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 4

PDGFRα+ fibroblast expansion accounts for higher expression of IL-33 in cad-11–/– adipose tissue.

Options: View larger image (or click on image) Download as PowerPoint
PDGFRα+ fibroblast expansion accounts for higher expression of IL-33 in ...
(A) IL-33 expression in adipose tissue of WT and cad-11–/– mice fed a HFD for 5 weeks (left graph: n = 9 HFD-WT and n = 9 HFD-KO, pooled from 2 independent experiments; right graph: n = 7 HFD-WT and n = 10 HFD-KO, pooled from 2 independent experiments). (B) Il33 mRNA expression in SVF cells and adipocytes isolated from adipose tissue of mice fed a HFD for 12 weeks (n = 4 WT-SVF, n = 6 KO-SVF, n = 5 WT-adipocytes, and n = 7 KO-adipocytes, pooled from 2 independent experiments). (C) Il33 mRNA expression in adipose tissue and flow-isolated PDGFRα+ fibroblasts (n = 5 WT-eWAT, n = 5 KO-eWAT, n = 5 WT-PDGFRα+, and n = 5 KO-PDGFRα+). Data are representative of 2 independent experiments. (D) Percentage of PDGFRα+ fibroblasts in SVF cells from mice fed a ND or HFD for 5 weeks (n = 4 ND-WT, n = 4 ND-KO, n = 5 HFD-WT, and n = 5 HFD-KO). Results are representative of more than 3 independent experiments. (E) Representative flow cytometric plots of BrdU uptake in PDGFRα+ fibroblasts from WT and cad-11–/– mice fed a HFD for 1 week. (F) Percentage of BrdU+ cells among PDGFRα+ fibroblasts (n = 5 ND-WT, n = 5 ND-KO). Results are representative of 2 independent experiments. Data are expressed as the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001, by unpaired Student’s t test (A–D and F).