Expression and Regulation of Chemokines in Murine and Human Type 1 Diabetes

Sarkar, Sagartirtha; Lee, Catherine E.; Victorino, Francisco; Nguyen, Tom; Walters, Jay A.; Burrack, Adam L.; Eberlein, Jens; Hildemann, Steven; Homann, Dirk

doi:10.2337/db11-0853

Cited by 119 publications

(129 citation statements)

References 56 publications

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“…NOD mouse islets also show increased expression of CCL20 and CXCL10, with a peak at around 10 to 12 weeks of life, which precedes the outbreak of diabetes by 2 to 4 weeks. CCL20 is the only ligand for CCR6, which is expressed in Th17 and regulatory T cells [10,48]. CXCL10 and CXCL9 are present in pancreatic islets from type 1 diabetic patients [11,48], while infiltrating lymphocytes express the CXCL10 receptor, C-X-C chemokine receptor type 3 [11], suggesting a 'dialogue' between chemokine-producing islet cells and the invading immune cells.…”

Section: Discussionmentioning

confidence: 99%

“…CCL20 is the only ligand for CCR6, which is expressed in Th17 and regulatory T cells [10,48]. CXCL10 and CXCL9 are present in pancreatic islets from type 1 diabetic patients [11,48], while infiltrating lymphocytes express the CXCL10 receptor, C-X-C chemokine receptor type 3 [11], suggesting a 'dialogue' between chemokine-producing islet cells and the invading immune cells. In NOD mice, the severity of insulitis is reduced in IL-17-or IL-17/IFN-γ receptor-deficient animals [49], indicating the importance of IL-17A in the attraction of immune cells.…”

Section: Discussionmentioning

confidence: 99%

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IL-17A increases the expression of proinflammatory chemokines in human pancreatic islets

et al. 2013

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Aims/hypothesis Cytotoxic T cells and macrophages contribute to beta cell destruction in type 1 diabetes at least in part through the production of cytokines such as IL-1β, IFN-γ and TNF-α. We have recently shown the IL-17 pathway to be activated in circulating T cells and pancreatic islets of type 1 diabetes patients. Here, we studied whether IL-17A upregulates the production of chemokines by human pancreatic islets, thus contributing to the build-up of insulitis. Methods Human islets (from 18 donors), INS-1E cells and islets from wild-type and Stat1 knockout mice were studied. Dispersed islet cells were left untreated, or were treated with IL-17A alone or together with IL-1β+IFN-γ or TNF-α+IFN-γ.RNA interference was used to knock down signal transducer and activator of transcription 1 (STAT1). Chemokine expression was assessed by quantitative RT-PCR, ELISA and histology. Cell viability was evaluated with nuclear dyes. Results IL-17A augmented IL-1β+IFN-γ-and TNF-α+IFN-γ-induced chemokine mRNA and protein expression, and apoptosis in human islets. Beta cells were at least in part the source of chemokine production. Knockdown of STAT1 in human islets prevented cytokine-or IL-17A+cytokine-induced apoptosis and the expression of particular chemokines, e.g. chemokine (C-X-C motif) ligands 9 and 10. Similar observations were made in islets isolated from Stat1 knockout mice. Conclusions/interpretation Our findings indicate that IL-17A exacerbates proinflammatory chemokine expression and secretion by human islets exposed to cytokines. This suggests that IL-17A contributes to the pathogenesis of type 1 diabetes by two mechanisms, namely the exacerbation of beta cell apoptosis and increased local production of chemokines, thus potentially aggravating insulitis.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

IL-17A increases the expression of proinflammatory chemokines in human pancreatic islets

et al. 2013

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“…3A), which suggested that NLRP3 deficiency also affected homing of diabetogenic cells to islets. An array of chemokine genes is expressed in islet cells (28). Thus, we speculated that the impaired migration of CD4 + T cells to NLRP3 −/− NOD islets could be due to suppressed chemokine gene expression by NLRP3 −/− NOD pancreatic islets.…”

Section: Reviewersmentioning

confidence: 99%

NLRP3 deficiency protects from type 1 diabetes through the regulation of chemotaxis into the pancreatic islets

Ding

et al. 2015

Proc. Natl. Acad. Sci. U.S.A.

