Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX, 77204, USA.
Department of Thyroid and Breast Surgery, The Affiliated Huaian No.1 People's Hospital of Nanjing Medical University, 1 West Huanghe Road, Huaian, 223300, Jiangsu, China.
Sci Rep. 2019 Oct 31;9(1):15762. doi: 10.1038/s41598-019-52265-8.
Proinflammatory processes in adipose tissue contribute to development of breast cancer and insulin resistance. Crown-like structures (CLS) are histologic hallmarks of the proinflammatory process in adipose tissue. CLS are microscopic foci of dying adipocytes surrounded by macrophages mostly derived from monocytes in blood. Estrogen receptor β (ERβ) is expressed in microglia, macrophages within the central nervous system (CNS), where it evokes an anti-inflammatory response. The present study investigates the function of ERβ in macrophages within CLS. We report that even though monocytes in the blood have no detectable levels of ERβ, macrophages in CLS do express ERβ. In ERβ-/- mice, there was a significant increase in the number of CLS in both subcutaneous adipose tissue (SAT) and visceral adipose tissue (VAT). CLS in these mice were dominated by pro-inflammatory macrophages (M1 macrophages) with higher expression of osteopontin (OPN) and an increase in number of proliferating macrophages. In mice made obese by Western diet, treatment with an ERβ selective agonist (LY3201) reduced the number of CLS in both SAT and VAT with downregulation of OPN, activated hypoxia-inducible factor-1α (HIF-1α), proliferation and upregulation prolyl hydroxylase 2 (PHD2), the enzyme which prevents activation of HIF1α, in macrophages. We conclude that ERβ expression is induced in macrophages in CLS within adipose tissue where it plays a pivotal role in suppression of CLS. Thus ERβ agonists may be used to alleviate CLS-related breast cancer and insulin resistance in adipose tissue.
脂肪组织中的促炎过程有助于乳腺癌和胰岛素抵抗的发展。冠状结构 (CLS) 是脂肪组织促炎过程的组织学标志。CLS 是死亡脂肪细胞的微观焦点，周围是巨噬细胞，主要来自血液中的单核细胞。雌激素受体 β (ERβ) 在中枢神经系统 (CNS) 中的小胶质细胞和巨噬细胞中表达，在那里它引发抗炎反应。本研究调查了 ERβ 在 CLS 中巨噬细胞中的功能。我们报告说，尽管血液中的单核细胞没有检测到 ERβ，但 CLS 中的巨噬细胞确实表达 ERβ。在 ERβ-/- 小鼠中，无论是皮下脂肪组织 (SAT) 还是内脏脂肪组织 (VAT) 中 CLS 的数量都显著增加。这些小鼠的 CLS 主要由促炎巨噬细胞 (M1 巨噬细胞) 组成，其骨桥蛋白 (OPN) 表达更高，增殖巨噬细胞数量增加。在通过西方饮食肥胖的小鼠中，用 ERβ 选择性激动剂 (LY3201) 治疗可减少 SAT 和 VAT 中 CLS 的数量，同时下调 OPN、激活缺氧诱导因子-1α (HIF-1α)、增殖和上调脯氨酰羟化酶 2 (PHD2)，该酶可防止 HIF1α 的激活，在巨噬细胞中。我们得出结论，ERβ 在脂肪组织中的 CLS 中的巨噬细胞中表达被诱导，在那里它在抑制 CLS 中发挥关键作用。因此，ERβ 激动剂可用于缓解与 CLS 相关的乳腺癌和胰岛素抵抗。
