Drivers of heterogeneity in synovial fibroblasts in rheumatoid arthritis

被引:77
作者
Smith, Melanie H. [1 ,2 ,3 ]
Gao, Vianne R. [4 ,5 ,6 ]
Periyakoil, Preethi K. [4 ]
Kochen, Alejandro [7 ,8 ]
DiCarlo, Edward F. [9 ]
Goodman, Susan M. [1 ,5 ,6 ]
Norman, Thomas M. [4 ]
Donlin, Laura T. [5 ,6 ,7 ,8 ]
Leslie, Christina S. [4 ]
Rudensky, Alexander Y. [2 ,3 ]
机构
[1] Hosp Special Surg, Dept Med, Div Rheumatol, New York, NY 10019 USA
[2] Mem Sloan Kettering Canc Ctr, Ludwig Ctr Canc Immunotherapy, Immunol Program Sloan Kettering Inst, New York, NY 10065 USA
[3] Mem Sloan Kettering Canc Ctr, Howard Hughes Med Inst, New York, NY 10065 USA
[4] Mem Sloan Kettering Canc Ctr, Computat & Syst Biol Program, New York, NY 10065 USA
[5] Weill Cornell Med Coll, New York, NY USA
[6] Grad Sch, New York, NY USA
[7] Hosp Special Surg, David Z Rosensweig Genom Res Ctr, New York, NY USA
[8] Hosp Special Surg, Arthrit & Tissue Degenerat Program, New York, NY USA
[9] Hosp Special Surg, Dept Pathol & Lab Med, New York, NY USA
关键词
ENRICHMENT ANALYSIS; INTERFERON-GAMMA; EXPRESSION; CELLS; CUX1;
D O I
10.1038/s41590-023-01527-9
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
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. 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-gamma, IL-1 beta 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.
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页码:1200 / +
页数:29
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