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Notch signalling drives synovial fibroblast identity and arthritis pathology

2020; Nature Portfolio; Volume: 582; Issue: 7811 Linguagem: Inglês

10.1038/s41586-020-2222-z

1476-4687

Kevin Wei, Ilya Korsunsky, Jennifer L. Marshall, Anqi Gao, Gerald F. Watts, Triin Major, Adam P. Croft, Jordan Watts, Philip Blazar, Jeffrey K. Lange, Thomas S. Thornhill, Andrew Filer, Karim Raza, Laura T. Donlin, Jennifer S. Albrecht, Jennifer H. Anolik, William Apruzzese, Brendan F. Boyce, David L. Boyle, S. Louis Bridges, Jane H. Buckner, Vivian P. Bykerk, Edward F. DiCarlo, James P. Dolan, Thomas Eisenhaure, Gary S. Firestein, Chamith Y. Fonseka, Susan M. Goodman, Ellen M. Gravallese, Peter K. Gregersen, Joel M. Guthridge, María Gutiérrez‐Arcelus, Nir Hacohen, V. Michael Holers, Laura B. Hughes, Lionel B. Ivashkiv, Eddie A. James, Judith A. James, A. Helena Jonsson, Josh Keegan, Stephen Kelly, Yvonne Lee, Eddie A. James, David Lieb, Arthur M. Mandelin, Mandy J. McGeachy, Michael A. McNamara, Joseph Mears, Nida Meednu, Fumitaka Mizoguchi, Larry W. Moreland, Jennifer P. Nguyen, Chad Nusbaum, Akiko Noma, Dana E. Orange, Harris Perlman, Costantino Pitzalis, Javier Rangel‐Moreno, Deepak A. Rao, Mina Rohani‐Pichavant, Christopher T. Ritchlin, William H. Robinson, Karen Salomon-Escoto, Anupamaa Seshadri, Jennifer Seifert, Kamil Slowikowski, Danielle Sutherby, Darren Tabechian, Jason D. Turner, Paul J. Utz, Fan Zhang, Christian W. Siebel, Christopher D. Buckley, Soumya Raychaudhuri, Michael B. Brenner,

Cell Adhesion Molecules Research

The synovium is a mesenchymal tissue composed mainly of fibroblasts, with a lining and sublining that surround the joints. In rheumatoid arthritis the synovial tissue undergoes marked hyperplasia, becomes inflamed and invasive, and destroys the joint1,2. It has recently been shown that a subset of fibroblasts in the sublining undergoes a major expansion in rheumatoid arthritis that is linked to disease activity3–5; however, the molecular mechanism by which these fibroblasts differentiate and expand is unknown. Here we identify a critical role for NOTCH3 signalling in the differentiation of perivascular and sublining fibroblasts that express CD90 (encoded by THY1). Using single-cell RNA sequencing and synovial tissue organoids, we found that NOTCH3 signalling drives both transcriptional and spatial gradients—emanating from vascular endothelial cells outwards—in fibroblasts. In active rheumatoid arthritis, NOTCH3 and Notch target genes are markedly upregulated in synovial fibroblasts. In mice, the genetic deletion of Notch3 or the blockade of NOTCH3 signalling attenuates inflammation and prevents joint damage in inflammatory arthritis. Our results indicate that synovial fibroblasts exhibit a positional identity that is regulated by endothelium-derived Notch signalling, and that this stromal crosstalk pathway underlies inflammation and pathology in inflammatory arthritis. NOTCH3 signalling is shown to be the underlying driver of the differentiation and expansion of a subset of synovial fibroblasts implicated in the pathogenesis of rheumatoid arthritis.