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
Karol BomsztykUniversity of Washington