Acceleration of diabetes development in CXC chemokine receptor 3 (CXCR3)-deficient NOD mice

Yamada, Yoshifumi; Okubo, Yoshiaki; Shimada, Akira; Oikawa, Yoichi; Yamada, Satoru; Narumi, Shosaku; Matsushima, Kouji; Itoh, Hiroshi

doi:10.1007/s00125-012-2547-8

Cited by 35 publications

(43 citation statements)

References 25 publications

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“…Individual treatments reduced inflammatory infiltrates without effectively preventing diabetes development in some experimental settings (12) or even worsening the disease in others. For example, NOD mice deficient in CXCR3 (CXCL19/CXCL10 receptor) or CCR5 (CCL3/CCL4/CCL5 receptors) developed spontaneous diabetes earlier than wild-type NOD mice (39,40). In our study we established a relationship involving the CXCR1/2 chemokine receptors and the development of insulitis and diabetes in mice.…”

Section: Discussionmentioning

confidence: 67%

CXCR1/2 Inhibition Blocks and Reverses Type 1 Diabetes in Mice

et al. 2014

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Chemokines and their receptors have been associated with or implicated in the pathogenesis of type 1 diabetes (T1D), but the identification of a single specific chemokine/receptor pathway that may constitute a suitable target for the development of therapeutic interventions is still lacking. Here, we used multiple low-dose (MLD) streptozotocin (STZ) injections and the NOD mouse model to investigate the potency of CXCR1/2 inhibition to prevent inflammation- and autoimmunity-mediated damage of pancreatic islets. Reparixin and ladarixin, noncompetitive allosteric inhibitors, were used to pharmacologically blockade CXCR1/2. Transient blockade of said receptors was effective in preventing inflammation-mediated damage in MLD-STZ and in preventing and reversing diabetes in NOD mice. Blockade of CXCR1/2 was associated with inhibition of insulitis and modification of leukocytes distribution in blood, spleen, bone marrow, and lymph nodes. Among leukocytes, CXCR2+ myeloid cells were the most decreased subpopulations. Together these results identify CXCR1/2 chemokine receptors as “master regulators” of diabetes pathogenesis. The demonstration that this strategy may be successful in preserving residual β-cells holds the potential to make a significant change in the approach to management of human T1D.

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Section: Discussionmentioning

confidence: 67%

CXCR1/2 Inhibition Blocks and Reverses Type 1 Diabetes in Mice

et al. 2014

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“…When CXCR3 is knocked out, there is a delay in the onset of virally induced diabetes (Frigerio, et al 2002) and in diabetes induced by multiple low doses of streptozotocin (Burke et al 2016). By contrast, when CXCR3 null mice are crossed onto the NOD background, TID development is accelerated (Yamada, et al 2012). What appear to be contrary findings could be due to genetic differences in the different mouse strains, the distinct models of T1D, or functional selectivity of CXCR3 activation that is related to strain and/or the models of diabetes.…”

Section: Introductionmentioning

confidence: 99%

Pancreatic islet inflammation: an emerging role for chemokines

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Karlstad

et al. 2017

Journal of Molecular Endocrinology

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Both Type 1 and Type 2 diabetes exhibit features of inflammation associated with alterations in pancreatic islet function and mass. These immunological disruptions, if unresolved, contribute to the overall pathogenesis of disease onset. This review presents the emerging role of pancreatic islet chemokine production as a critical factor regulating immune cell entry into pancreatic tissue as well as an important facilitator of changes in tissue resident leukocyte activity. Signaling through two specific chemokine receptors (i.e., CXCR2 and CXCR3) is presented to illustrate key points regarding ligand-mediated regulation of innate and adaptive immune cell responses. The prospective roles of chemokine ligands and their corresponding chemokine receptors to influence the onset and progression of autoimmune- and obesity-associated forms of diabetes are discussed.

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“…Due caution, however, is required, because disruption of the CXCR3-chemokine axis has produced some unexpected results, such as enhanced rather than reduced autoimmunity, albeit in experimental models. 19,20 Where should the transplant community go from here? We believe that sufficient information exists that heightened expression of CXCL10 and related chemokines in urine, at the mRNA or protein level, is associated with ongoing acute rejection in the kidney allograft.…”

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confidence: 99%