Neutrophil aconitate decarboxylase 1/itaconate axis suppresses extracellular traps via alkylating GSDMD and alleviates murine liver injury

Neutrophil extracellular traps (NETs) have been confirmed to cause inflammation exacerbation and tissue injury in various diseases. Aconitate decarboxylase 1 (ACOD1), which catalyzes cis-aconitate decarboxylate to itaconate (ITA), has been found to participate in hepatic diseases. However, further investigation is needed to elucidate the function of ACOD1/ITA in liver injury, particularly with regard to neutrophil ACOD1. We aim to explore the relationship between ACOD1 and NETs, along with its mechanism in liver injury. Acod1 was predominately expressed in neutrophils in healthy and injured liver with single-cell RNA Sequencing datasets. Acod1 deficiency promoted NETs and aggravated fatty liver injury induced by methionine-choline-deficient and high-fat diet, accompanied by increasing neutrophil Gasdermin D (GSDMD) cleavage. In vitro, ITA suppressed GSDMD cleavage and NETosis in murine neutrophils. Pharmacological blockade of GSDMD suppressed liver tissue and neutrophil GSDMD cleavage, accompanied by a decrease in NETosis, resulting in the amelioration of fatty liver injury. Mechanistically, ITA alkylated GSDMD at the Cys192 residue, suppressing the cleavage of GSDMD. Furthermore, infusion of wild-type neutrophils presented a reduction in NETs and an alleviation of liver injury compared to Acod1^-/- neutrophils. Conclusion: ACOD1/ITA axis suppresses the formation of NETs by alkylating GSDMD, and alleviates murine liver injury, providing innovative ideas for the treatment of liver diseases.