Enhanced Th2 cell differentiation and function in the absence of Nox2.

BACKGROUND: Patients with chronic granulomatous disease (CGD), whom inherit abnormal function of NADPH oxidase 2 (Nox2), suffer from hyperinflammatory responses in lung as well as bacterial and fungal infection. There have been studies to reveal the function of Nox2 in hyperinflammatory diseases, especially in asthma, but the exact role of Nox2 in asthma is still unclear and controversial. Therefore, we attempted to clarify the exact role of Nox2 in asthma, using various experimental asthma models. METHODS: Asthma phenotypes were analyzed in response to various allergen-induced experimental asthma using Nox2-deficient mice and recombinase gene-activating-1-deficient mice. To understand the underlying mechanisms of exaggerated Th2 effector functions, we investigated the degree of T-cell activation, levels of activation-induced cell death (AICD), and regulatory T (Treg)-cell differentiation in Nox2-deficient T cells. RESULTS: Asthma phenotypes were increased through enhanced Th2 differentiation and function in Nox2-null mice regardless of dose and route of various allergens. Nox2-deficient T cells also showed hyperactivation, reduced AICD, and diminished Treg-cell differentiation through increased AKT phosphorylation (T308/S473) and enhanced mitochondrial ROS production. CONCLUSION: Our findings indicate that Nox2 deficiency results in exaggerated experimental asthma, which is caused by enhanced Th2 effector function in a T-cell-intrinsic manner.

Interleukin-17A negatively regulates lymphangiogenesis in T helper 17 cell-mediated inflammation.

During inflammation lymphatic vessels (LVs) are enlarged and their density is increased to facilitate the migration of activated immune cells and antigens. However, after antigen clearance, the expanded LVs shrink to maintain homeostasis. Here we show that interleukin (IL)-17A, secreted from T helper type 17 (TH17) cells, is a negative regulator of lymphangiogenesis during the resolution phase of TH17-mediated immune responses. Moreover, IL-17A suppresses the expression of major lymphatic markers in lymphatic endothelial cells and decreases in vitro LV formation. To investigate the role of IL-17A in vivo, we utilized a cholera toxin-mediated inflammation model and identified inflammation and resolution phases based on the numbers of recruited immune cells. IL-17A, markedly produced by TH17 cells even after the peak of inflammation, was found to participate in the negative regulation of LV formation. Moreover, blockade of IL-17A resulted in not only increased density of LVs in tissues but also their enhanced function. Taken together, these findings improve the current understanding of the relationship between LVs and inflammatory cytokines in pathologic conditions.