Loss of β‐arrestin 2 exacerbates experimental autoimmune encephalomyelitis with reduced number of <scp>F</scp>oxp3<sup>+</sup> <scp>CD</scp>4<sup>+</sup> regulatory <scp>T</scp> cells

Liu, Chang; Wei, Bin; Pei, Gang

doi:10.1111/imm.12152

Cited by 13 publications

(22 citation statements)

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“…Use of siRNA to modulate β-arrestin2 expression and lack of data on T cell activation status in these studies makes them difficult to compare to ours. However, a recent study using a modified T cell differentiation protocol (magnetically enriched naïve T cells and different concentration of CD3/CD28) demonstrated a decrease in Treg induction in β-arr2 −/− T cells but no difference in Th1/2/17 polarization (6). Consistent with the colitis model shown here, β-arrestin2 mediated Treg induction appeared to be important in protection against EAE and the β-arr2 −/− mice consequently exhibited more severe disease (6).…”

Section: Discussionmentioning

confidence: 99%

“…The family of GPCRs includes various receptors including the ones involved in immune responses such as chemotaxis, proliferation and differentiation of leukocytes. β-arrestins are important players in inflammation and consequent pathogenesis of sepsis (3, 4), allergic asthma (5), EAE (6) and rheumatoid arthritis (7). Their involvement in innate responses to TLRs (8), adenovirus (9) and microbial stimulation (4) has also been demonstrated.…”

Section: Introductionmentioning

confidence: 99%

“…Their involvement in innate responses to TLRs (8), adenovirus (9) and microbial stimulation (4) has also been demonstrated. Further in T cells, CD28 mediated PDE4 recruitment (10) and T cell differentiation into Tregs was found to be dependent on β-arrestin2 expression (6). Involvement of G proteins in T cell activation (11) and colitis (12) has also been previously demonstrated.…”

Section: Introductionmentioning

confidence: 99%

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Protective Role of β-arrestin2 in Colitis Through Modulation of T-cell Activation

Sharma

Malik

Steury

et al. 2015

Inflammatory Bowel Diseases

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β-arrestin2 (β-arr2) identified as a scaffolding protein in GPCR desensitization, is a negative regulator of inflammation in polymicrobial sepsis. In this study we wanted to investigate the role of β-arr2 in intestinal inflammation, a site of persistent microbial stimulation. In the absence of β-arr2, mice exhibited greater extent of mucosal inflammation determined by cellular infiltration and expression of inflammatory mediators even under homeostatic conditions. Further, β-arr2 deficient mice were more susceptible to DSS induced colitis as demonstrated by greater body weight loss, higher disease activity index and shortened colon as compared to wild type (WT) mice. We also show that T cells from β-arr2 KO mice exhibit altered activation status under both basal and colitic conditions, implicating their involvement in disease induction. Further assessment of the role of β-arr2 in intrinsic T cell differentiation confirmed its importance in T cell polarization. Utilizing the T cell transfer model of colitis we demonstrate that T-cell specific-β-arr2 is important in limiting colitic inflammation; however it plays a paradoxical role in concurrent systemic wasting disease. Together, our study highlights a critical negative regulatory role of β-arr2 in intestinal inflammation and demonstrates a distinct role of T-cell-specific β-arr2 in systemic wasting disease.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Protective Role of β-arrestin2 in Colitis Through Modulation of T-cell Activation

Sharma

Malik

Steury

et al. 2015

Inflammatory Bowel Diseases

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“…barr2 knockout mice (barr2 -/-) were generated and identified as described previously (15,16 Figure S2). However, knocking out βarr2 resulted in impaired glucose tolerance ( Figures 1A, B) and a defect in glucose-stimulated insulin secretion in these mice under HFD condition ( Figure 1C).…”

Section: Animals and Glucose Tolerance Testmentioning

confidence: 99%

“…barr2 knockout mice (barr2 -/-) were generated and identified as described previously (15,16 Figure S1). Mice were fed either a normal chow diet (20% kcal protein, 10% kcal fat and 70% kcal carbohydrate; Slaccas Co.) or a high-fat diet (HFD) (20% kcal protein, 45% kcal fat and 35% kcal carbohydrates; Research Diets) from 6 wks of age.…”

Section: Animals and Glucose Tolerance Testmentioning

confidence: 99%

Deletion of β-Arrestin2 in Mice Limited Pancreatic β-Cell Expansion under Metabolic Stress through Activation of the JNK Pathway

