HMGB1-C1q complexes regulate macrophage function by switching between leukotriene and specialized proresolving...

Area of Science:

• Immunology
• Molecular Biology
• Inflammation Research

Background:

• Macrophage polarization is key in inflammation and its resolution.
• High-mobility group box 1 (HMGB1) binding to RAGE promotes a pro-inflammatory monocyte phenotype.
• HMGB1/C1q complexes cross-link RAGE and LAIR-1, inducing an anti-inflammatory phenotype.

Purpose of the Study:

• To investigate the role of lipid mediators induced by HMGB1 and HMGB1/C1q in regulating macrophage polarization.
• To examine the impact of these lipid mediators on IRF5, a critical transcription factor for pro-inflammatory macrophages.

Main Methods:

• Analysis of lipid mediator production (leukotrienes, lipoxins, resolvins) induced by HMGB1 and HMGB1/C1q.
• Assessment of RAGE and LAIR-1 dependency for mediator induction.
• Evaluation of IRF5 regulation by lipid mediators and their effect on monocyte differentiation.
• Development and testing of a molecular mimic of HMGB1/C1q.

Main Results:

• HMGB1 induced RAGE-dependent leukotriene production.
• HMGB1/C1q induced RAGE- and LAIR-1-dependent pro-resolving lipid mediators (lipoxin A4, resolvin D1, D2).
• Leukotrienes promoted IRF5 induction, while resolvins blocked IRF5 and prevented inflammatory macrophage differentiation.
• A molecular mimic of HMGB1/C1q induced an anti-inflammatory monocyte phenotype.

Conclusions:

• HMGB1 and HMGB1/C1q differentially regulate lipid mediator production, influencing macrophage polarization.
• Targeting HMGB1/C1q interactions offers a potential strategy to control non-resolving inflammation by modulating IRF5 and macrophage phenotype.