Adipocyte associated glucocorticoid signaling regulates normal fibroblast function which is lost in inflammatory arthritis
Heather J. Faust, Tan‐Yun Cheng, Ilya Korsunsky, Gerald F. Watts, Shani T. Gal-Oz, William V. Trim, Suppawat Kongthong, A. Helena Jonsson, Daimon P. Simmons, Fan Zhang, Robert F. Padera, Susan Chubinskaya, Accelerating Medicines Partnership: RA/SLE Network, Jennifer S. Albrecht, Jennifer H. Anolik, William Apruzzese, Jennifer L. Barnas, Joan M. Bathon, Ami Ben‐Artzi, Brendan F. Boyce, David L. Boyle, S. Louis Bridges, Vivian P. Bykerk, Debbie Campbell, Arnold Ceponis, Adam Chicoine, Michelle Curtis, Kevin D. Deane, Edward F. DiCarlo, Laura T. Donlin, Patrick Dunn, Andrew Filer, Hayley Carr, Gary S. Firestein, Lindsy Forbess, Laura Geraldino‐Pardilla, Susan M. Goodman, Ellen M. Gravallese, Deepak A. Rao, Peter K. Gregersen, Joel M. Guthridge, María Gutiérrez‐Arcelus, V. Michael Holers, Diane Horowitz, Laura B. Hughes, Lionel B. Ivashkiv, Kazuyoshi Ishigaki, Judith A. James, Joyce B. Kang, Gregory Keras, Amit Lakhanpal, James A. Lederer, Myles Lewis, Yuhong Li, Katherine P. Liao, Arthur M. Mandelin, Ian Mantel, Kathryne E. Marks, Mark Maybury, Andrew McDavid, Mandy J. McGeachy, Joseph Mears, Nida Meednu, Nghia Millard, Larry W. Moreland, Saba Nayar, Alessandra Nerviani, Dana E. Orange, Harris Perlman, Costantino Pitzalis, Javier Rangel‐Moreno, Karim Raza, Yakir Reshef, Christopher T. Ritchlin, Felice Rivellese, William H. Robinson, Laurie Rumker, Ilfita Sahbudin, Saori Sakaue, Jennifer Seifert, Dagmar Scheel‐Toellner, Anvita Singaraju, Kamil Slowikowski, Melanie H. Smith, Darren Tabechian, Paul J. Utz, Kathryn Weinand, Dana Weisenfeld, Michael H. Weisman, Qian Xiao, Zhu Zhu, Zhihan J. Li, Andrew Cordle, Aaron Wyse, Kevin Wei, Soumya Raychaudhuri, Lydia Lynch, D. Branch Moody, Michael B. Brenner
Abstract
Fibroblasts play critical roles in tissue homeostasis, but in pathologic states they can drive fibrosis, inflammation, and tissue destruction. Little is known about what regulates the homeostatic functions of fibroblasts. Here, we perform RNA sequencing and identify a gene expression program in healthy synovial fibroblasts characterized by enhanced fatty acid metabolism and lipid transport. We identify cortisol as the key driver of the healthy fibroblast phenotype and that depletion of adipocytes, which express high levels of Hsd11b1, results in loss of the healthy fibroblast phenotype in mouse synovium. Additionally, fibroblast-specific glucocorticoid receptor Nr3c1 deletion in vivo leads to worsened arthritis. Cortisol signaling in fibroblasts mitigates matrix remodeling induced by TNF and TGF-β1 in vitro, while stimulation with these cytokines represses cortisol signaling and adipogenesis. Together, these findings demonstrate the importance of adipocytes and cortisol signaling in driving the healthy synovial fibroblast state that is lost in disease. Fibroblasts play critical roles in tissue homeostasis, but in pathologic states they can drive fibrosis, inflammation, and tissue destruction. Here, Faust et al. find that healthy human synovial fibroblasts under the influence of adjacent adipocytes have altered lipid metabolism driven by cortisol signaling. Both adipocytes and these characteristics are lost in inflammatory arthritis.