A single cell atlas of frozen shoulder capsule identifies features associated with inflammatory fibrosis resolution
A single cell atlas of frozen shoulder capsule identifies features associated with inflammatory fibrosis resolution
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DOI：
10.1038/s41467-024-45341-9
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发表时间：
2024-02-19
影响因子：
16.6
通讯作者：
Dakin，Stephanie G.
中科院分区：
文献类型：
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作者：
Ng，Michael T. H.;Borst，Rowie;Dakin，Stephanie G.
冻结肩是一种自发自我解决的慢性炎症性纤维化人类疾病，它区别于大多数进行性和不可逆的纤维化疾病的条件。使用单细胞分析，我们鉴定了促炎性MERTKlowCD 48+巨噬细胞和MERTK + LYVE 1 + MRC 1+巨噬细胞，它们富含炎症负调节因子，并共存于冷冻肩关节囊组织中。患者源性细胞的微培养物鉴定了MERTK+巨噬细胞与促消退DKK 3+和POR 4+成纤维细胞之间的整合素介导的细胞-基质相互作用，表明基质重塑在冻结肩消退中发挥作用。跨组织分析揭示了肩关节囊MERTK+巨噬细胞与疾病缓解期类风湿性关节炎患者滑膜组织中富集的相应群体之间的共享基因表达盒，支持MERTK+巨噬细胞介导炎症和纤维化消退的概念。人胎肩组织的单细胞转录组学分析和空间分析鉴定出MERTK + LYVE 1 + MRC 1+巨噬细胞以及DKK 3+和POR 4+成纤维细胞群，与冻结肩中的类似，表明在肩发育期间建立了解决纤维化的模板。MerTK+巨噬细胞与促消退的DKK 3+和POT 3+成纤维细胞之间的相互作用可促进冻结肩的消退，为持续性纤维化疾病的潜在治疗消退提供基础。
Frozen shoulder is a spontaneously self-resolving chronic inflammatory fibrotic human disease, which distinguishes the condition from most fibrotic diseases that are progressive and irreversible. Using single-cell analysis, we identify pro-inflammatory MERTKlowCD48+macrophages and MERTK + LYVE1 + MRC1+ macrophages enriched for negative regulators of inflammation which co-exist in frozen shoulder capsule tissues. Micro-cultures of patient-derived cells identify integrin-mediated cell-matrix interactions between MERTK+ macrophages and pro-resolving DKK3+ and POSTN+ fibroblasts, suggesting that matrix remodelling plays a role in frozen shoulder resolution. Cross-tissue analysis reveals a shared gene expression cassette between shoulder capsule MERTK+ macrophages and a respective population enriched in synovial tissues of rheumatoid arthritis patients in disease remission, supporting the concept that MERTK+ macrophages mediate resolution of inflammation and fibrosis. Single-cell transcriptomic profiling and spatial analysis of human foetal shoulder tissues identify MERTK + LYVE1 + MRC1+ macrophages and DKK3+ and POSTN+ fibroblast populations analogous to those in frozen shoulder, suggesting that the template to resolve fibrosis is established during shoulder development. Crosstalk between MerTK+ macrophages and pro-resolving DKK3+ and POSTN+ fibroblasts could facilitate resolution of frozen shoulder, providing a basis for potential therapeutic resolution of persistent fibrotic diseases.