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M2 Macrophage Polarization Mediates Anti-inflammatory Effects of Endothelial Nitric Oxide Signaling.

Authors Lee WJ, Tateya S, Cheng AM, Rizzo-DeLeon N, Wang NF, Handa P, Wilson CL, Clowes AW, Sweet IR, Bomsztyk K, Schwartz MW, Kim F Submitted By Submitted Externally on 6/9/2015 Status Published Journal Diabetes Year 2015 Date Published 4/6/2015 Volume : Pages Not Specified : Not Specified PubMed Reference 25845662 Abstract Endothelial nitric oxide (NO) signaling plays a physiological role to limit obesity-associated insulin resistance and inflammation. This study was undertaken to investigate whether this NO effect involves polarization of macrophages towards an anti-inflammatory M2 phenotype.Mice with transgenic endothelial nitric oxide synthase (eNOS) overexpression were protected against high-fat diet (HFD)-induced hepatic inflammation and insulin resistance, and this effect was associated with reduced pro-inflammatory M1 and increased anti-inflammatory M2 activation of Kupffer cells. In cell culture studies, exposure of macrophages to endothelial NO similarly reduced inflammatory (M1) and increased anti-inflammatory (M2) gene expression. Similar effects were induced by macrophage overexpression of vasodilator-stimulated phosphoprotein (VASP), a key downstream mediator of intracellular NO signaling. Conversely, VASP deficiency induced pro-inflammatory M1 macrophage activation, and transplantation of bone marrow from VASP-deficient donor mice into normal recipients caused hepatic inflammation and insulin resistance resembling that induced in normal mice by consumption of a HFD. These data suggest that pro-inflammatory macrophage M1 activation and macrophage-mediated inflammation are tonically inhibited by NO->VASP signal transduction, and that reduced NO->VASP signaling is involved in the effect of HFD feeding to induce M1 activation of Kupffer cells and associated hepatic inflammation. Our data implicate endothelial NO-VASP signaling as a physiological determinant of macrophage polarization and show that signaling via this pathway is required to prevent hepatic inflammation and insulin resistance.

Investigators with authorship
Name Institution Karol Bomsztyk University of Washington

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