112

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Studies in animal models and human subjects have shown that both innate and adaptive immunity contribute to the pathogenesis of type 1 diabetes (T1D). Whereas the role of TLR signaling pathways in T1D has been extensively studied, the contribution of the nucleotidebinding oligomerization domain, leucine-rich repeat and pyrin domaincontaining protein (NLRP) 3 inflammasome pathway remains to be explored. In this study, we report that NLRP3 plays an important role in the development of T1D in the nonobese diabetic (NOD) mouse model. NLRP3 deficiency not only affected T-cell activation and Th1 differentiation, but also modulated pathogenic T-cell migration to the pancreatic islet. The presence of NLRP3 is critical for the expression of the chemokine receptors CCR5 and CXCR3 on T cells. More importantly, NLRP3 ablation reduced the expression of chemokine genes CCL5 and CXCL10 on pancreatic islet cells in an IRF-1-dependent manner. Our results suggest that molecules involved in chemotaxis, accompanied by the activation of the NLRP3 inflammasome, may be effective targets for the treatment of T1D.NLRP3 | islet | type 1 diabetes | chemokine | NOD mouse

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“…In addition, CCL5 is also present in islets isolated from individuals with type 1 diabetes, where it may play a role in attracting activated T cells. It is also upregulated by cytokines [7,8] and the coxsackie B3 enterovirus [9] in islets from non-diabetic donors.…”

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confidence: 99%

The novel chemokine receptor, G-protein-coupled receptor 75, is expressed by islets and is coupled to stimulation of insulin secretion and improved glucose homeostasis

et al. 2013

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Aims/hypothesis Chemokine (C-C motif) ligand 5 (CCL5) acts at C-C chemokine receptors (CCRs) to promote immune cell recruitment to sites of inflammation, but is also an agonist at G-protein-coupled receptor 75 (GPR75), which has very limited homology with CCRs. GPR75 is coupled to Gq to elevate intracellular calcium, so we investigated whether islets express this receptor and whether its activation by CCL5 increases beta cell calcium levels and insulin secretion. Methods Islet CCL5 receptor mRNA expression was measured by quantitative RT-PCR and GPR75 was detected in islets by western blotting and immunohistochemistry. In some experiments GPR75 was downregulated by transient transfection with small interfering RNA. Real-time changes in intracellular calcium were determined by single-cell microfluorimetry. Dynamic insulin secretion from perifused islets was quantified by radioimmunoassay. Glucose homeostasis in lean and obese mice was determined by measuring glucose and insulin tolerance, and insulin secretion in vivo. Results Mouse and human islets express GPR75 and its ligand CCL5. Exogenous CCL5 reversibly increased intracellular calcium in beta cells via GPR75, this phenomenon being dependent on phospholipase C activation and calcium influx. CCL5 also stimulated insulin secretion from mouse and human islets in vitro, and improved glucose tolerance in lean mice and in a mouse model of hyperglycaemia and insulin resistance (ob/ob ). The improvement in glucose tolerance was associated with enhanced insulin secretion in vivo, without changes in insulin sensitivity. Conclusions/interpretation Although CCL5 is implicated in the pathogenesis of diabetes through activation of CCRs, it has beneficial effects on beta cells through GPR75 activation.

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Expression and Regulation of Chemokines in Murine and Human Type 1 Diabetes

Cited by 119 publications

References 56 publications

IL-17A increases the expression of proinflammatory chemokines in human pancreatic islets

IL-17A increases the expression of proinflammatory chemokines in human pancreatic islets

NLRP3 deficiency protects from type 1 diabetes through the regulation of chemotaxis into the pancreatic islets

The novel chemokine receptor, G-protein-coupled receptor 75, is expressed by islets and is coupled to stimulation of insulin secretion and improved glucose homeostasis

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