Lin

Zhao

Song

et al. 2016

Mol Med

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β-Arrestin2 (βarr2) is an adaptor protein that interacts with numerous signaling molecules and regulates insulin sensitivity. We reported previously that βarr2 was abundantly expressed in mouse pancreatic β-cells, and loss of βarr2 leads to impairment of acuteand late-phase insulin secretion. In the present study, we examined the dynamic changes of β-cell mass in barr2-deficient (barr2 -/-) mice in vivo and explored the underlying mechanisms involved. barr2-/-mice with exclusively luciferase overexpression in β-cellswere generated and fed a high-fat diet (HFD). β-Cell mass was determined by in vivo noninvasive bioluminescence imaging from 4 to 20 wks of age. Proliferation was measured by 5-bromo-2-deoxyuridine (BrdU) incorporation and fluorescence-activated cell sorter analysis. Quantitative real-time polymerase chain reaction (qRT-PCR) and immunoblotting were conducted for gene and protein expression. We found that β-cell mass was reduced dramatically in barr2 -/-mice at 12 wks old compared with that of their respective HFD-fed controls. The percentage of BrdU-and Ki67-positive cells reduced in islets from barr2 -/-mice. Exposure of barr2 -/-islets to high levels of glucose and free fatty acids (FFAs) exacerbated cell death, which was associated with upregulation of the JNK pathway in these islets. Conversely, overexpression of βarr2 amplified β-cell proliferation with a concomitant increase in cyclinD2 expression and a decrease in p21 expression and protected β-cells from glucose-and FFA-induced cell death through JNK-activation inhibition.In conclusion, βarr2 plays roles in regulation of pancreatic β-cell mass through the modulation of cell cycle regulatory genes and the inhibition of JNK activation induced by glucolipotoxity, which implicates a role for βarr2 in the development of type 2 diabetes. China. Phone: +86-21-24058657; Fax: 86-21-64368031; E-mail: wangchen@sjtu.edu.cn. Submitted June 24, 2015; Accepted for publication February 22, 2016; Published Online (www.molmed.org) February 29, 2016. R E S E A R C H A R T I C L EM O L M E D 2 2 : 7 4 -8 4 , 2 0 1 6 | L i n E T A L . | 7 5Histology Study and Morphometric Analyses Pancreases were removed from 16-wk-old barr2 +/+ and barr2 -/-mice, immediately weighed, fixed and embedded. To determine the count and area of islets, 8-10 randomly chosen sections per mouse that were separated by at least 100 μm were stained with hematoxylin and eosin (H&E). The entire pancreatic sections were scanned using a Nikon Eclipse Ni-E Microscope (Nikon), and a tile image of the tissue section was generated using the NIS-Elements AR 4.20 (Nikon). The fractional area of the islet in the pancreas, islet count per unit pancreatic area (islet density) and islet size were manually quantified using Image-Pro Plus 6.0 (Media Cybernetics), as described previously (21). The average of all the sections was taken as a measure for the entire organ. The total islet mass was calculated as pancreatic weight × mean fractional pancreatic islet area. For immunofluorescence analysis, pan...

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Identification of common key genes and pathways between type 1 diabetes and multiple sclerosis using transcriptome and interactome analysis

et al. 2020

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Loss of β‐arrestin 2 exacerbates experimental autoimmune encephalomyelitis with reduced number of Foxp3⁺ CD4⁺ regulatory T cells

Cited by 13 publications

References 27 publications

Protective Role of β-arrestin2 in Colitis Through Modulation of T-cell Activation

Protective Role of β-arrestin2 in Colitis Through Modulation of T-cell Activation

Deletion of β-Arrestin2 in Mice Limited Pancreatic β-Cell Expansion under Metabolic Stress through Activation of the JNK Pathway

Identification of common key genes and pathways between type 1 diabetes and multiple sclerosis using transcriptome and interactome analysis

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Loss of β‐arrestin 2 exacerbates experimental autoimmune encephalomyelitis with reduced number of Foxp3+ CD4+ regulatory T cells

Cited by 13 publications

References 27 publications

Protective Role of β-arrestin2 in Colitis Through Modulation of T-cell Activation

Protective Role of β-arrestin2 in Colitis Through Modulation of T-cell Activation

Deletion of β-Arrestin2 in Mice Limited Pancreatic β-Cell Expansion under Metabolic Stress through Activation of the JNK Pathway

Identification of common key genes and pathways between type 1 diabetes and multiple sclerosis using transcriptome and interactome analysis

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Loss of β‐arrestin 2 exacerbates experimental autoimmune encephalomyelitis with reduced number of Foxp3⁺ CD4⁺ regulatory T cells