Offense and defense: itaconate mediates bidirectional immune regulation of host-bacteria interaction.

Abstract

Itaconate has garnered significant attention in recent years due to its immunomodulatory and antimicrobial functions. During inflammation and pathogenic infections, itaconate is formed through the decarboxylation of cis-aconitate in the mitochondrial tricarboxylic acid cycle and accumulates in large quantities to counteract excessive inflammation and pathogenic infections. However, many pathogenic bacteria have also evolved pathways to directly degrade itaconate or indirectly resist its stimulatory effects. We first review the research history and metabolic pathways of itaconate. Then we focus on exploring its direct mechanism of inhibiting pathogenic bacteria growth and reproduction by post-translational modification of metabolic enzymes such as isocitrate lyase, aldolase, and IMP dehydrogenase. Additionally, we examine its indirect mechanism of coordinating immune cell functions to eliminate pathogenic bacteria. Pathogenic bacteria counteract this by directly degrading itaconate through the IcT-IcH-CcL cascade reaction or by adapting through metabolic reprogramming to enable chronic infection. Subsequently, we discuss the spatiotemporal specificity of itaconate during the early and late stages of pathogenic bacteria infection, highlighting its role in regulating immune defense strategies at different phases. Finally, we discuss the potential and limitations of itaconate-related interventions as adjunctive strategies for bacterial disease control, particularly in the context of drug-resistant infections. This review elucidates the mechanism of itaconate in host-microbial crosstalk from the perspective of bidirectional resistance between host and bacteria, emphasizing its crucial role as a metabolic messenger in mediating co-evolutionary, co-developmental, and co-metabolic interactions between the host and bacteria. Current evidence of itaconate-mediated bidirectional interactions may help guide future mechanistic studies and the development of itaconate-related adjunctive strategies for bacterial disease control. Further in vivo, clinical, and field validation is still required before these findings can be translated into therapeutic or agricultural applications.