HMGB1–C1q complexes regulate macrophage function by switching between leukotriene and specialized proresolving mediator biosynthesis

T Liu, A Xiang, T Peng, AC Doran… - Proceedings of the …, 2019 - National Acad Sciences
T Liu, A Xiang, T Peng, AC Doran, KJ Tracey, BJ Barnes, I Tabas, M Son, B Diamond
Proceedings of the National Academy of Sciences, 2019National Acad Sciences
Macrophage polarization is critical to inflammation and resolution of inflammation. We
previously showed that high-mobility group box 1 (HMGB1) can engage receptor for
advanced glycation end product (RAGE) to direct monocytes to a proinflammatory
phenotype characterized by production of type 1 IFN and proinflammatory cytokines. In
contrast, HMGB1 plus C1q form a tetramolecular complex cross-linking RAGE and LAIR-1
and directing monocytes to an antiinflammatory phenotype. Lipid mediators, as well as …
Macrophage polarization is critical to inflammation and resolution of inflammation. We previously showed that high-mobility group box 1 (HMGB1) can engage receptor for advanced glycation end product (RAGE) to direct monocytes to a proinflammatory phenotype characterized by production of type 1 IFN and proinflammatory cytokines. In contrast, HMGB1 plus C1q form a tetramolecular complex cross-linking RAGE and LAIR-1 and directing monocytes to an antiinflammatory phenotype. Lipid mediators, as well as cytokines, help establish a milieu favoring either inflammation or resolution of inflammation. This study focuses on the induction of lipid mediators by HMGB1 and HMGB1 plus C1q and their regulation of IRF5, a transcription factor critical for the induction and maintenance of proinflammatory macrophages. Here, we show that HMGB1 induces leukotriene production through a RAGE-dependent pathway, while HMGB1 plus C1q induces specialized proresolving lipid mediators lipoxin A4, resolvin D1, and resolvin D2 through a RAGE- and LAIR-1–dependent pathway. Leukotriene exposure contributes to induction of IRF5 in a positive-feedback loop. In contrast, resolvins (at 20 nM) block IRF5 induction and prevent the differentiation of inflammatory macrophages. Finally, we have generated a molecular mimic of HMGB1 plus C1q, which cross-links RAGE and LAIR-1 and polarizes monocytes to an antiinflammatory phenotype. These findings may provide a mechanism to control nonresolving inflammation in many pathologic conditions.
National Acad Sciences