CD47 prevents the elimination of diseased fibroblasts in scleroderma
CD47 prevents the elimination of diseased fibroblasts in scleroderma
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DOI：
10.1172/jci.insight.140458
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发表时间：
2020-08-20
期刊：
影响因子：
8
通讯作者：
Wernig, Gerlinde
中科院分区：
文献类型：
--
作者：
Lerbs, Tristan;Cui, Lu;Wernig, Gerlinde
硬皮病是一种毁灭性的纤维化自身免疫性疾病。目前的治疗方法在预防疾病进展方面部分有效，但不能去除纤维化组织。在这里，我们评估了硬皮病成纤维细胞是否利用“不要吃我信号”CD47，以及阻断 CD47 是否能让身体的免疫系统清除患病的成纤维细胞。为了测试这种方法，我们使用了 Jun 诱导的硬皮病模型。我们首先在患者样本中证明，硬皮病上调转录因子 JUN 并增加 JUN 和 CD47 的启动子可及性。接下来，我们建立了硬皮病模型，证明 Jun 通过小鼠中 CD26+Sca1- 成纤维细胞的刺猬依赖性扩张介导皮肤纤维化。在独立于生态位的适应性转移模型中，JUN 控制移植物存活并赋予成纤维细胞增强的自我更新能力。在体内，JUN 增强 CD47 的表达，抑制 CD47 消除异位成纤维细胞移植物并增加体外吞噬作用。在同基因小鼠中，消耗巨噬细胞可改善皮肤纤维化。在治疗上，CD47 和 IL-6 联合阻断可逆转小鼠皮肤纤维化，并导致异位移植的硬皮细胞的快速消除。总而言之，我们的研究证明了结合不同免疫疗法治疗硬皮病的有效性，并为临床试验中结合 CD47 和 IL-6 抑制提供了理论依据。
Scleroderma is a devastating fibrotic autoimmune disease. Current treatments are partly effective in preventing disease progression but do not remove fibrotic tissue. Here, we evaluated whether scleroderma fibroblasts take advantage of the "don't-eat-me-signal" CD47 and whether blocking CD47 enables the body's immune system to get rid of diseased fibroblasts. To test this approach, we used a Jun-inducible scleroderma model. We first demonstrated in patient samples that scleroderma upregulated transcription factor JUN and increased promoter accessibilities of both JUN and CD47. Next, we established our scleroderma model, demonstrating that Jun mediated skin fibrosis through the hedgehog-dependent expansion of CD26+Sca1- fibroblasts in mice. In a niche-independent adaptive transfer model, JUN steered graft survival and conferred increased self-renewal to fibroblasts. In vivo, JUN enhanced the expression of CD47, and inhibiting CD47 eliminated an ectopic fibroblast graft and increased in vitro phagocytosis. In the syngeneic mouse, depleting macrophages ameliorated skin fibrosis. Therapeutically, combined CD47 and IL-6 blockade reversed skin fibrosis in mice and led to the rapid elimination of ectopically transplanted scleroderma cells. Altogether, our study demonstrates the efficiency of combining different immunotherapies in treating scleroderma and provides a rationale for combining CD47 and IL-6 inhibition in clinical trials.