm tissue sections were deparaffinized with xylene, and the tissue was rehydrated through a series of graded alcohol and then processed for antigen retrieval using citrate antigen retrieval buffer (DAKO). ...

Morphine mediated neutrophil infiltration in intestinal tissue play essential role in histological damage and microbial dysbiosis

... Alterations of the gut microbiota are of utmost importance in chronic opioid users, since they play a role in developing severe constipation, which is currently considered as the most important side effect of chronic opioid use, as a consequence of the activity of exogenous opioids on MOR dislocated in the myoenteric and submucosal plexuses. According to several studies, while severe opioid-induced constipation is associated with barrier disruption and bacterial translocation, which enhance systemic inflammatory response overall [38], non-opioid-induced constipation (for instance, resulting from low food intake or a low-fiber diet) is not associated with alterations of the epithelium and microbiota translocation. This observation highlights the different underlying mechanism that supports different types of constipation [31]. ...

Opioid Use, Gut Dysbiosis, Inflammation, and the Nervous System

Journal of Neuroimmune Pharmacology

... In addition to being required for efficient HIV replication, Tat also is capable of being internalized by, and affecting, neighboring uninfected cells. Tat is an important mediator in the development of neuroHIV, contributing to glial activation, neuroinflammation, and neuronal injury, 10,13,[16][17][18] in part through increasing pro-inflammatory cytokine release, enhancing monocyte recruitment into the brain, and decreasing BBB integrity and function. 13 These mechanisms underscore the clinical relevance of Tat, as evidenced by studies demonstrating that even in virally suppressed patients on chronic antiretroviral therapy, active Tat viral proteins remain elevated within the cerebrospinal fluid ...

HIV Tat-Mediated Induction of Monocyte Transmigration Across the Blood–Brain Barrier: Role of Chemokine Receptor CXCR3

... This is in line with other studies that have demonstrated sex-dependent differences in cognitive behaviors and memory in animal models of various neurological conditions, including HIV-1 infection. For example, Moidunny et al. [46] associated sex-dependent contextual fear memory deficits in male Tg26 mice with reduced SYN1, while Koss et al. [47] found that female mice performed better in a working memory task, but worse in a reference memory task compared to male mice. Thus, while the impact of sex on cognitive outcomes in HAND may be more complex, our findings add to a growing body of literature that highlights the importance of considering sex differences in research on cognitive function in neurological disorders. ...

Glycogen synthase kinase‐3 inhibition rescues sex‐dependent contextual fear memory deficit in human immunodeficiency virus‐1 transgenic mice

... Gut microbes contribute to this barrier function by competing with potential pathogens and secreting compounds that strengthen intestinal lining (Rogers et al., 2023). A compromised gut barrier can lead to disruptions in microbiota, increasing gut permeability and susceptibility to inflammation and disease (Mak et al., 2021;Meng et al., 2020). Beyond barrier function, the gut microbiota serves several vital functions in the body. ...

Opioids Impair Intestinal Epithelial Repair in HIV-Infected Humanized Mice

... In the central nervous system, OSM is mainly expressed by neurons, astrocytes and microglia. [42][43][44] OSM has been implicated in the homeostasis of neural progenitor cells (NPCs) in physiological settings, a pool of cells for the production of new neural cells located in the subventricular zone, hippocampus and olfactory bulb in the adult mammalian brain. [45][46][47][48] It has been reported that the number of OSMRβ-positive neurons in the site of injury was significantly decreased following a sciatic nerve axotomy. ...

Oncostatin M promotes excitotoxicity by inhibiting glutamate uptake in astrocytes: Implications in HIV-associated neurotoxicity

Journal of Neuroinflammation

... OSMR is known to be expressed in osteosarcoma, and binding of OSM to OSMR enhances apoptosis through JAK-STAT and p53 [18]. OSM in the dorsal root ganglion is involved in the survival of nociceptive neurons by binding to OSMR [41], and this pathway has also been found to suppress hyperpolarization by glutamate in studies using primary neurons [42]. Thus, OSM has been suggested to have different effects on the various nerve cells of the central nervous system. ...

Interleukin-6-type cytokines in neuroprotection and neuromodulation: OSM, but not LIF, requires neuronal adenosine A1 receptor function
  • Citing Article
  • June 2010

Purinergic Signalling

... In this study, the average mean for each factor was calculated by taking the average mean value of the three respective statements of the factor. It can be interpreted that the respondents mostly answer with "Strongly Agree" since the range of mean is between 4.04 to 4.34 [20]. The highest mean between of all the factors that influence knowledge transfer process is Employee Behavior with 4.34 while the lowest mean is Knowledge Transfer Process with 4.04. ...

INTERLEUKIN (IL)-6-TYPE CYTOKINES IN NEUROPROTECTION: IL-6 AND OSM PROTECT NEURONS AGAINST EXCITOTOXICITY DIFFERENTLY FROM LIF
  • Citing Conference Paper
  • October 2009

Glia

... Although we are currently unable to answer the origin cells of the ADEVs released, we speculate that both lysed astrocytes and reactive perilesional reactive astrocytes (33) contribute to the release. Astrocytic EVs contain several neuroprotective factors, such as heat shock proteins, apolipoproteins, glutamate transporters, and unique mRNAs (32,(34)(35)(36). In particular, APOE, one of the abundant apolipoprotein released by astrocytes in the brain (37), is further enriched in ADEVs isolated from AQP4-Ab-seropositive patients with NMOSD. ...

Adenosine A2B receptor-mediated leukemia inhibitory factor release from astrocytes protects cortical neurons against excitotoxicity

Journal of Neuroinflammation