Itaconate as a Potent Regulator of Neutrophil Responses in Host Defence and Inflammation

Itaconate, derived from cis-aconitate decarboxylation by immune-responsive gene 1 (IRG1; also called cis-aconitate decarboxylase 1, ACOD1), is an intermediate metabolite of the tricarboxylic acid (TCA) cycle in the mitochondria. The production of itaconate in myeloid cells is rapidly increased to high levels in pathological conditions, such as infection and cancer. It is well known that itaconate plays an essential role in regulating macrophage-mediated inflammation and immune response through multiple mechanisms, such as regulating signal transduction and protein modification. As the first responders upon infections and injuries, neutrophils contribute to pathogen clearance and inflammation by several mechanisms, such as phagocytosis, producing reactive oxygen species (ROS), and forming neutrophil extracellular traps (NETs). Increasing evidence shows that neutrophils can also produce itaconate, which in turn modulates neutrophil activation, thereby affecting the elimination of pathogens, the resolution of inflammation, and tumour progression. In this review, we summarize the recent advancements in understanding the effects of endogenous itaconate and its derivatives on neutrophil responses, with a focus on the underlying mechanisms and potential therapeutic applications in infectious and inflammatory diseases.