Affiliation:
1. State Key Laboratory of Pharmaceutical Biotechnology,Department of Cardiology of Nanjing Drum Tower Hospital,The Affiliated Hospital of Nanjing University Medical School
Abstract
Abstract
Background
The role of immune response gene 1 (IRG1) and its product itaconate in sepsis-induced cardiac dysfunction (SIMD) has yet to be fully understood, despite its known anti-inflammatory and antioxidant effects mediated through diverse mechanisms.
Methods
In order to create an experimental sepsis model in vivo, mice were administered lipopolysaccharide (LPS) at a dosage of 10 mg/kg. The levels of itaconate/IRG1 in the cardiac tissue of mice with systemic inflammatory response syndrome (SIMD) were assessed. Sepsis was induced in both IRG1-knockout (IRG1−/−) mice and wild-type mice. Additionally, the impact of exogenous supplementation of 4-octyl itaconate (4-OI) on SIMD was further investigated. In order to ascertain the function and mechanism of 4-OI in an in vitro setting, we subjected bone marrow-derived macrophages and RAW264.7 cells to treatment with 4-OI and Nuclear factor, erythroid 2 like 2 (NRF2)–small interfering RNA prior to the administration of LPS. The impact of 4-OI was assessed through flow cytometry, western blot analysis, and quantitative real–time polymerase chain reaction (qPCR).
Results
During sepsis-induced myocardial dysfunction (SIMD), there was a significant increase in itaconic acid levels in the heart. In addition, the absence of IRG1 worsened septic myocardial injury, resulting in impaired cardiac function, heightened inflammatory response in the myocardial tissue, and increased infiltration of cardiac macrophages. Flow cytometry analysis revealed an increase in the polarization of M1 macrophages in the myocardial tissue, while M2 polarization decreased. Furthermore, there was an elevated infiltration of peripheral Ly6clow monocytes from the spleen into the myocardial tissue. Conversely, administration of 4-OI effectively preserved cardiac function and mitigated systemic inflammation. Mechanistically, 4-OI inhibited macrophage inflammation and promoted their polarization by activating the NRF2/HO-1 signaling pathway in vitro. Consistently, IRG1 expression serves as a natural protective mechanism against excessive inflammatory response during SIMD, and exogenous supplementation of 4-OI is protective in SIMD by regulating macrophage polarization.
Conclusion
IRG1/itaconate increased survival rate and attenuated cardiac dysfunction in SIMD by activating the NRF2 signaling pathway in macrophages.
Publisher
Research Square Platform LLC
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