CXCL12 Is a constitutive and inflammatory chemokine in the intestinal immune system

Dotan, Iris; Werner, Lael; Vigodman, Sharon; Weiss, S; Brazowski, Eli; Maharshak, Nitsan; Chen, Ofer; Tulchinsky, Hagit; Halpern, Zamir; Guzner-Gur, Hanan

doi:10.1002/ibd.21106

Cited by 106 publications

(101 citation statements)

References 41 publications

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“…Put together, these novel and interesting results suggest that chronic THC administration induces the expression of a select cluster of miRNAs that may exert anti-inflammatory effects in the intestine by directly targeting CXCL12 expression, a chemokine well known to regulate the trafficking of T cells and macrophages into the intestinal lamina propria, causing progression of GI inflammation (45,46). THC and SIV exert synergistic and additive effects on intestinal expression of miR-29b, miR-101, miR-130a, miR-218, and miR-374 at 60 days p.i.…”

Section: Plasma and Intestinal Viral Loads Cd4 And Cd8 T Cell Statusmentioning

confidence: 96%

Chronic Administration of Δ ⁹ -Tetrahydrocannabinol Induces Intestinal Anti-Inflammatory MicroRNA Expression during Acute Simian Immunodeficiency Virus Infection of Rhesus Macaques

Chandra

Kumar

Torben

et al. 2015

J Virol

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Recreational and medical use of cannabis among human immunodeficiency virus (HIV)-infected individuals has increased in recent years. In simian immunodeficiency virus (SIV)-infected macaques, chronic administration of ⌬9 -tetrahydrocannabinol (⌬ 9 -THC) inhibited viral replication and intestinal inflammation and slowed disease progression. Persistent gastrointestinal disease/inflammation has been proposed to facilitate microbial translocation and systemic immune activation and promote disease progression. Cannabinoids including ⌬ 9 -THC attenuated intestinal inflammation in mouse colitis models and SIV-infected rhesus macaques. To determine if the anti-inflammatory effects of ⌬ 9 -THC involved differential microRNA (miRNA) modulation, we profiled miRNA expression at 14, 30, and 60 days postinfection (days p.i.) in the intestine of uninfected macaques receiving ⌬ 9 -THC (n ‫؍‬ 3) and SIV-infected macaques administered either vehicle (VEH/ SIV; n ‫؍‬ 4) or THC (THC/SIV; n ‫؍‬ 4). Chronic ⌬ 9 -THC administration to uninfected macaques significantly and positively modulated intestinal miRNA expression by increasing the total number of differentially expressed miRNAs from 14 to 60 days p.i. At 60 days p.i., ϳ28% of miRNAs showed decreased expression in the VEH/SIV group compared to none showing decrease in the THC/SIV group. Furthermore, compared to the VEH/SIV group, THC selectively upregulated the expression of miR-10a, miR-24, miR-99b, miR-145, miR-149, and miR-187, previously been shown to target proinflammatory molecules. NOX4, a potent reactive oxygen species generator, was confirmed as a direct miR-99b target. A significant increase in NOX4 ؉ crypt epithelial cells was detected in VEH/SIV macaques compared to the THC/SIV group. We speculate that miR-99b-mediated NOX4 downregulation may protect the intestinal epithelium from oxidative stress-induced damage. These results support a role for differential miRNA induction in THC-mediated suppression of intestinal inflammation. Whether similar miRNA modulation occurs in other tissues requires further investigation. IMPORTANCE Gastrointestinal (GI) tract disease/inflammation is a hallmark of HIV/SIV infection. Previously, we showed that chronic treatment of SIV-infected macaques with ⌬9 -tetrahydrocannabinol (⌬ 9 -THC) increased survival and decreased viral replication and infection-induced gastrointestinal inflammation. Here, we show that chronic THC administration to SIV-infected macaques induced an anti-inflammatory microRNA expression profile in the intestine at 60 days p.i. These included several miRNAs bioinformatically predicted to directly target CXCL12, a chemokine known to regulate lymphocyte and macrophage trafficking into the intestine. Specifically, miR-99b was significantly upregulated in THC-treated SIV-infected macaques and confirmed to directly target NADPH oxidase 4 (NOX4), a reactive oxygen species generator known to damage intestinal epithelial cells. Elevated miR-99b expression was associated with a significantly decreased number of NOX4...

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Section: Plasma and Intestinal Viral Loads Cd4 And Cd8 T Cell Statusmentioning

confidence: 96%

Chronic Administration of Δ ⁹ -Tetrahydrocannabinol Induces Intestinal Anti-Inflammatory MicroRNA Expression during Acute Simian Immunodeficiency Virus Infection of Rhesus Macaques

Chandra

Kumar

Torben

et al. 2015

J Virol

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“…PBMCs from healthy volunteers were isolated using Ficoll-Hypaque (GE Healthcare, Otelfingen, Switzerland) as previously described (19,20 . From those, 80-90% were confirmed by flow cytometry to be Foxp3 + (data not shown).…”

