Stromal cell cadherin-11 regulates adipose tissue inflammation and diabetes
Sook Kyung Chang, … , Alexander S. Banks, Michael B. Brenner
Sook Kyung Chang, … , Alexander S. Banks, Michael B. Brenner
Published July 31, 2017
Citation Information: J Clin Invest. 2017;127(9):3300-3312. https://doi.org/10.1172/JCI86881.
View: Text | PDF
Research Article Inflammation Metabolism

Stromal cell cadherin-11 regulates adipose tissue inflammation and diabetes

Abstract

M2 macrophages, innate lymphoid type 2 cells (ILC2s), eosinophils, Tregs, and invariant NK T cells (iNKT cells) all help to control adipose tissue inflammation, while M1 macrophages, TNF, and other inflammatory cytokines drive inflammation and insulin resistance in obesity. Stromal cells regulate leukocyte responses in lymph nodes, but the role of stromal cells in adipose tissue inflammation is unknown. PDGFRα+ stromal cells are major producers of IL-33 in adipose tissue. Here, we show that mesenchymal cadherin-11 modulates stromal fibroblast function. Cadherin-11–deficient mice displayed increased stromal production of IL-33, with concomitant enhancements in ILC2s and M2 macrophages that helped control adipose tissue inflammation. Higher expression levels of IL-33 in cadherin-11–deficient mice mediated ILC2 activation, resulting in higher IL-13 expression levels and M2 macrophage expansion in adipose tissue. Consistent with reduced adipose tissue inflammation, cadherin-11–deficient mice were protected from obesity-induced glucose intolerance and adipose tissue fibrosis. Importantly, anti–cadherin-11 mAb blockade similarly improved inflammation and glycemic control in obese WT mice. These results suggest that stromal fibroblasts expressing cadherin-11 regulate adipose tissue inflammation and thus highlight cadherin-11 as a potential therapeutic target for the management of obesity.

Authors

Sook Kyung Chang, Ayano C. Kohlgruber, Fumitaka Mizoguchi, Xavier Michelet, Benjamin J. Wolf, Kevin Wei, Pui Y. Lee, Lydia Lynch, Danielle Duquette, Victòria Ceperuelo-Mallafré, Alexander S. Banks, Michael B. Brenner

×

Figure 2

Reduced inflammation and increased M2 macrophages in adipose tissue of obese cad-11–/– mice.

Options: View larger image (or click on image) Download as PowerPoint
Reduced inflammation and increased M2 macrophages in adipose tissue of o...
WT and cad-11–/– mice were fed a HFD for 12 weeks, unless otherwise indicated. (A) Representative fluorescence microscopic images with H&E and anti-CD68 macrophage whole-mount staining (scale bars: 20 μm), and IHC with staining for isotype control (Ctl) and F4/80 (scale bars: 10 μm) in eWAT. (B) Representative flow cytometric analysis for adipose tissue macrophages in the CD45+ gate of SVF cells (left panel) and the F4/80hiCD11b+ gate of macrophages (right panel). (C) Percentage and number of F4/80hiCD11b+ macrophages (total), CD301+CD11c– macrophages among total macrophages (M2), and CD301–CD11c+ macrophages among total macrophages (M1) in eWAT (n = 4 ND-WT, n = 3 ND-KO, n = 5 HFD-WT, and n = 5 HFD-KO). Data are representative of more than 3 independent experiments. ATMs, adipose tissue macrophages. (D) qPCR analysis of the indicated genes in adipose tissue from mice fed a ND (n = 10 ND-WT and n = 10 ND-KO; pooled from 2 independent experiments) or a HFD (n = 6 HFD-WT and n = 5 HFD-KO; 1 of 3 independent experiments) for 10 weeks. Data are expressed as the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001, by 2-way ANOVA (C) and unpaired Student’s t test (D).