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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.
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Research Article Inflammation Metabolism

Stromal cell cadherin-11 regulates adipose tissue inflammation and diabetes

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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

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Figure 3

The levels of IL-13 produced by ILC2s are significantly higher in adipose tissue of obese cad-11–/– mice than in that of WT mice.

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The levels of IL-13 produced by ILC2s are significantly higher in adipos...
(A) qPCR analysis of pro- and antiinflammatory genes in BMDMs cultured in AT-CM for 3 days. For each experiment, AT-CM was obtained from the adipose tissue of WT and cad-11–/– mice fed a HFD for 5 weeks (n = 3 HFD-WT and n = 3 HFD-KO). Data are representative of 3 independent experiments. (B) BMDMs were untreated or predifferentiated into either M1 or M2 macrophages. After direct coculturing with fibroblasts derived from adipose tissue of WT or cad-11–/– mice, the percentage of surface CD206+ BMDMs was analyzed by flow cytometry (data from 1 of 3 experiments with similar results are shown, and in each experiment, different fibroblast lines derived from WT or cad-11–/– mice were used). (C and D) Comparison of mRNA levels of Il13 and Il4 in adipose tissue from WT and cad-11–/– mice fed a ND (C, n = 5 ND-WT and n = 5 ND-KO) or a HFD (D, left graph: n = 10 HFD-WT and n = 9 HFD-KO; D, right graph: n = 10 HFD-WT and n = 6 HFD-KO; data were pooled from 2 independent experiments). (E) IL-13 protein in adipose tissue from HFD-fed mice was detected by ELISA (n = 5 HFD-WT and n = 5 HFD-KO). Data are representative of 2 independent experiments. (F) Il13 mRNA expression in SVF cells and adipocytes fractioned after digestion of adipose tissue from HFD-fed mice (n = 4 WT-SVF, n = 6 KO-SVF, n = 5 WT-adipocytes, and n = 7 KO-adipocytes; data were pooled from 2 independent experiments). (G) Representative flow cytometric analysis of ILC2s in adipose tissue. (H) Percentage of ILC2s among CD45+ lymphocytes in adipose tissue of WT and cad-11–/– mice fed a HFD for 5 weeks (n = 10 WT and n = 7 KO; data were pooled from 2 independent experiments). (I) mRNA levels of Il13 and Il5 in flow-isolated ILC2s from adipose tissue of WT and cad-11–/– mice fed a HFD for 12 weeks (n = 3 HFD-WT and n = 3 HFD-KO). Data are expressed as the mean ± SEM. *P < 0.05, **P < 0.01, and ***P < 0.001, by unpaired Student’s t test (A, B, D–F, H, and I).

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