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.

中文翻译：

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基质细胞钙黏着蛋白11调节脂肪组织炎症和糖尿病

M2巨噬细胞，先天性2型淋巴样细胞（ILC2），嗜酸性粒细胞，Treg和不变的NK T细胞（iNKT细胞）均有助于控制脂肪组织的炎症，而M1巨噬细胞，TNF和其他炎性细胞因子可驱动肥胖症中的炎症和胰岛素抵抗。基质细胞调节淋巴结中的白细胞反应，但基质细胞在脂肪组织炎症中的作用尚不清楚。PDGFRα ⁺基质细胞是脂肪组织中IL-33的主要产生者。在这里，我们显示间质钙粘蛋白11调节基质成纤维细胞功能。缺乏Cadherin-11的小鼠显示出IL-33的基质产生增加，ILC2s和M2巨噬细胞也随之增强，有助于控制脂肪组织的炎症。在缺乏钙粘素11的小鼠中较高的IL-33表达水平介导ILC2激活，从而导致较高的IL-13表达水平和脂肪组织中的M2巨噬细胞扩增。与减少脂肪组织炎症相一致，缺乏钙粘素11的小鼠免于肥胖引起的葡萄糖耐受不良和脂肪组织纤维化。重要的是，抗cadherin-11 mAb阻滞剂同样可以改善肥胖WT小鼠的炎症和血糖控制。