Abstract 1566: Adiponectin Primes Human Monocytes Into Alternative M2 Macrophages With Anti-inflammatory Properties: A Novel Mechanism of Obesity Induced Atherosclerosis
Altered macrophage kinetics is a pivotal mechanism of visceral obesity-induced inflammation and cardiometabolic risk. Since monocytes can differentiate into proatherogenic M1 macrophages as well as alternative anti-inflammatory M2 macrophages, approaches that limit M1 while promoting M2 differentiation represent a unique therapeutic strategy. We hypothesized that adiponectin, an adipokine widely implicated in obesity, may prime human monocytes towards the anti-inflammatory M2 phenotype. Primary human monocytes were differentiated into M2 macrophages with human recombinant interleukin (IL)-4 in the presence or absence of human recombinant adiponectin (10 μg/ml). Adiponectin caused an 8-fold increase in IL-4-enhanced transcript expression of the M2 macrophage markers, mannose receptor (MR) and alternative macrophage activation-associated chemokine1 (AMAC-1). Flow cytometry analyses confirmed parallel elevations of MR protein levels in adiponectin-treated IL-4 differentiated M2 macrophages. IL-4-decreased expression of the macrophage associated antigen (CD163), another M2 macrophage marker, an effect that was pronounced in adiponectin treated cells. Upregulation of MR and AMAC-1 expression were attenuated in monocytes concomitantly incubated with IL-4, adiponectin and the PPARα antagonist GW6471. To determine if adiponectin-treated M2 macrophages can alter the inflammatory properties of activated M1 macrophages, we incubated resting macrophages in medium supplemented with supernatant from M2 or adiponectin-treated M2 cultures before M1 phenotype was induced with lipopolysaccaride (LPS). M2-derived culture supernatant pronouncedly suppressed M1 macrophage secretions of the pro-inflammatory cytokines, chemokine (C-C motif) ligand 3, TNFα and MCP-1. This inhibitory response was exacerbated in M1 macrophages treated with medium from M2 macrophages exposed to adiponectin. We report a novel immunoregulatory mechanism through which adiponectin primes human monocyte differentiation into anti-inflammatory M2 macrophages. Conditions associated with low adiponectin levels, such as visceral obesity and insulin resistance, may promote atherosclerosis, in part through aberrant macrophage kinetics.