R213G polymorphism in SOD3 protects against bleomycin-induced inflammation and attenuates induction of proinflammatory pathways

Abstract

Extracellular superoxide dismutase (EC-SOD), one of three mammalian SOD isoforms, is the sole extracellular enzymatic defense against superoxide. A known human single nucleotide polymorphism (SNP) in the matrix-binding domain of EC-SOD characterized by an arginine-to-glycine substitution at position 213 (R213G) redistributes EC-SOD from the matrix into extracellular fluids. We previously reported that knock-in mice harboring the human R213G SNP (R213G mice) exhibited enhanced resolution of inflammation with subsequent protection against fibrosis following bleomycin treatment compared with wild-type (WT) littermates. Herein we set out to determine the underlying pathways with RNA-Seq analysis of WT and R213G lungs 7 days post-PBS and bleomycin. RNA-Seq analysis uncovered significant differential gene expression changes induced in WT and R213G strains in response to bleomycin. Ingenuity Pathways Analysis was used to predict differentially regulated up- and downstream processes based on transcriptional changes. Most prominent was the induction of inflammatory and immune responses in WT mice, which were suppressed in the R213G mice. Specifically, PKC signaling in T lymphocytes, IL-6, and NFΚB signaling were opposed in WT mice when compared with R213G. Several upstream regulators such as IFNγ, IRF3, and IKBKG were implicated in the divergent responses between WT and R213G mice. Our data suggest that the redistributed EC-SOD due to the R213G SNP attenuates the dysregulated inflammatory responses observed in WT mice. We speculate that redistributed EC-SOD protects against dysregulated alveolar inflammation via reprogramming of recruited immune cells toward a proresolving state.

Extracellular superoxide dismutase, a molecular transducer of health benefits of exercise

“…Consistent with this notion is the finding that EcSOD R213G polymorphism is associated with reduced risk of COPD for smokers, but not for non-smoker (57,115). Gaurav were suppressed in EcSOD R213G mice (37) . Similar findings were observed for models of allergic airway inflammation (38,47).…”

Discovering myeloid cell heterogeneity in the lung by means of next generation sequencing

“…Using NGS approaches, genetic studies on pulmonary fibrosis have made great progress, most of which have led to the discovery of mutations in genes related to telomere homeostasis [59]. Whole-lung transcriptome profiling showed dysregulated canonical pathways in the fibrosis mouse model, including the pathways for bacteria/virus recognition, inflammation, leukocyte extravasation, and ROS production [60]. By using scRNA-seq, Peyser et al [61] found that early events in lung fibrosis might not involve significant changes in fibroblast number, while the numbers of macrophages, dendritic cells (DCs), and proliferating myeloid cells are increased.…”

MicroRNA regulation postbleomycin due to the R213G extracellular superoxide dismutase variant is predicted to suppress inflammatory and immune pathways

“…All mouse work was approved by the University of Colorado-Anschutz Medical Campus Institutional Animal Care and Use Committee. The lung tissue used in this study was obtained from the same cohort of mice used in our recently published study that analyzed mRNA sequencing data to enable direct comparison between the miR and mRNA sequencing analysis (14). As published, mice received standard chow and water ad libitum and were housed in the vivarium with a 14:10 h light-dark schedule.…”

“…Mice with a knock-in R213G EC-SOD SNP have reduced bleomycin-induced pulmonary fibrosis and enhanced resolution of inflammation relative to wild-type (WT) mice (35). Previous studies found disparate transcriptomic profiles between WT and R213G mice responsible for differential inflammation and immune function (14). However, it is unclear whether epigenetic regulation contributes to the differential expression of these immune and inflammatory genes.…”