Neutrophil Irgm1 ameliorates sepsis-induced myocardial dysfunction by promoting Alox15 degradation

Area of Science:

• Immunology
• Cardiology
• Molecular Biology

Background:

• Sepsis-induced myocardial dysfunction (SIMD) is a severe complication driven by immune dysregulation, with neutrophils playing a key role.
• The function of Immunity-Related GTPase Family M protein (IRGM) in neutrophils during SIMD is not well understood.

Purpose of the Study:

• To investigate the role of neutrophil Irgm1 in SIMD pathogenesis.
• To elucidate the underlying molecular mechanisms of Irgm1's action in SIMD.

Main Methods:

• Analysis of IRGM expression in neutrophils from SIMD patients.
• Generation of neutrophil-specific Irgm1-deficient mice to study CLP-induced SIMD.
• Investigation of Irgm1 interaction with RNF213 and its effect on Alox15 ubiquitination and degradation.
• Measurement of 15-HETE levels and assessment of cardiac function in mice.
• Administration of an Alox15-targeting drug in a mouse model of SIMD.

Main Results:

• IRGM expression was elevated in SIMD patients' neutrophils and correlated inversely with disease severity.
• Neutrophil-specific Irgm1 deficiency exacerbated cardiac dysfunction and inflammation in mice.
• Irgm1 targets Alox15 for degradation via RNF213, inhibiting neutrophil ferroptosis and 15-HETE production, thereby alleviating SIMD.
• Alox15 and 15-HETE levels correlated positively with SIMD severity in patients.
• Pharmacological inhibition of Alox15 improved cardiac function in SIMD mice.

Conclusions:

• Neutrophil Irgm1 plays a critical protective role in attenuating SIMD.
• Irgm1 restrains neutrophil ferroptosis and 15-HETE production, offering a novel therapeutic strategy.
• Irgm1 shows potential as a prognostic biomarker and therapeutic target for SIMD.