The R213G polymorphism in SOD3 protects against allergic airway inflammation
Rohit Gaurav, Jason T. Varasteh, Michael R. Weaver, Sean R. Jacobson, Laura Hernandez-Lagunas, Qing Liu, Eva Nozik-Grayck, Hong Wei Chu, Rafeul Alam, Børge G. Nordestgaard, Camilla J. Kobylecki, Shoaib Afzal, Geoffrey L. Chupp, Russell P. Bowler
Rohit Gaurav, Jason T. Varasteh, Michael R. Weaver, Sean R. Jacobson, Laura Hernandez-Lagunas, Qing Liu, Eva Nozik-Grayck, Hong Wei Chu, Rafeul Alam, Børge G. Nordestgaard, Camilla J. Kobylecki, Shoaib Afzal, Geoffrey L. Chupp, Russell P. Bowler
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Research Article Inflammation Pulmonology

The R213G polymorphism in SOD3 protects against allergic airway inflammation

Abstract

Oxidative stress is important in the pathogenesis of allergic asthma. Extracellular superoxide dismutase (EC-SOD; SOD3) is the major antioxidant in lungs, but its role in allergic asthma is unknown. Here we report that asthmatics have increased SOD3 transcript levels in sputum and that a single nucleotide polymorphism (SNP) in SOD3 (R213G; rs1799895) changes lung distribution of EC-SOD, and decreases likelihood of asthma-related symptoms. Knockin mice analogous to the human R213G SNP had lower airway hyperresponsiveness, inflammation, and mucus hypersecretion with decreased interleukin-33 (IL-33) in bronchoalveolar lavage fluid and reduced type II innate lymphoid cells (ILC2s) in lungs. SOD mimetic (Mn (III) tetrakis (N-ethylpyridinium-2-yl) porphyrin) attenuated Alternaria-induced expression of IL-33 and IL-8 release in BEAS-2B cells. These results suggest that R213G SNP potentially benefits its carriers by resulting in high EC-SOD in airway-lining fluid, which ameliorates allergic airway inflammation by dampening the innate immune response, including IL-33/ST2–mediated changes in ILC2s.

Authors

Rohit Gaurav, Jason T. Varasteh, Michael R. Weaver, Sean R. Jacobson, Laura Hernandez-Lagunas, Qing Liu, Eva Nozik-Grayck, Hong Wei Chu, Rafeul Alam, Børge G. Nordestgaard, Camilla J. Kobylecki, Shoaib Afzal, Geoffrey L. Chupp, Russell P. Bowler

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Figure 3

R213G protects mice from airway hyperresponsiveness and inflammatory cell infiltration.

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R213G protects mice from airway hyperresponsiveness and inflammatory cel...
(A) C57BL/6 WT, R213G HET, R213G HM, and EC-SOD OE mice were sensitized and challenged with ovalbumin or saline as indicated in Figure 2A. Saline control contained all the genotypes that were included in OVA. (B) On day 32, methacholine challenge was performed on FlexiVent to measure airway resistance (R) with doses ranging from 0 to 50 mg/ml in saline. Two-way ANOVA was used with Bonferroni multiple comparisons. (C) Total protein was measured in BALF to estimate protein leakage into the airway lumen (Saline = 21, WT OVA = 14, R213G HET OVA = 9, R213G HM OVA = 11, EC-SOD OE OVA = 7). One-way ANOVA was used with Tukey’s multiple comparison test. (D) Inflammatory cell infiltration was measured as total cell count in the BALF (Saline = 47, WT OVA = 18, R213G HET OVA = 12, R213G HM OVA = 11, EC-SOD OE OVA = 13). One-way ANOVA was used with Tukey’s multiple comparison test. (E) Cytospin slides (n = 5/group), stained with H&E were manually counted to identify cell types/5 high-power fields (5HPF). Investigators were blinded to the sample group allocation for cell counts. Bottom and top of the boxes are the 25th and 75th percentile and the band near the middle of the box is the 50th percentile (the median). Two-way ANOVA was used with Bonferroni multiple comparisons. Error bars represent ± SEM. *P < 0.05, **P < 0.01, ***P < 0.001, ****P < 0.0001.