1. Immune-response gene 1 deficiency aggravates inflammation-triggered cardiac dysfunction by inducing M1 macrophage polarization and aggravating Ly6C high monocyte recruitment.
- Author
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Shen S, Li J, Wei Z, Liu Y, Kang L, Gu R, Sun X, Xu B, and Li Q
- Subjects
- Animals, Mice, Succinates pharmacology, RAW 264.7 Cells, Monocytes metabolism, Antigens, Ly genetics, Antigens, Ly metabolism, Sepsis genetics, Male, Lipopolysaccharides, Mice, Inbred C57BL, Hydro-Lyases, Macrophages drug effects, Inflammation genetics, Mice, Knockout, NF-E2-Related Factor 2 genetics, NF-E2-Related Factor 2 metabolism
- Abstract
The immune response gene 1 (IRG1) and its metabolite itaconate are implicated in modulating inflammation and oxidative stress, with potential relevance to sepsis-induced myocardial dysfunction (SIMD). This study investigates their roles in SIMD using both in vivo and in vitro models. Mice were subjected to lipopolysaccharide (LPS)-induced sepsis, and cardiac function was assessed in IRG1 knockout (IRG1-/-) and wild-type mice. Exogenous 4-octyl itaconate (4-OI) supplementation was also examined for its protective effects. In vitro, bone marrow-derived macrophages and RAW264.7 cells were treated with 4-OI following Nuclear factor, erythroid 2 like 2 (NRF2)-small interfering RNA administration to elucidate the underlying mechanisms. Our results indicate that IRG1 deficiency exacerbates myocardial injury during sepsis, while 4-OI administration preserves cardiac function and reduces inflammation. Mechanistic insights reveal that 4-OI activates the NRF2/HO-1 pathway, promoting macrophage polarization and attenuating inflammation. These findings underscore the protective role of the IRG1/itaconate axis in SIMD and suggest a therapeutic potential for 4-OI in modulating macrophage responses., (© 2024. The Author(s).)
- Published
- 2024
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