Carnosic acid and carnosol promote lipid mediator class-switching toward inflammation resolution in human macrophages

Lipid mediators (LM), formed from polyunsaturated fatty acids (PUFA) through cyclooxygenase- and lipoxygenase (LOX)-dependent pathways, contribute to all stages of inflammation and are thus valuable targets for drugs that intervene with inflammatory diseases. Novel pharmacotherapeutic concepts attempt to support LM class-switching from pro-inflammatory 5-LOX-derived leukotrienes and cyclooxygenase-derived prostaglandins towards omega-3-PUFA-based specialized pro-resolving mediators (SPM), which accomplishes resolution of inflammation. Rosemary (Rosmarinus officinalis, contained in Canephron® N) and its bioactive components carnosic acid (CA) and carnosol (CS) suppress pro-inflammatory prostaglandin and leukotriene formation, but neither the impact of rosemary/Canephron® N nor of CA and CS on the biosynthesis of 15-LOX-derived SPM has been investigated yet. Here, we studied whether BNO 2103 (a mixture of pulverized rosemary leaves, centaury herb, and lovage root contained in Canephron® N), and its bioactive components CA and CS could promote LM class-switching from pro-inflammatory towards pro-resolving LM in human monocyte-derived macrophages (MDM), as well as in primary peritoneal macrophages from patients with liver cirrhosis ex vivo. BNO 2103, CA, and CS efficiently suppressed pro-inflammatory leukotriene and prostaglandin formation in activated human inflammatory macrophages while activating 15-LOX to enhance SPM production in pro-resolving M2-MDMs. Intriguingly, these LM class-switching activities exerted by CA are Ca^2 +-independent and further boosted by concomitant supply of omega-3 PUFA with synergistic elevation of SPM and their precursors. Together, CA and CS from rosemary act as LM class-switching agents that suppress pro-inflammatory signaling but strongly promote pro-resolving LM, supporting the potential of rosemary-based phytotherapeutic drugs like Canephron® N for use in resolution pharmacology.