美国纪念斯隆凯特琳癌症中心Alexander Y. Rudensky，Christina S. Leslie和美国特殊外科医院Melanie H. Smith共同合作，近期取得重要工作进展。他们研究发现类风湿关节炎滑膜成纤维细胞异质性的驱动因素。相关研究成果2023年6月5日在线发表于《自然—免疫学》杂志上。

据介绍，非屏障免疫静止组织的炎症与大量血源性先天免疫细胞和适应性免疫细胞的涌入有关，来自后者的信号可能会改变和扩大驻留细胞的激活状态。然而，在人类炎症性疾病中，迁移细胞和驻留细胞类型之间的局部通讯仍然知之甚少。

研究人员使用配对的单细胞RNA和ATAC测序、多重成像和空间转录组学以及细胞外源性因子信号的体外建模，探索了类风湿性关节炎患者炎症关节中成纤维细胞样滑膜细胞（FLS）异质性的驱动因素。分析表明，局部暴露于髓细胞和T细胞来源的细胞因子、TNF、IFN-γ、IL-1β或缺乏这些细胞因子会驱动四种不同的FLS状态，其中一些状态与其他受疾病影响组织（包括皮肤和结肠）中的成纤维细胞状态非常相似。

总之，这一研究结果强调了炎症滑膜内并发、空间分布的细胞因子信号传导的作用。

附：英文原文

Title: Drivers of heterogeneity in synovial fibroblasts in rheumatoid arthritis

Author: Smith, Melanie H., Gao, Vianne R., Periyakoil, Preethi K., Kochen, Alejandro, DiCarlo, Edward F., Goodman, Susan M., Norman, Thomas M., Donlin, Laura T., Leslie, Christina S., Rudensky, Alexander Y.

Issue&Volume: 2023-06-05

Abstract: Inflammation of non-barrier immunologically quiescent tissues is associated with a massive influx of blood-borne innate and adaptive immune cells. Cues from the latter are likely to alter and expand activated states of the resident cells. However, local communications between immigrant and resident cell types in human inflammatory disease remain poorly understood. Here, we explored drivers of fibroblast-like synoviocyte (FLS) heterogeneity in inflamed joints of patients with rheumatoid arthritis using paired single-cell RNA and ATAC sequencing, multiplexed imaging and spatial transcriptomics along with in vitro modeling of cell-extrinsic factor signaling. These analyses suggest that local exposures to myeloid and T cell-derived cytokines, TNF, IFN-γ, IL-1β or lack thereof, drive four distinct FLS states some of which closely resemble fibroblast states in other disease-affected tissues including skin and colon. Our results highlight a role for concurrent, spatially distributed cytokine signaling within the inflamed synovium. Smith et al. present a resource detailing drivers of transcriptional heterogeneity of synovial fibroblasts cell states in the inflamed joints of human patients with rheumatoid arthritis.

DOI: 10.1038/s41590-023-01527-9

Source: https://www.nature.com/articles/s41590-023-01527-9