Arachidonic acid fuels inflammation by unlocking macrophage protein phosphatase 5 after myocardial infarction.

Abstract

An overactive inflammatory response and immune cell infiltration following myocardial infarction (MI) impair cardiac tissue repair. This study investigates the mechanistic role of the arachidonic acid (AA) metabolic cascade in mediating post-MI inflammation. Single-cell RNA-sequencing analysis was performed to characterize cardiac macrophage heterogeneity in post-MI mice. Metabolomic analyses were conducted to profile polyunsaturated fatty acid metabolites in both plasma from MI patients and cardiac tissue from infarcted mice to identify key factors influencing MI progression. Leukotriene B4 (LTB4), an AA metabolite, was consistently elevated in MI patients and mouse models, demonstrating significantly higher plasma concentrations in recurrent MI cases. Mechanistically, AA promotes nuclear translocation of protein phosphatase 5 (PP5), which subsequently dephosphorylates 5-lipoxygenase at Thr218, driving sustained LTB4 production. This process enhances CXCL13-mediated B-cell recruitment and amplifies inflammation through macrophage-B-cell crosstalk. Disruption of PP5 in mouse macrophages prevents these adverse changes. The findings elucidate the conserved role of 5-lipoxygenase phosphorylation regulated LTB4 levels in MI and identify PP5 as a potential therapeutic target for the treatment of MI.