Macrophage Proresolving Mediators-the When and Where

Area of Science:

• Immunology and Inflammation Research
• Lipid Mediator Metabolism
• Cellular Signaling in Host Defense

Background:

• Macrophages and neutrophils are key immune cells involved in acute inflammation, host defense, and tissue repair.
• Lipid mediators (LMs) play critical roles in orchestrating inflammatory and proresolving processes.
• Understanding LM dynamics in phagocytes is crucial for developing targeted therapies for inflammatory diseases.

Purpose of the Study:

• To investigate the contribution of macrophages to local LM levels.
• To examine how neutrophils and their microparticles regulate macrophage LM profiles.
• To characterize LM signature profiles in distinct human phagocyte subpopulations.

Main Methods:

• Lipid mediator metabololipidomics was performed on neutrophils (PMNs), apoptotic PMNs, and macrophages.
• Deuterium-labeled precursors were used to trace LM biosynthesis during efferocytosis.
• Macrophage LM profiles were analyzed in M1 and M2 subtypes before and after apoptotic PMN uptake.

Main Results:

• Efferocytosis of apoptotic PMNs increased specialized proresolving mediator (SPM) biosynthesis, further enhanced by PMN microparticles.
• M2 macrophages exhibited higher SPM levels (e.g., maresin 1) and lower leukotriene B4 (LTB4) and prostaglandin levels compared to M1 macrophages.
• Uptake of apoptotic PMNs modulated macrophage LM profiles, downregulating LTB4 and increasing SPMs in M2 macrophages, and reducing overall LMs by ~25% in M2 cells.

Conclusions:

• Distinct LM signature profiles exist for human phagocytes and their subpopulations.
• Neutrophil microparticles dynamically regulate endogenous macrophage LMs during acute inflammation.
• Maresin 1 and its intermediates possess potent proresolving, anti-inflammatory, and tissue-regenerative properties, influencing macrophage phenotype.