PROJECT SUMMARY/ABSTRACT Systemic Lupus Erythematosus (SLE) is a disease characterized by high levels of HMGB1 and low levels of C1q. The damage-associated molecular pattern (DAMP) HMGB1 and its receptor RAGE trigger production of interferon and pro-inflammatory cytokines and induce an M1-like polarization. Complement component C1q exerts a suppressive effect on monocyte activation. Exposure of monocytes to HMGB1 plus C1q leads to an M2-like polarization. This polarization of monocytes to an anti-inflammatory M2-like program is not seen when monocytes are exposed to C1q alone. As both HMGB1 and C1q are evolutionarily old molecules and are highly conserved, we believe this is likely an important paradigm for monocyte differentiation and resolution of inflammation. Imbalances in M1/ M2 polarization are maladaptive; in the extreme, as mentioned above, they lead to SLE and in less extreme forms to ?non-resolving inflammation?. We propose further studies in human monocytes to explore the molecular mechanism of macrophage polarization by HMGB1 and HMGB1 plus C1q. We hypothesize that HMGB1 signaling through RAGE and HMGB1 plus C1q co-ligating RAGE and LAIR-1 have functions relevant to the maintenance of homeostasis both in humans and mice through regulating cytokine expression, lipid mediators and microRNAs. We will first test the contribution of Vav and SHP-1 to macrophage mediated inflammation and resolution (Aim 1). Next, we will determine whether HMGB1 and HMGB1 plus C1q differentially regulate production of leukotrienes and specialized pro-resolving mediators (SPMs) (Aim 2). Finally, we will delineate up-or down-regulated microRNAs in HMGB1 and HMGB1 plus C1q exposed cells. We will define their tolerance mechanisms (Aim 3). These lines of investigation will 1) offer novel insights into the molecular mechanism of M2-like macrophage polarization, 2) contribute new models to the study of immune regulation, and 3) improve our understanding, and therapeutic options for SLE, and conditions with poor resolution of inflammation.