Section: Cell Isolationmentioning

confidence: 99%

“…From those, 80-90% were confirmed by flow cytometry to be Foxp3 + (data not shown). Lamina propria mononuclear cells (LPMCs) were isolated from mucosa of patients undergoing colectomy owing to noninflammatory disorders as previously described (19). Briefly, minced mucosa was digested in DTT (Sigma-Aldrich, Taufkirchen, Germany), two dispase (Life Technologies) cycles, and collagenase (Roche Applied Science, Mannheim, Germany) plus DNase (Worthington Biochemical, Lakewood, NJ).…”

Section: Cell Isolationmentioning

confidence: 99%

Identification of Pancreatic Glycoprotein 2 as an Endogenous Immunomodulator of Innate and Adaptive Immune Responses

Werner

Paclik

Fritz

et al. 2012

The Journal of Immunology

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Pancreatic autoantibodies are Crohn disease-specific serologic markers. The function and immunological role of their recently identified autoantigen, glycoprotein 2 (GP2), are unknown. We therefore investigated the impact of GP2 on modulation of innate and adaptive immune responses to evaluate its potential therapeutic use in mucosal inflammation. Our data indicate a previously unknown function for GP2 as an immunomodulator. GP2 was ubiquitously expressed on cells vital to mucosal immune responses. The expression of GP2 was upregulated on activated human T cells, and it was further influenced by pharmaceutical TNF-α inhibitors. Recombinant GP2 significantly decreased human intestinal epithelial cells, mucosal and peripheral T cell proliferation, apoptosis, and activation, and it distinctly modulated cytokine secretion. Furthermore, intestinal epithelial cells stimulated with GP2 potently attracted T cells. In conclusion, we demonstrate a novel role for GP2 in immune regulation that could provide a platform for new therapeutic interventions in the treatment of Crohn disease.

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“…They demonstrated that the proportion of immature plasma cells was correlated positively with clinical activities of UC and CD and expression of CXCR3 and CXCR4 of immature plasma cells in UC patients was significantly higher than in controls. In addition, Dotan, et al reported that CXCR4 was expressed by intestinal epithelial cells (IECs) and lamima propria cells and CXCR4 positive cells are significantly increased in lamina propria of IBD (32). Moreover, recent report indicated that evaluation of CXCR4 expression on CD4 T cells by FACS analysis could be a biomarker of Leukocytapheresis with a leukocyte removal filter (Cellsoba; Asahi Medical, Tokyo, Japan) (33).…”

Section: How Is Cxcl12/cxcr4 Axis Involved In the Pathophysiology Of mentioning

confidence: 99%

“…These data strongly suggested that CXCR4 positive cells could be involved in the pathophysiology of IBD. As for expression of CXCL12 expressing cells in patients with IBD, Dotan et al reported as follows: CXCL12 expression of normal intestinal mucosa was more limited to the surface epithelium, while the expression was enhanced and more diffuse in IBD mucosa (32). This up-regulation was specific to IBD mucosa, and did not occur in non-IBD inflammatory conditions.…”

Section: How Is Cxcl12/cxcr4 Axis Involved In the Pathophysiology Of mentioning

confidence: 99%

CXCL12-CXCR4 Axis in Ulcerative Colitis

Nakase¹,

Matsuura²,

Mikami³

et al. 2011

Ulcerative Colitis - Epidemiology, Pathogenesis and Complications

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CXCL12 Is a constitutive and inflammatory chemokine in the intestinal immune system

Cited by 106 publications

References 41 publications

Chronic Administration of Δ ⁹ -Tetrahydrocannabinol Induces Intestinal Anti-Inflammatory MicroRNA Expression during Acute Simian Immunodeficiency Virus Infection of Rhesus Macaques

Chronic Administration of Δ ⁹ -Tetrahydrocannabinol Induces Intestinal Anti-Inflammatory MicroRNA Expression during Acute Simian Immunodeficiency Virus Infection of Rhesus Macaques

Identification of Pancreatic Glycoprotein 2 as an Endogenous Immunomodulator of Innate and Adaptive Immune Responses

CXCL12-CXCR4 Axis in Ulcerative Colitis

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CXCL12 Is a constitutive and inflammatory chemokine in the intestinal immune system

Cited by 106 publications

References 41 publications

Chronic Administration of Δ 9 -Tetrahydrocannabinol Induces Intestinal Anti-Inflammatory MicroRNA Expression during Acute Simian Immunodeficiency Virus Infection of Rhesus Macaques

Chronic Administration of Δ 9 -Tetrahydrocannabinol Induces Intestinal Anti-Inflammatory MicroRNA Expression during Acute Simian Immunodeficiency Virus Infection of Rhesus Macaques

Identification of Pancreatic Glycoprotein 2 as an Endogenous Immunomodulator of Innate and Adaptive Immune Responses

CXCL12-CXCR4 Axis in Ulcerative Colitis

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Product

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Chronic Administration of Δ ⁹ -Tetrahydrocannabinol Induces Intestinal Anti-Inflammatory MicroRNA Expression during Acute Simian Immunodeficiency Virus Infection of Rhesus Macaques

Chronic Administration of Δ ⁹ -Tetrahydrocannabinol Induces Intestinal Anti-Inflammatory MicroRNA Expression during Acute Simian Immunodeficiency Virus Infection of Rhesus Macaques