Liu Feng, Shi Hui, Turner Jason D, Anscombe Rachel, Li Jiaqi, Sekine Takuya, Hammitzsch Ariane, Agarwal Devika, Mahony Christopher, Chen Jiewei, Kendrick Ben, Du Dajiang, Tong Qiang, Duan Lihua, Dooley Kyla, Fang Hai, Korsunsky Ilya, Madhu Roopa, Cribbs Adam P, Friedrich Matthias, Marsden Brian D, Chen Yi-Ling, Ogg Graham, Adams Anna, Chen Warner, Leonardo Steven, McCann Fiona E, Buckley Christopher D, Rooney Terence, Freeman Thomas, Uhlig Holm H, Dendrou Calliope, Croft Adam, Filer Andrew, Bowness Paul, Chen Liye
Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Oxford, United Kingdom.
Rheumatology Research Group, Institute of Inflammation and Ageing, University of Birmingham, Birmingham, United Kingdom.
Ann Rheum Dis. 2025 Jul;84(7):1151-1163. doi: 10.1016/j.ard.2025.04.018. Epub 2025 May 24.
Interleukin (IL)-17A is a key driver of spondyloarthritis (SpA) joint pathology. We aimed to identify its cellular source in synovial tissue from patients with 2 forms of SpA, namely axial SpA (AxSpA) and psoriatic arthritis (PsA).
Synovial tissue from patients with SpA was profiled using single-cell RNA sequencing (scRNA-seq; AxSpA, n = 5; PsA, n = 6) or spatial RNA profiling (PsA, n = 4). CellPhoneDB was used to infer cell-cell communication. Tissue-resident memory Th17 (TRM17)-like cells were generated in vitro using blood memory CD4+ T cells from SpA patients. An epigenetic inhibitor library, siRNA, and clustered regularly interspaced short palindromic repeats (CRISPR) were used to identify epigenetic regulator(s) for TRM17.
scRNA-seq showed that CD4+CXCR6+ TRM17 cells are the predominant spontaneous IL17A producers in SpA synovium. Cell-cell communication and single-cell spatial analysis support the interaction between TRM17 and CLEC10A+ dendritic cells, which were activated in SpA. Both sublining and lining fibroblasts in SpA synovium showed evidence of interleukin (IL)-17A activation. In vitro-generated CD4+ TRM17-like cells phenocopied joint tissue TRM17, producing IL-17A/F upon T cell-receptor (TCR) stimulation, which was further enhanced by cytokines. Perturbation of BRD1 inhibited the generation of TRM17-like cells.
CD4+ TRM17 cells are the predominant source of IL-17A in SpA synovial tissue. TCR stimulation is essential for the secretion of IL-17A by CD4+TRM17-like cells. The epigenetic regulator bromodomain-containing protein 1 (BRD1) contributes to the generation of CD4+TRM17. Depleting CD4+TRM17 cells in SpA is thus a therapeutic strategy with potential to induce long-term remission.
白细胞介素（IL）-17A是脊柱关节炎（SpA）关节病理的关键驱动因素。我们旨在确定其在两种SpA患者滑膜组织中的细胞来源，即轴向SpA（AxSpA）和银屑病关节炎（PsA）。
使用单细胞RNA测序（scRNA-seq；AxSpA，n = 5；PsA，n = 6）或空间RNA分析（PsA，n = 4）对SpA患者的滑膜组织进行分析。使用CellPhoneDB推断细胞间通讯。使用SpA患者的血液记忆CD4+T细胞在体外生成组织驻留记忆Th17（TRM17）样细胞。使用表观遗传抑制剂文库、小干扰RNA（siRNA）和成簇规律间隔短回文重复序列（CRISPR）来鉴定TRM17的表观遗传调节因子。
scRNA-seq显示，CD4+CXCR6+TRM17细胞是SpA滑膜中主要的自发IL17A产生细胞。细胞间通讯和单细胞空间分析支持TRM17与SpA中被激活的CLEC10A+树突状细胞之间的相互作用。SpA滑膜中的深层和成纤维细胞衬里均显示白细胞介素（IL）-17A激活的证据。体外生成的CD4+TRM17样细胞模拟关节组织TRM17，在T细胞受体（TCR）刺激后产生IL-17A/F，细胞因子可进一步增强这种产生。BRD1的干扰抑制了TRM17样细胞的产生。
CD4+TRM17细胞是SpA滑膜组织中IL-17A的主要来源。TCR刺激对于CD4+TRM17样细胞分泌IL-17A至关重要。含溴结构域蛋白1（BRD1）这一表观遗传调节因子有助于CD4+TRM17的产生。因此，清除SpA中的CD4+TRM17细胞是一种有可能诱导长期缓解的治疗策略。
