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Aberrant ROCK activation promotes the development of type I diabetes in NOD mice.

ABSTRACT: Aberrant production of IL-21 by T cells is critical for the development of type 1 diabetes (T1D) in NOD mice. The pathogenic effects of IL-21 are partly due to its ability to promote the generation of T(H)-17 cells. Interferon Regulatory Factor (IRF4) is a crucial regulator of IL-17 and IL-21 production. We recently found that the serine-threonine kinase ROCK2 phosphorylates IRF4 and regulates its ability to control IL-17 and IL-21 production. Here we show that NOD T cells aberrantly activate ROCK2. We furthermore demonstrate that ROCK inhibition corrects the abnormal IRF4 function in NOD T cells and diminishes their production of IL-17 and IL-21. Importantly, administration of a ROCK inhibitor to NOD mice protects against diabetes development. These studies thus support the idea that ROCK2 is inappropriately activated in NOD T cells and that ROCK kinases could represent important therapeutic targets for the treatment of T1D.

SUBMITTER: Biswas PS

PROVIDER: S-EPMC3031108 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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Aberrant ROCK activation promotes the development of type I diabetes in NOD mice.

Biswas Partha S PS Gupta Sanjay S Chang Emily E Bhagat Govind G Pernis Alessandra B AB

Cellular immunology 20101106 2

Aberrant production of IL-21 by T cells is critical for the development of type 1 diabetes (T1D) in NOD mice. The pathogenic effects of IL-21 are partly due to its ability to promote the generation of T(H)-17 cells. Interferon Regulatory Factor (IRF4) is a crucial regulator of IL-17 and IL-21 production. We recently found that the serine-threonine kinase ROCK2 phosphorylates IRF4 and regulates its ability to control IL-17 and IL-21 production. Here we show that NOD T cells aberrantly activate RO ...[more]

PMID: 21111405

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Sex-dependent effects of bisphenol A on type 1 diabetes development in non-obese diabetic (NOD) mice.

Project description:Type 1 diabetes (T1D) is an autoimmune disease caused by immune-mediated pancreatic ?-cell destruction. The endocrine disrupting chemical bisphenol A (BPA) has widespread human exposure and can modulate immune function and the gut microbiome (GMB), which may contribute to the increasing T1D incidence worldwide. It was hypothesized that BPA had sex-dependent effects on T1D by modulating immune homeostasis and GMB. Adult female and male non-obese diabetic (NOD) mice were orally administered BPA at environmentally relevant doses (30 or 300 µg/kg). Antibiotic-treated adult NOD females were exposed to 0 or 30 µg/kg BPA. BPA accelerated T1D development in females, but delayed males from T1D. Consistently, females had a shift towards pro-inflammation (e.g., increased macrophages and Bacteroidetes), while males had increases in anti-inflammatory immune factors and a decrease in both anti- and pro-inflammatory GMB. Although bacteria altered during sub-acute BPA exposure differed from bacteria altered from chronic BPA exposure in both sexes, the GMB profile was consistently pro-inflammatory in females, while males had a general decrease of both anti- and pro-inflammatory gut microbes. However, treatment of females with the antibiotic vancomycin failed to prevent BPA-induced glucose intolerance, suggesting changes in Gram-positive bacteria were not a primary mechanism. In conclusion, BPA exposure was found to have sex dimorphic effects on T1D with detrimental effects in females, and immunomodulation was identified as the primary mechanism.

| S-EPMC6511313 | biostudies-literature

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