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

Abstract

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.

High Mobility Group Box 1 Expression in Oral Inflammation and Regeneration

“…Furthermore, we recently reported that RvD2 induces active resolution of inflammation through pulp-like tissue regeneration after root canal infection (80). It is possible that the HMGB1-C1q complex induces the production of RvD2 for dental pulp regeneration, as suggested by Liu et al (25).…”

“…On the other hand, the C1 complex (C1q), which normally triggers the classical pathway, is thought to regulate both inflammation and regeneration by the coexistence of DAMPs. Liu et al (25) reported that the HMGB1-C1q complex induces production of proresolving mediators such as resolvin (Rv)D1 and RvD2. The resolution of inflammation and macrophage polarization may result in tissue regeneration.…”

HMGB1 in Systemic Lupus Erythematosus

“…Further studies showed that HMGB1 through a positive feedback loop involving IRF5 increases leukotriene B4 production in activated monocytes while HMGB1 plus C1q increase the production of specialized pro-resolving lipid mediators (82). In the same study, a fusion protein that contains the RAGEbinding fragment of HMGB1 and the LAIR-1-binding fragment of C1q were shown to crosslink the two receptors the same way HMGB1 and C1q do and to exert the same pro-resolving effects both in vivo and in vitro (82). Recognizing that HMGB1 can be harnessed to enhance tolerogenic properties of the immune system opens up novel opportunities for potential therapeutics.…”

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“…98 Moreover, a complement factor C1q also interacted with HMGB1 (K D = 200 nM) and formed a tetramolecular complex with RAGE and LAIR-1, resulting in the production of anti-inflammatory cytokines (eg, IL-10) and proresolution lipid mediators. 99,100 Thus, in a sharp contrast to exogenous PAMPs (eg, CpG-DNA and LPS), many endogenous proteins can bind HMGB1 to tilt the balance towards anti-inflammatory responses via distinct signaling pathways. 95,[98][99][100]…”

“…99,100 Thus, in a sharp contrast to exogenous PAMPs (eg, CpG-DNA and LPS), many endogenous proteins can bind HMGB1 to tilt the balance towards anti-inflammatory responses via distinct signaling pathways. 95,[98][99][100]…”