Aromatase Controls Sjogren Syndrome-Like Lesions through Monocyte Chemotactic Protein-1 in Target Organ and Adipose Tissue-Associated Macrophages
Aromatase Controls Sjogren Syndrome-Like Lesions through Monocyte Chemotactic Protein-1 in Target Organ and Adipose Tissue-Associated Macrophages
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DOI：
10.1016/j.ajpath.2014.09.006
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发表时间：
2015-01-01
影响因子：
6
通讯作者：
Ishimaru, Naozumi
中科院分区：
文献类型：
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作者：
Iwasa, Akihiko;Arakaki, Rieko;Ishimaru, Naozumi
几种自身免疫性疾病是已知的绝经后妇女发展。然而，雌激素缺乏影响自身免疫的机制尚不清楚。芳香化酶是一种将雄激素转化为雌激素的酶。在此，我们使用雌性芳香化酶基因敲除（ArK 0）小鼠作为雌激素缺乏症的模型，以研究自身免疫的发病和发展的分子机制。组织学分析显示，ArK 0小鼠泪腺和唾液腺中的炎性病变随年龄增加而增加。将ArK 0小鼠的脾细胞或骨髓细胞连续转移到重组激活基因2敲除小鼠中不能诱导自身免疫性病变。编码促炎细胞因子和单核细胞趋化蛋白-1的mRNA在ArK 0小鼠的白色脂肪组织中的表达增加，并且显著高于野生型小鼠。此外，在ArK 0小鼠的白色脂肪组织中观察到炎性M1巨噬细胞数量增加。一个显着增加单核细胞趋化蛋白-1基因表达的唾液腺组织中ArK 0被发现与肥胖。此外，舍格伦综合征小鼠模型中的自身免疫性病变通过施用芳香酶抑制剂而加剧。这些结果表明，芳香化酶可能通过控制靶器官和脂肪组织相关的巨噬细胞在干燥综合征样病变的发病机制中发挥关键作用。
Several autoimmune diseases are known to develop in postmenopausal women. However, the mechanism by which estrogen deficiency influences autoimmunity is unknown. Aromatase is an enzyme that converts androgens to estrogens. Herein, we used female aromatase gene knockout (ArK0) mice as a model of estrogen deficiency to investigate the molecular mechanism that underlies the onset and development of autoimmunity. Histological analyses showed that inflammatory Lesions in the lacrimal and salivary glands of ArK0 mice increased with age. Adoptive transfer of spleen cells or bone marrow cells from ArK0 mice into recombination activating gene 2 knockout mice failed to induce the autoimmune lesions. Expression of mRNA encoding proinflammatory cytokines and monocyte chemotactic protein-1 increased in white adipose tissue of ArK0 mice and was significantly higher than that in wildtype mice. Moreover, an increased number of inflammatory M1 macrophages was observed in white adipose tissue of ArK0 mice. A significantly increased monocyte chemotactic protein-1 mRNA expression of the salivary gland tissue in ArK0 was found together with adiposity. Furthermore, the autoimmune lesions in a murine model of Sjogren syndrome were exacerbated by administration of an aromatase inhibitor. These results suggest that aromatase may play a key role in the pathogenesis of Sjogren syndrome-like lesions by controlling the target organ and adipose tissue-associated macrophage.