IL33 contributes to diesel pollution-mediated increase in experimental asthma severity.

BACKGROUND: Exposure to traffic pollution, notably diesel exhaust particles (DEP), increases risk for asthma and asthma exacerbations. The contribution of cytokines generated by stressed lung epithelial cells (IL25, IL33, TSLP) to DEP-induced asthma severity remains poorly understood. METHODS: BALB/c mice were exposed intratracheally once to DEP or 9 times over 3-weeks to either saline, DEP, and/or house dust mite extract (HDM). Airway hyper-responsiveness (AHR), pulmonary inflammation, and T-cell subsets were assessed 24 hours after the last exposure in mice sufficient and deficient for the IL33 receptor ST2. RESULTS: DEP exposure induces oxidative stress, IL6, neutrophils and pulmonary accumulation of IL33, but not IL25 or TSLP or other features of allergic disease. When mice are co-exposed to DEP and low doses of HDM, DEP increases IL33 lung levels and Th2 responses. ST2 deficiency partially protected mice from HDM + DEP induced AHR in association with decreased type 2 inflammation and lung levels of IL5+ IL17A+ co-producing T-cells. Upon in vitro HDM challenge of lung cells from HDM ± DEP exposed ST2-/- mice, secretion of IL5, IL13, IL6 and IL17A was abrogated by a mechanism involving IL33 signaling in both dendritic cells and T-cells. HDM + DEP exposed bone marrow derived dendritic cells and IL33 pulsed BMDC promote a mixed Th2/Th17 response that was dependent on ST2 expression by CD4+ T-cells. CONCLUSION: IL33 contributes to DEP mediated increase in allergen-induced Th2 inflammation and AHR in a mouse model of severe steroid resistant asthma, potentially through the accumulation of pathogenic IL5+ IL17A+ CD4+ effector T-cells.

Vitamin D supplementation attenuates asthma development following traffic-related particulate matter exposure.

BACKGROUND: Recent literature suggests that children who are vitamin D deficient are uniquely susceptible to the effects of traffic-related air pollution (TRAP) exposure. This is highly significant because large segments of the population reside in zones of high TRAP exposure. OBJECTIVE: We sought to determine whether vitamin D supplementation mitigates the effect of TRAP exposure on asthma development, asthma exacerbation, and/or airway inflammation and to determine the timing of vitamin D supplementation that confers maximal health benefit. METHODS: Using established mouse models of asthma, we examined the effect of prenatal and postnatal vitamin D supplementation on asthma development, as well as the utility of vitamin D as a treatment for established asthma in the context of diesel exhaust particle (DEP) exposure. RESULTS: DEP and allergen coexposure resulted in increased airway hyperresponsiveness (AHR) and accumulation of pathogenic TH2/TH17 cells in the lungs of vitamin D-deficient mice compared with control mice. Prenatal and postnatal vitamin D supplementation significantly attenuated the development of AHR and decreased pulmonary accumulation of TH2/TH17 cells after coexposure to TRAP and allergen but not to allergen alone. Restoration of normal vitamin D status had no effect on AHR once asthma was already established. CONCLUSIONS: Our data establish that vitamin D confers protection against asthma development specifically in the context of TRAP exposure. Although vitamin D replacement did not reverse established asthma, restoration of normal vitamin D status in early life significantly attenuated the development of AHR in the setting of DEP-exacerbated allergic asthma and reduced numbers of lung TH2/TH17 cells, which portend the development of severe asthma.

Loss of GTPase of immunity-associated protein 5 (Gimap5) promotes pathogenic CD4+ T-cell development and allergic airway disease.

BACKGROUND: GTPase of immunity-associated protein 5 (GIMAP5) is essential for lymphocyte homeostasis and survival. Recently, human GIMAP5 single nucleotide polymorphisms have been linked to an increased risk for asthma, whereas loss of Gimap5 in mice has been associated with severe CD4+ T cell-driven immune pathology. OBJECTIVE: We sought to identify the molecular and cellular mechanisms by which Gimap5 deficiency predisposes to allergic airway disease. METHODS: CD4+ T-cell polarization and development of pathogenic CD4+ T cells were assessed in Gimap5-deficient mice and a human patient with a GIMAP5 loss-of-function (LOF) mutation. House dust mite-induced airway inflammation was assessed by using a complete Gimap5 LOF (Gimap5sph/sph) and conditional Gimap5fl/flCd4Cre/ert2 mice. RESULTS: GIMAP5 LOF mutations in both mice and human subjects are associated with spontaneous polarization toward pathogenic TH17 and TH2 cells in vivo. Mechanistic studies in vitro reveal that impairment of Gimap5-deficient TH cell differentiation is associated with increased DNA damage, particularly during TH1-polarizing conditions. DNA damage in Gimap5-deficient CD4+ T cells could be controlled by TGF-ß, thereby promoting TH17 polarization. When challenged with house dust mite in vivo, Gimap5-deficient mice displayed an exacerbated asthma phenotype (inflammation and airway hyperresponsiveness), with increased development of TH2, TH17, and pathogenic TH17/TH2 cells. CONCLUSION: Activation of Gimap5-deficient CD4+ T cells is associated with increased DNA damage and reduced survival that can be overcome by TGF-ß. This leads to selective survival of pathogenic TH17 cells but also TH2 cells in human subjects and mice, ultimately promoting allergic airway disease.