Macrophage polarization is critical to inflammation and resolution of inflammation. We previously showed that HMGB1 can engage RAGE to direct monocytes to a pro-inflammatory phenotype characterized by production of type 1 interferon and pro-inflammatory cytokines. In contrast, HMGB1 plus C1q form a tetra-molecular complex cross-linking RAGE and LAIR-1 and directing monocytes to an anti-inflammatory 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 of pro-inflammatory macrophages. Here, we show that HMGB1 induces leukotriene production through a RAGE-dependent pathway, while HMGB1 plus C1q induce specialized pro-resolving lipid mediators through a RAGE and LAIR-1 dependent pathway. Leukotriene exposure contributes to induction of IRF5 in a positive feedback loop. Resolvins, in contrast, block IRF5 induction and prevent the differentiation of inflammatory macrophages. Finally, we have generated a molecular mimic of HMGB1 plus C1q which crosslinks RAGE and LAIR-1 and can polarize monocytes to an anti-inflammatory phenotype. These findings may provide a mechanism to control non-resolving inflammation in many pathologic conditions.