CysLT1 Receptor Is Protective against Oxidative Stress in a Model of Irritant-Induced Asthma

The bronchoconstrictive and proinflammatory properties of cysteinyl leukotrienes (cysLTs) in allergic asthma mediate their effects predominantly through the cysLT1 receptor (cysLT1R). However, the role of cysLTs and cysLT1R in innate immune-triggered asthma is largely unexplored. We explored the syn...

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Bibliographic Details
Published in:The Journal of immunology (1950) 2016-07, Vol.197 (1), p.266-277
Main Authors: McGovern, Toby, Goldberger, Madison, Chen, Michael, Allard, Benoit, Hamamoto, Yoichiro, Kanaoka, Yoshihide, Austen, K Frank, Powell, William S, Martin, James G
Format: Article
Language:English
Subjects:
Allergens - immunology
Animals
Asthma - chemically induced
Asthma - immunology
Cadherins - metabolism
Cells, Cultured
Chlorine - immunology
Humans
Immunity, Innate
Irritants - immunology
Keratinocytes - immunology
Mice
Mice, Inbred BALB C
Mice, Knockout
Neutrophils - immunology
NF-E2-Related Factor 2 - genetics
NF-E2-Related Factor 2 - metabolism
Oxidative Stress
Receptors, Leukotriene - genetics
Receptors, Leukotriene - metabolism
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Summary:The bronchoconstrictive and proinflammatory properties of cysteinyl leukotrienes (cysLTs) in allergic asthma mediate their effects predominantly through the cysLT1 receptor (cysLT1R). However, the role of cysLTs and cysLT1R in innate immune-triggered asthma is largely unexplored. We explored the synthesis of cysLTs and cysLT1R as determinants of airway responses in an oxidative stress-induced model of irritant asthma. Wild-type (WT) mice exposed to 100 ppm Cl2 for 5 min had airway neutrophilia, increased cysLT production, and pulmonary expression of cysLT-related biosynthetic genes. CysLT1R-deficient (CysLTr1(-/-)) mice that were exposed to Cl2 demonstrated airway hyperresponsiveness to inhaled methacholine significantly greater than in WT BALB/c mice. Compared to WT mice, airway neutrophilia and keratinocyte chemoattractant production levels were higher in CysLTr1(-/-) mice and airway hyperresponsiveness was ameliorated using a granulocyte depletion Ab. CysLTr1(-/-) mice also demonstrated prolonged bronchial epithelial cell apoptosis following Cl2 WT mice showed increased antioxidant and NF erythroid 2-related factor 2 (Nrf2) gene expression, Nrf2 nuclear translocation in bronchial epithelial cells, and increased reduced glutathione/oxidized glutathione following Cl2 exposure whereas CysLTr1(-/-) mice did not. Furthermore, CysLTr1(-/-) mice demonstrated increased pulmonary E-cadherin expression and soluble E-cadherin shedding compared with WT mice. Loss of a functional cysLT1R results in aberrant antioxidant response and increased susceptibility to oxidative injury, apparently via a cysLT1R-dependent impairment of Nrf2 function.
ISSN:0022-1767
1550-6606
DOI:10.4049/jimmunol.1501084