The R213G polymorphism in SOD3 protects against allergic airway inflammation
Rohit Gaurav ... Geoffrey L. Chupp, Russell P. Bowler
Rohit Gaurav ... Geoffrey L. Chupp, Russell P. Bowler
Published September 7, 2017
Citation Information: JCI Insight. 2017;2(17):e95072. doi:10.1172/jci.insight.95072.
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Categories: 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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Sputum SOD3 transcript increases with asthma severity. Sputum samples we...

Figure 1

Sputum SOD3 transcript increases with asthma severity.

Sputum samples were collected from the Yale Center for Asthma and Airway Diseases (YCAAD) cohort consisting of asthmatic patients (n = 112) that were divided into 3 groups based on transcriptomic endotypes of asthma (TEA) as described in (32). TEA1 (n = 34) is the most severe endotype followed by TEA2 (n = 19) and TEA3 (n = 47). CTRL (n = 12) is the non-atopic healthy control. Graph shows distribution of each individual represented by a dot in respective groups. RNA sequencing was performed to find that the SOD3 transcript was highest in the TEA1 cluster (P = 6.0737 × 10–12) and decreased with asthma severity to control levels in TEA3. The y axis represents the transcript level. 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).