Chang Sook Kyung, Kohlgruber Ayano C, Mizoguchi Fumitaka, Michelet Xavier, Wolf Benjamin J, Wei Kevin, Lee Pui Y, Lynch Lydia, Duquette Danielle, Ceperuelo-Mallafré Victòria, Banks Alexander S, Brenner Michael B
Division of Rheumatology, Immunology, and Allergy, Brigham and Women's Hospital and Harvard Medical School, Boston, Massachusetts, USA.
Division of Immunology, Boston Children's Hospital, Boston, Massachusetts, USA.
J Clin Invest. 2017 Sep 1;127(9):3300-3312. doi: 10.1172/JCI86881. Epub 2017 Jul 31.
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.
M2巨噬细胞、2型固有淋巴细胞（ILC2）、嗜酸性粒细胞、调节性T细胞（Tregs）和不变自然杀伤T细胞（iNKT细胞）均有助于控制脂肪组织炎症，而M1巨噬细胞、肿瘤坏死因子（TNF）和其他炎性细胞因子则在肥胖过程中驱动炎症和胰岛素抵抗。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白细胞介素-33（IL-33）的主要产生者。在此，我们表明间充质钙黏蛋白-11调节基质成纤维细胞功能。钙黏蛋白-11缺陷小鼠的基质IL-33产生增加，同时ILC2和M2巨噬细胞增多，这有助于控制脂肪组织炎症。钙黏蛋白-11缺陷小鼠中较高的IL-33表达水平介导了ILC2的激活，导致脂肪组织中较高的白细胞介素-13（IL-13）表达水平和M2巨噬细胞扩增。与脂肪组织炎症减轻一致，钙黏蛋白-11缺陷小鼠免受肥胖诱导的葡萄糖不耐受和脂肪组织纤维化的影响。重要的是，抗钙黏蛋白-11单克隆抗体阻断同样改善了肥胖野生型小鼠的炎症和血糖控制。这些结果表明，表达钙黏蛋白-11的基质成纤维细胞调节脂肪组织炎症，因此突出了钙黏蛋白-11作为肥胖管理潜在治疗靶点的地位。
