Evidence for an enhanced adhesion of DC to fibronectin and a role of CCL19 and CCL21 in the accumulation of DC around the pre-diabetic islets in NOD mice

Bouma, Gerben; Coppens, Jojanneke M. C.; Mourits, Sabine; Nikolić, Tatjana; Sozzani, Silvano; Drexhage, Hemmo A.; Versnel, Marjan A.

doi:10.1002/eji.200526251

Cited by 40 publications

(33 citation statements)

References 36 publications

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“…Other experimental therapies targeting cytokines including IL-16, IL-21, and TNF inhibited the recruitment of diabetogenic T cells to the pancreas, reduced insulitis, and prevented T1D (11)(12)(13). NOD islets in situ produce chemokines, particularly CCL5 (14), that recruit inflammatory cells, which suggests that β cells themselves could contribute to the initiation and expansion of peri-islet insulitis. Blockade of chemokine signaling via transgenic expression of a chemokine-blocking protein or decoy receptor by β cells has markedly decreased insulitis and T1D incidence in NOD mice (15,16).…”

Section: Introductionmentioning

confidence: 99%

Heparan sulfate and heparanase play key roles in mouse β cell survival and autoimmune diabetes

Ziolkowski

Popp²,

Freeman³

et al. 2012

J. Clin. Invest.

145

200

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The autoimmune type 1 diabetes (T1D) that arises spontaneously in NOD mice is considered to be a model of T1D in humans. It is characterized by the invasion of pancreatic islets by mononuclear cells (MNCs), which ultimately leads to destruction of insulin-producing β cells. Although T cell dependent, the molecular mechanisms triggering β cell death have not been fully elucidated. Here, we report that a glycosaminoglycan, heparan sulfate (HS), is expressed at extraordinarily high levels within mouse islets and is essential for β cell survival. In vitro, β cells rapidly lost their HS and died. β Cell death was prevented by HS replacement, a treatment that also rendered the β cells resistant to damage from ROS. In vivo, autoimmune destruction of islets in NOD mice was associated with production of catalytically active heparanase, an HS-degrading enzyme, by islet-infiltrating MNCs and loss of islet HS. Furthermore, in vivo treatment with the heparanase inhibitor PI-88 preserved intraislet HS and protected NOD mice from T1D. Our results identified HS as a critical molecular requirement for islet β cell survival and HS degradation as a mechanism for β cell destruction. Our findings suggest that preservation of islet HS could be a therapeutic strategy for preventing T1D.

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Section: Introductionmentioning

confidence: 99%

Heparan sulfate and heparanase play key roles in mouse β cell survival and autoimmune diabetes

Ziolkowski

Popp²,

Freeman³

et al. 2012

J. Clin. Invest.

145

200

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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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“…The essential components in the activation of the autoimmune attack are the effector CD4 ϩ and CD8 ϩ T cells and APCs. The mechanisms underlying the influx of T cells and macrophages into the affected organs are not entirely known, but there is evidence that chemokines may be critical components (10).…”

mentioning

confidence: 99%

CCR7 Deficiency in NOD Mice Leads to Thyroiditis and Primary Hypothyroidism

Martín

Marinkovic

Canasto-Chibuque

et al. 2009

The Journal of Immunology

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CCR7 is involved in the initiation of immune responses and has been recently implicated in the control of tolerance. To analyze the role of CCR7 in autoimmunity, we backcrossed CCR7ko/ko mice (in which ko signifies deficient) onto the autoimmune-prone NOD background. Surprisingly, NODCCR7ko/ko mice never developed diabetes, but showed severe inflammation in multiple tissues including thyroid, lung, stomach, intestine, uterus, and testis. NODCCR7ko/ko mice had a marked enlargement of the thyroid gland (goiter) that was associated with circulating autoantibodies against thyroglobulin, and development of primary hypothyroidism (decreased levels of serum thyroxin, and augmented levels of thyroid-stimulating hormone in the pituitary gland), features found in Hashimoto’s thyroiditis. Cells isolated from diseased thyroids and activated splenocytes from NODCCR7ko/ko animals induced goiter in NOD.SCID recipients, demonstrating that autoreactive cells were generated in the absence of CCR7. Moreover, thyroid disease could be accelerated in young NODCCR7ko/ko mice by immunization with thyroglobulin. These results demonstrate the complexity in the generation of multiple autoimmune phenotypes in NOD mice and indicate that CCR7 is a key molecule in their development.

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Evidence for an enhanced adhesion of DC to fibronectin and a role of CCL19 and CCL21 in the accumulation of DC around the pre-diabetic islets in NOD mice

Cited by 40 publications

References 36 publications

Heparan sulfate and heparanase play key roles in mouse β cell survival and autoimmune diabetes

Heparan sulfate and heparanase play key roles in mouse β cell survival and autoimmune diabetes

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

CCR7 Deficiency in NOD Mice Leads to Thyroiditis and Primary Hypothyroidism

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