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Redistribution of EC‐SOD resolves bleomycin‐induced inflammation via increased apoptosis of recruited alveolar macrophages
Author(s) -
Allawzi Ayed,
McDermott Ivy,
Delaney Cassidy,
Nguyen Kianna,
Banimostafa Laith,
Trumpie Ashley,
HernandezLagunas Laura,
Riemondy Kent,
Gillen Austin,
Hesselberth Jay,
Kasmi Karim El,
Sucharov Carmen C.,
Janssen William J.,
Stenmark Kurt,
Bowler Russell,
NozikGrayck Eva
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201901038rr
Subject(s) - apoptosis , microbiology and biotechnology , glutathione , inflammation , bleomycin , chemistry , superoxide dismutase , in vivo , oxidative stress , biology , immunology , biochemistry , genetics , enzyme , chemotherapy
A human single nucleotide polymorphism (SNP) in the matrix‐binding domain of extracellular superoxide dismutase (EC‐SOD), with arginine to glycine substitution at position 213 (R213G), redistributes EC‐SOD from the matrix into extracellular fluids. We reported that, following bleomycin (bleo), knockin mice harboring the human R213G SNP (R213G mice) exhibit enhanced resolution of inflammation and protection against fibrosis, compared with wild‐type (WT) littermates. In this study, we tested the hypothesis that the EC‐SOD R213G SNP promotes resolution via accelerated apoptosis of recruited alveolar macrophage (AM). RNA sequencing and Ingenuity Pathway Analysis 7 d postbleo in recruited AM implicated increased apoptosis and blunted inflammatory responses in the R213G strain exhibiting accelerated resolution. We validated that the percentage of apoptosis was significantly elevated in R213G recruited AM vs. WT at 3 and 7 d postbleo in vivo. Recruited AM numbers were also significantly decreased in R213G mice vs. WT at 3 and 7 d postbleo. ChaC glutathione‐specific γ‐glutamylcyclotransferase 1 (Chac1), a proapoptotic γ‐glutamyl cyclotransferase that depletes glutathione, was increased in the R213G recruited AM. Overexpression of Chac1 in vitro induced apoptosis of macrophages and was blocked by administration of cell‐permeable glutathione. In summary, we provide new evidence that redistributed EC‐SOD accelerates the resolution of inflammation through redox‐regulated mechanisms that increase recruited AM apoptosis.—Allawzi, A., McDermott, I., Delaney, C., Nguyen, K., Banimostafa, L., Trumpie, A., Hernandez‐Lagunas, L., Riemondy, K., Gillen, A., Hesselberth, J., ElKasmi, K., Sucharov, C. C., Janssen, W. J., Stenmark, K., Bowler, R., Nozik‐Grayck, E. Redistribution of EC‐SOD resolves bleomycin‐induced inflammation via increased apoptosis of recruited alveolar macrophages. FASEB J. 33, 13465–13475 (2019). www.fasebj.org