The R213G polymorphism in SOD3 protects against allergic airway inflammation

TY - JOUR

T1 - The R213G polymorphism in SOD3 protects against allergic airway inflammation

AU - Gaurav, Rohit

AU - Varasteh, Jason T

AU - Weaver, Michael R

AU - Jacobson, Sean R

AU - Hernandez-Lagunas, Laura

AU - Liu, Qing

AU - Nozik-Grayck, Eva

AU - Chu, Hong Wei

AU - Alam, Rafeul

AU - Nordestgaard, Børge G

AU - Kobylecki, Camilla J

AU - Afzal, Shoaib

AU - Chupp, Geoffrey L

AU - Bowler, Russell P

PY - 2017/9/7

Y1 - 2017/9/7

N2 - 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.

AB - 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.

KW - Journal Article

U2 - 10.1172/jci.insight.95072

DO - 10.1172/jci.insight.95072

M3 - Journal article

C2 - 28878123

SN - 2379-3708

VL - 2

JO - JCI insight

JF - JCI insight

IS - 17

M1 - e95072

ER -