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Chen P.,Johns Hopkins University | Chen P.,Fudan University | Chen P.,U.S. National Institutes of Health | Baldeviano G.C.,Johns Hopkins University | And 7 more authors.
Clinical and Experimental Immunology | Year: 2012

A.SW and B10.S mice share the same major histocompatibility complex (MHC) haplotype (H-2 s). However, A.SW mice are susceptible to experimental autoimmune myocarditis (EAM) and develop severe disease after immunization with myosin, whereas B10.S mice are resistant. We found that naive A.SW mice have intrinsically increased total CD4 + T cell counts and increased proportions of CD4 + T cells in their spleens compared to B10.S mice. Among total CD4 + T cells, naive A.SW mice have a lower relative frequency of forkhead box protein 3 (FoxP3 +)CD25 + regulatory T cells (T regs). A.SW mice also had a higher proportion of CD4 + T cells and a lower proportion of T regs in their hearts and spleen during EAM, with greater T cell activation and proliferation, compared to B10.S mice. These differences in the T cell compartment were not antigen-specific, as ovalbumin/complete Freund's adjuvant (OVA/CFA) or CFA immunization elicited the same differences in CD4 + T cells and T regs between A.SW and B10.S mice. Moreover, A.SW mice had more T helper type 17 (Th17) cells and B10.S had more Th1 cells in their hearts. The higher percentage of CD4 + T cells and their enhanced potential to differentiate towards the Th17 pathway was also observed in naive A.SW mice. Interleukin (IL)-6 is required for Th17 induction. Interestingly, IL-6Rα expression was greater on naive A.SW CD4 + T cells, compared to B10.S CD4 + T cells, indicating that this intrinsic difference, together with a relatively lower T reg proportion of CD4 + T cells, might lead to heightened Th17 responses and greater susceptibility to autoimmunity in A.SW mice. © 2012 The Authors. Clinical and Experimental Immunology © 2012 British Society for Immunology.

Wu L.,Johns Hopkins University | Ong S.F.,Johns Hopkins University | Talor M.V.,Johns Hopkins University | Barin J.G.,Johns Hopkins University | And 9 more authors.
Journal of Experimental Medicine | Year: 2014

Inflammatory dilated cardiomyopathy (DCMi) is a major cause of heart failure in individuals below the age of 40. We recently reported that IL-17A is required for the development of DCMi. We show a novel pathway connecting IL-17A, cardiac fibroblasts (CFs), GM-CSF, and heart-infiltrating myeloid cells with the pathogenesis of DCMi. Il17ra-/- mice were protected from DCMi, and this was associated with significantly diminished neutrophil and Ly6Chi monocyte/macrophage (MO/M φ) cardiac infiltrates. Depletion of Ly6Chi MO/Mφ also protected mice from DCMi. Mechanistically, IL-17A stimulated CFs to produce key chemokines and cytokines that are critical downstream effectors in the recruitment and differentiation of myeloid cells. Moreover, IL-17A directs Ly6Chi MO/Mφ in trans toward a more proinflammatory phenotype via CF-derived GM-CSF. Collectively, this IL-17A- fibroblast-GM-CSF-MO/Mφ axis could provide a novel target for the treatment of DCMi and related inflammatory cardiac diseases. © 2014 Wu et al.

Wei Z.,Johns Hopkins University | Peterson J.M.,Johns Hopkins University | Lei X.,Johns Hopkins University | Cebotaru L.,Johns Hopkins University | And 4 more authors.
Journal of Biological Chemistry | Year: 2012

Despite the prevalence of insulin resistance and type 2 diabetes mellitus, their underlying mechanisms remain incompletely understood. Many secreted endocrine factors and the intertissue cross-talk they mediate are known to be dysregulated in type 2 diabetes mellitus. Here, we describe CTRP12, a novel adipokine with anti-diabetic actions. The mRNA and circulating levels of CTRP12 were decreased in a mouse model of obesity, but its expression in adipocytes was increased by the anti-diabetic drug rosiglitazone. A modest rise in circulating levels of CTRP12 by recombinant protein administration was sufficient to lower blood glucose in wild-type, leptin-deficient ob/ob, and diet-induced obese mice. A short term elevation of serum CTRP12 by adenovirus-mediated expression improved glucose tolerance and insulin sensitivity, normalized hyperglycemia and hyperinsulinemia, and lowered postprandial insulin resistance in obese and diabetic mice. CTRP12 improves insulin sensitivity in part by enhancing insulin signaling in the liver and adipose tissue. Further, CTRP12 also acts in an insulin-independent manner; in cultured hepatocytes and adipocytes, CTRP12 directly activated the PI3K-Akt signaling pathway to suppress gluconeogenesis and promote glucose uptake, respectively. Collectively, these data establish CTRP12 as a novel metabolic regulator linking adipose tissue to whole body glucose homeostasis through insulin-dependent and independent mechanisms. © 2012 by The American Society for Biochemistry and Molecular Biology, Inc.

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