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

## TL;DR

This study shows that a protein called Irgm1 in neutrophils helps reduce heart damage caused by sepsis by breaking down another protein called Alox15.

## Contribution

The novel finding is that neutrophil Irgm1 prevents sepsis-induced heart dysfunction by promoting Alox15 degradation and inhibiting ferroptosis.

## Key findings

- Irgm1 expression in neutrophils is upregulated in sepsis-induced myocardial dysfunction and correlates inversely with disease severity.
- Neutrophil-specific Irgm1 deficiency in mice worsens cardiac dysfunction and inflammation during sepsis.
- Irgm1 interacts with RNF213 to degrade Alox15, reducing 15-HETE production and neutrophil ferroptosis, which alleviates SIMD.

## Abstract

Sepsis-induced myocardial dysfunction (SIMD), a severe sepsis complication, is characterized by immune dysregulation, with neutrophils playing a central role. While the immunity-related GTPase family M protein (IRGM) in humans and its murine ortholog Irgm1 are key immune regulators, the precise contribution of neutrophil Irgm1 to SIMD pathogenesis remains unclear. This study aims to explore the involvement of neutrophil Irgm1 in SIMD and uncover its mechanisms. This research found that IRGM expression was upregulated in peripheral blood neutrophils from patients with SIMD and inversely correlated with disease severity. In mice, neutrophil-specific Irgm1 deficiency worsened CLP-induced cardiac dysfunction and myocardial inflammation. Mechanistically, Irgm1 interacted with the E3 ubiquitin ligase RING finger protein 213 (RNF213) to facilitate 15-lipoxygenase (Alox15) ubiquitination and degradation, thereby inhibiting neutrophil ferroptosis and suppressing the production of 15-HETE, which alleviates SIMD. In patients with SIMD, the expression levels of Alox15 and the concentrations of 15-HETE were positively correlated with disease severity. Notably, intraperitoneal administration of Alox15-targeting drug PD146176 significantly improved cardiac function in SIMD mice. Collectively, this study highlights the pivotal role of the Irgm1 in attenuating SIMD by restraining neutrophil ferroptosis and 15-HETE production. Irgm1 may serve as a promising prognostic biomarker and a valuable therapeutic target for SIMD.

Image 1