Systemic Dermatitis Model Mice Exhibit Atrophy of Visceral Adipose Tissue and Increase Stromal Cells via Skin-Derived Inflammatory Cytokines
Systemic Dermatitis Model Mice Exhibit Atrophy of Visceral Adipose Tissue and Increase Stromal Cells via Skin-Derived Inflammatory Cytokines
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DOI：
10.3390/ijms21093367
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发表时间：
2020-05-01
影响因子：
5.6
通讯作者：
Yamanaka, Keiichi
中科院分区：
文献类型：
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作者：
Mizutani, Kento;Shirakami, Eri;Yamanaka, Keiichi
脂肪组织（AT）是最大的内分泌器官，产生被称为脂肪细胞因子的生物活性产物，它调节几种代谢途径，特别是在炎症条件下。另一方面，有证据表明慢性炎症性皮肤病与血管硬化改变、心脏肥大和严重的多器官系统性淀粉样变性密切相关。牛皮癣是一种常见的慢性难治性炎症性皮肤病，一些研究表明，脂肪因子水平与疾病严重程度有关。慢性皮肤病也与代谢综合征有关，包括异常组织重塑；然而，其机制尚不清楚。我们使用角蛋白14特异性caspase-1过表达转基因（KCASP1Tg）小鼠解决了这个问题，这些小鼠从8周龄开始患有严重的糜烂性皮炎，随后进行再上皮化。全身和性腺白色AT （GWAT）重量均降低。各脂肪细胞数量多，体积小，形状不规则；大量炎症细胞，包括活化的CD4+或CD8+ T细胞和toll样受体4/ cd11b阳性活化单核细胞，浸润到GWAT。我们假设皮肤病变中炎症细胞因子的产生是这种淋巴细胞/单核细胞活化和AT失调的关键因素。我们在小鼠皮炎模型中验证了我们的假设，即AT由于全身性炎症而显示出产热能力受损。暴露于4℃后，脂肪细胞中产热基因解偶联蛋白1 mRNA表达升高；然而，KCASP1Tg小鼠的体温迅速下降，表明由于萎缩，AT的产热能力受损。肿瘤坏死因子(TNF)- α、IL-1 β和干扰素(INF)- γ水平在KCASP1Tg小鼠耳部皮肤病变中显著升高。为了研究这些细胞因子的直接作用，我们给BL/6野生小鼠腹腔注射tnf - α、IL-1 β和inf - γ，导致脂肪细胞变小，基质细胞浸润丰富，表明这些细胞因子对脂肪细胞有协同作用。全身性皮炎模型小鼠AT萎缩，间质细胞增多。这些发现可通过腹腔注射炎性细胞因子重现，炎性细胞因子的产生在发炎的皮肤病变中增加。
Adipose tissue (AT) is the largest endocrine organ, producing bioactive products called adipocytokines, which regulate several metabolic pathways, especially in inflammatory conditions. On the other hand, there is evidence that chronic inflammatory skin disease is closely associated with vascular sclerotic changes, cardiomegaly, and severe systemic amyloidosis in multiple organs. In psoriasis, a common chronic intractable inflammatory skin disease, several studies have shown that adipokine levels are associated with disease severity. Chronic skin disease is also associated with metabolic syndrome, including abnormal tissue remodeling; however, the mechanism is still unclear. We addressed this problem using keratin 14-specific caspase-1 overexpressing transgenic (KCASP1Tg) mice with severe erosive dermatitis from 8 weeks of age, followed by re-epithelization. The whole body and gonadal white AT (GWAT) weights were decreased. Each adipocyte was large in number, small in size and irregularly shaped; abundant inflammatory cells, including activated CD4+ or CD8+ T cells and toll-like receptor 4/CD11b-positive activated monocytes, infiltrated into the GWAT. We assumed that inflammatory cytokine production in skin lesions was the key factor for this lymphocyte/monocyte activation and AT dysregulation. We tested our hypothesis that the AT in a mouse dermatitis model shows an impaired thermogenesis ability due to systemic inflammation. After exposure to 4 degrees C, the mRNA expression of the thermogenic gene uncoupling protein 1 in adipocytes was elevated; however, the body temperature of the KCASP1Tg mice decreased rapidly, revealing an impaired thermogenesis ability of the AT due to atrophy. Tumor necrosis factor (TNF)-alpha, IL-1 beta and interferon (INF)-gamma levels were significantly increased in KCASP1Tg mouse ear skin lesions. To investigate the direct effects of these cytokines, BL/6 wild mice were administered intraperitoneal TNF-alpha, IL-1 beta and INF-gamma injections, which resulted in small adipocytes with abundant stromal cell infiltration, suggesting those cytokines have a synergistic effect on adipocytes. The systemic dermatitis model mice showed atrophy of AT and increased stromal cells. These findings were reproducible by the intraperitoneal administration of inflammatory cytokines whose production was increased in inflamed skin lesions.