IL-6 trans-signaling in a humanized mouse model of scleroderma.
IL-6 trans-signaling in a humanized mouse model of scleroderma.
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DOI：
10.1073/pnas.2306965120
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发表时间：
2023-09-12
影响因子：
11.1
通讯作者：
Flavell, Richard A.
中科院分区：
文献类型：
--
作者：
Odell, Ian D.;Agrawal, Kriti;Sefik, Esen;Odell, Anahi V.;Caves, Elizabeth;Kirkiles-Smith, Nancy C.;Horsley, Valerie;Hinchcliff, Monique;Pober, Jordan S.;Kluger, Yuval;Flavell, Richard A.
硬皮病是一种导致皮肤和内脏器官纤维化的自身免疫性疾病。尚未发现能够完全重现人类疾病的小鼠模型。因此，我们测试了MISTRG6品系的人源化小鼠是否可以移植健康或硬皮病人类皮肤移植物。我们发现健康和硬皮病皮肤移植物保留了皮肤和骨髓来源的免疫细胞。此外，硬皮病皮肤移植物的纤维化通过植入不匹配的同种异体造血干细胞而得到缓解。机制研究支持一种转信号模型，即 CD4 T 细胞衍生的可溶性白细胞介素 6 (IL-6) 受体与干扰素驱动的 IL-6 细胞因子复合，从而驱动皮肤纤维化。因此，硬皮病皮肤移植到 MSTRG6 人源化小鼠中重现了硬皮病的关键信号通路，可能是研究人类疾病的有用模型。纤维化受到免疫细胞和间充质细胞之间相互作用的调节。然而，由于缺乏完全人源化的模型系统，人们对细胞类型调节人类纤维化病理学的能力知之甚少。 MSTRG6 小鼠通过同源小鼠/人类基因替换进行改造，在植入人类造血干细胞 (HSC) 后，可以发育出像人类一样的免疫系统。我们利用 MSTRG6 小鼠来模拟硬皮病，将全硬化性硬斑病患者的健康或硬皮病皮肤移植到移植了不匹配的同种异体 HSC 的人源化小鼠中。我们发现硬皮病皮肤移植物含有皮肤和骨髓来源的人 CD4 和 CD8 T 细胞以及人内皮细胞和周细胞。与健康皮肤不同，硬皮病皮肤中的成纤维细胞被耗尽并被小鼠成纤维细胞取代。此外，HSC 植入减轻了纤维化的多种特征，包括胶原蛋白和干扰素基因的表达以及人类 T 细胞的增殖和激活。纤维化的改善与 T 细胞活化标志物的减少以及间充质细胞表达人 IL-6 相关。机制研究支持了一个模型，即由 CD4 T 细胞衍生的可溶性 IL-6 受体与成纤维细胞衍生的 IL-6 复合驱动的 IL-6 反式信号传导促进细胞外基质基因过度表达。因此，移植了硬皮病皮肤的 MSTRG6 小鼠表现出以人 IL-6 信号传导为中心的多种纤维化反应，而健康骨髓源性免疫细胞的存在可以改善这种反应。我们的结果强调了 IL-6 反式信号传导在硬皮病发病机制中的重要性以及健康骨髓源性免疫细胞减轻疾病的能力。
Scleroderma is an autoimmune disease that causes skin and internal organ fibrosis. No mouse model has been identified that fully recapitulates human disease. Therefore, we tested whether the MISTRG6 strain of humanized mice could be transplanted with healthy or scleroderma human skin grafts. We found that healthy and scleroderma skin grafts retained skin and bone marrow–derived immune cells. Moreover, fibrosis in scleroderma skin grafts was alleviated by engraftment with unmatched allogeneic hematopoietic stem cells. Mechanistic studies supported a trans-signaling model whereby CD4 T cell–derived soluble interleukin-6 (IL-6) receptor complexed with interferon-driven IL-6 cytokine drives skin fibrosis. Thus, scleroderma skin transplants to MISTRG6 humanized mice recapitulate a key signaling pathway of scleroderma and may be a useful model to study human disease. Fibrosis is regulated by interactions between immune and mesenchymal cells. However, the capacity of cell types to modulate human fibrosis pathology is poorly understood due to lack of a fully humanized model system. MISTRG6 mice were engineered by homologous mouse/human gene replacement to develop an immune system like humans when engrafted with human hematopoietic stem cells (HSCs). We utilized MISTRG6 mice to model scleroderma by transplantation of healthy or scleroderma skin from a patient with pansclerotic morphea to humanized mice engrafted with unmatched allogeneic HSC. We identified that scleroderma skin grafts contained both skin and bone marrow–derived human CD4 and CD8 T cells along with human endothelial cells and pericytes. Unlike healthy skin, fibroblasts in scleroderma skin were depleted and replaced by mouse fibroblasts. Furthermore, HSC engraftment alleviated multiple signatures of fibrosis, including expression of collagen and interferon genes, and proliferation and activation of human T cells. Fibrosis improvement correlated with reduced markers of T cell activation and expression of human IL-6 by mesenchymal cells. Mechanistic studies supported a model whereby IL-6 trans-signaling driven by CD4 T cell–derived soluble IL-6 receptor complexed with fibroblast-derived IL-6 promoted excess extracellular matrix gene expression. Thus, MISTRG6 mice transplanted with scleroderma skin demonstrated multiple fibrotic responses centered around human IL-6 signaling, which was improved by the presence of healthy bone marrow–derived immune cells. Our results highlight the importance of IL-6 trans-signaling in pathogenesis of scleroderma and the ability of healthy bone marrow–derived immune cells to mitigate disease.
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影响因子：
4.7
作者：
Assassi, Shervin;del Junco, Deborah;Sutter, Kari;McNearney, Terry A.;Reveille, John D.;Karnavas, Andrew;Gourh, Pravitt;Estrada-Y-Martin, Rosa M.;Fischbach, Michael;Arnett, Frank C.;Mayes, Maureen D.
通讯作者：
Mayes, Maureen D.
影响因子：
3
作者：
IHN, H;SATO, S;TAKEHARA, K
通讯作者：
TAKEHARA, K
影响因子：
46.9
作者：
Fischer, M;Goldschmitt, J;RoseJohn, S
通讯作者：
RoseJohn, S
影响因子：
27.4
作者：
Eloranta, Maija-Leena;Franck-Larsson, Karin;Ronnblom, Lars
通讯作者：
Ronnblom, Lars
影响因子：
2.2
作者：
Chua, Siang Ling;Too, Wei Cun See;Few, Ling Ling
通讯作者：
Few, Ling Ling