CCR2 and CCR5 chemokine receptors differentially influence the development of autoimmune diabetes in the NOD mouse

Department of Immunology, The Scripps Research Institute, La Jolla, CA 92037, USA.
Autoimmunity (Impact Factor: 2.71). 10/2009; 43(2):156-63. DOI: 10.3109/08916930903246464
Source: PubMed


The infiltration of monocytes represents an important early event in the development of autoimmune diabetes in NOD mice. Given that chemokines are key regulators of leukocyte trafficking, we examined the requirement for the chemokine receptors beta(CC)-chemokine receptor-5 (CCR5) and beta(CC)-chemokine receptor-2 (CCR2), which recruit monocytes, in disease development in the NOD mouse. Whereas the onset of diabetes was significantly delayed in CCR2-/-NOD mice (25% at 30 weeks) compared to NOD mice (50% at 28 weeks), the pathogenesis of diabetes was accelerated in CCR5-/-NOD mice (75% at 23 weeks). The rapid development of diabetes in CCR5-/-NOD mice was associated with aggressive destructive insulitis and was accompanied by altered leukocyte migration into islets. In contrast, CCR2-/- NOD mice exhibited delayed inflammatory cell recruitment. Nevertheless, total diabetogenic splenocytes from CCR2-/-NOD and CCR5-/-NOD showed similar capability to adoptively transfer diabetes into NOD.scid recipients. Importantly, our data suggest that targeting of CCR2 may lead to therapies against Type 1 diabetes.

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    • "). In addition, CCR5 has been reported to directly regulate T-cell function in autoimmune diseases, including MS and RA (Solomon et al., 2010). "
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    ABSTRACT: Rheumatoid arthritis (RA) is a chronic autoimmune disease characterized by synovial inflammation triggered by infiltrating CD4 lymphocytes. The positioning and activation of lympho-cyte in inflamed synovial tissues are dependent on a number of factors including their chemokine receptor expression profile. We aimed to investigate which chemokine receptors pattern correlate with serum cytokine levels and with disease activity. Forty patients with RA (34 female and 6 male) with age range from 21 to 68 years were included. Twenty healthy volunteers (16 female and 4 male) with matched age (range 21–48 years) were served as healthy controls (HCs). Expression of chemo-kine receptors (CCR5, CX3CR1 and CCR7) together with the apoptosis-related marker (CD95) was analyzed using three-color flow cytometry analysis after gating on CD4 + peripheral blood lym-phocytes. Plasma levels of IL-6, IL-10, IL-12 and TNF-a cytokines were measured in all participants using ELISA. Disease activity score (DAS28-CRP) system was assessed and active disease was defined as DAS28 P3.2. Twenty-five (62.4%) patients were classified as active RA (ARA) and 15 (37.5%) patients with inactive RA (IRA). Percentages of CD4 + lymphocytes
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    • "One of the primary signals leading to immune cell infiltration into tissues, including the pancreatic islets, is the release of chemotactic cytokines, usually referred to as chemokines [6], [7]. Synthesis and secretion of chemokines from the β-cell population is a major signal for islet immune cell invasion [8], [9], [10] and chemokines are critical factors associated with the development of autoimmune diabetes [11], [12], [13], [14]. "
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