Distinct fibroblast subsets drive inflammation and damage in arthritis
Distinct fibroblast subsets drive inflammation and damage in arthritis
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DOI：
10.1038/s41586-019-1263-7
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发表时间：
2019-06-13
期刊：
影响因子：
64.8
通讯作者：
Buckley, Christopher D.
中科院分区：
文献类型：
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作者：
Croft, Adam P.;Campos, Joana;Buckley, Christopher D.
识别具有非重叠效应子功能的淋巴细胞亚群对于免疫介导的炎性疾病（IMID）靶向治疗的开发至关重要（1，2）。然而，目前尚不清楚是否也存在具有非重叠功能的成纤维细胞亚类，并负责在IMID中观察到的各种组织驱动过程，如炎症和损伤（3-5）。在这里，我们确定并描述了不同的成纤维细胞亚群的生物学负责介导炎症或关节炎组织损伤。我们发现，删除成纤维细胞活化蛋白-α（FAP α）（+）成纤维细胞抑制炎症和骨侵蚀的小鼠模型的解决和持续性关节炎。单细胞转录分析在FAPa+群体中鉴定出两个不同的成纤维细胞亚群：位于滑膜下层的FAP α（+）THY 1（+）免疫效应成纤维细胞，和限于滑膜衬里层的FAP α（+）THY 1（-）破坏性成纤维细胞。当过继性转移到关节中时，FAP alpha（+）THY 1（-）成纤维细胞选择性地介导骨和软骨损伤，对炎症的影响很小，而FAP alpha（+）THY 1（+）成纤维细胞的转移导致更严重和持久的炎性关节炎，对骨和软骨的影响很小。我们的研究结果描述了解剖学上离散、功能上不同且功能不重叠的成纤维细胞亚群，这对旨在调节炎症和组织损伤的细胞疗法具有重要意义。
The identification of lymphocyte subsets with non-overlapping effector functions has been pivotal to the development of targeted therapies in immune-mediated inflammatory diseases (IMIDs)(1,2). However, it remains unclear whether fibroblast subclasses with non-overlapping functions also exist and are responsible for the wide variety of tissue-driven processes observed in IMIDs, such as inflammation and damage(3-5). Here we identify and describe the biology of distinct subsets of fibroblasts responsible for mediating either inflammation or tissue damage in arthritis. We show that deletion of fibroblast activation protein-alpha (FAP alpha)(+) fibroblasts suppressed both inflammation and bone erosions in mouse models of resolving and persistent arthritis. Single-cell transcriptional analysis identified two distinct fibroblast subsets within the FAPa+ population: FAP alpha(+) THY1(+) immune effector fibroblasts located in the synovial sub-lining, and FAP alpha(+) THY1(-) destructive fibroblasts restricted to the synovial lining layer. When adoptively transferred into the joint, FAP alpha(+) THY1(-) fibroblasts selectively mediate bone and cartilage damage with little effect on inflammation, whereas transfer of FAP alpha(+) THY1(+) fibroblasts resulted in a more severe and persistent inflammatory arthritis, with minimal effect on bone and cartilage. Our findings describing anatomically discrete, functionally distinct fibroblast subsets with non-overlapping functions have important implications for cell-based therapies aimed at modulating inflammation and tissue damage.