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Neutralizing Th2 inflammation in neonatal islets prevents ?-cell failure in adult IUGR rats.

ABSTRACT: Intrauterine growth restriction (IUGR) leads to development of type 2 diabetes (T2D) in adulthood. The mechanisms underlying this phenomenon have not been fully elucidated. Inflammation is associated with T2D; however, it is unknown whether inflammation is causal or secondary to the altered metabolic state. Here we show that the mechanism by which IUGR leads to the development of T2D in adulthood is via transient recruitment of T-helper 2 (Th) lymphocytes and macrophages in fetal islets resulting in localized inflammation. Although this immune response is short-lived, it results in a permanent reduction in islet vascularity and impaired insulin secretion. Neutralizing interleukin-4 antibody therapy given only in the newborn period ameliorates inflammation and restores vascularity and ?-cell function into adulthood, demonstrating a novel role for Th2 immune responses in the induction and progression of T2D. In the neonatal stage, inflammation and vascular changes are reversible and may define an important developmental window for therapeutic intervention to prevent adult-onset diabetes.

SUBMITTER: Jaeckle Santos LJ

PROVIDER: S-EPMC3994952 | biostudies-literature | 2014 May

REPOSITORIES: biostudies-literature

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Neutralizing Th2 inflammation in neonatal islets prevents β-cell failure in adult IUGR rats.

Jaeckle Santos Lane J LJ Li Changhong C Doulias Paschalis-Thomas PT Ischiropoulos Harry H Worthen G Scott GS Simmons Rebecca A RA

Diabetes 20140109 5

Intrauterine growth restriction (IUGR) leads to development of type 2 diabetes (T2D) in adulthood. The mechanisms underlying this phenomenon have not been fully elucidated. Inflammation is associated with T2D; however, it is unknown whether inflammation is causal or secondary to the altered metabolic state. Here we show that the mechanism by which IUGR leads to the development of T2D in adulthood is via transient recruitment of T-helper 2 (Th) lymphocytes and macrophages in fetal islets resultin ...[more]

PMID: 24408314

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Project description:BackgroundAsthma is an allergic airway inflammation-driven disease that affects more than 300 million people world-wide. Targeted therapies for asthma are largely lacking. Although asthma symptoms can be prevented from worsening, asthma development cannot be prevented. Cdc42 GTPase has been shown to regulate actin cytoskeleton, cell proliferation and survival.ObjectivesTo investigate the role and targeting of Cdc42 in Th2 cell differentiation and Th2-mediated allergic airway inflammation.MethodsPost-thymic Cdc42-deficient mice were generated by crossing Cdc42flox/flox mice with dLckicre transgenic mice in which Cre expression is driven by distal Lck promoter. Effects of post-thymic Cdc42 deletion and pharmacological targeting Cdc42 on Th2 cell differentiation were evaluated in vitro under Th2-polarized culture conditions. Effects of post-thymic Cdc42 deletion and pharmacological targeting Cdc42 on allergic airway inflammation were evaluated in ovalbumin- and/or house dust mite-induced mouse models of asthma.ResultsPost-thymic deletion of Cdc42 led to reduced peripheral CD8+ T cells and attenuated Th2 cell differentiation, with no effect on closely related Th1, Th17 and induced regulatory T (iTreg) cells. Post-thymic Cdc42 deficiency ameliorated allergic airway inflammation. The selective inhibition of Th2 cell differentiation by post-thymic deletion of Cdc42 was recapitulated by pharmacological targeting of Cdc42 with CASIN, a Cdc42 activity-specific chemical inhibitor. CASIN also alleviated allergic airway inflammation. CASIN-treated Cdc42-deficient mice showed comparable allergic airway inflammation to vehicle-treated Cdc42-deficient mice, indicative of negligible off-target effect of CASIN. CASIN had no effect on established allergic airway inflammation.Conclusion and clinical relevanceCdc42 is required for Th2 cell differentiation and allergic airway inflammation, and rational targeting Cdc42 may serve as a preventive but not therapeutic approach for asthma control.

Dataset Information

Neutralizing Th2 inflammation in neonatal islets prevents ?-cell failure in adult IUGR rats.

Publications

Neutralizing Th2 inflammation in neonatal islets prevents β-cell failure in adult IUGR rats.

Similar Datasets

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