c-Rel orchestrates energy-dependent epithelial and macrophage reprogramming in fibrosis

Jack Leslie, Marina García Macia, Saimir Luli, Julie C. Worrell, William J. Reilly, Hannah L. Paish, Amber Knox, Ben S. Barksby, Lucy M. Gee, Marco Y. W. Zaki, Amy L. Collins, Rachel A. Burgoyne, Rainie Cameron, Charlotte Bragg, Xin Xu, Git W. Chung, Colin D. A. Brown, Andrew D. Blanchard, Carmel B. Nanthakumar, Morten KarsdalStuart M. Robinson, Derek M. Manas, Gourab Sen, Jeremy French, Steven A. White, Sandra Murphy, Matthias Trost, Johannes L. Zakrzewski, Ulf Klein, Robert F. Schwabe, Ingmar Mederacke, Colin Nixon, Tom Bird, Laure-Anne Teuwen, Luc Schoonjans, Peter Carmeliet, Jelena Mann, Andrew J. Fisher, Neil S. Sheerin, Lee A. Borthwick, Derek A. Mann, Fiona Oakley

Research output: Contribution to journalArticlepeer-review

Abstract

Fibrosis is a common pathological feature of chronic disease. Deletion of the NF-κB subunit c-Rel limits fibrosis in multiple organs, although the mechanistic nature of this protection is unresolved. Using cell-specific gene-targeting manipulations in mice undergoing liver damage, we elucidate a critical role for c-Rel in controlling metabolic changes required for inflammatory and fibrogenic activities of hepatocytes and macrophages and identify Pfkfb3 as the key downstream metabolic mediator of this response. Independent deletions of Rel in hepatocytes or macrophages suppressed liver fibrosis induced by carbon tetrachloride, while combined deletion had an additive anti-fibrogenic effect. In transforming growth factor-β1-induced hepatocytes, c-Rel regulates expression of a pro-fibrogenic secretome comprising inflammatory molecules and connective tissue growth factor, the latter promoting collagen secretion from HMs. Macrophages lacking c-Rel fail to polarize to M1 or M2 states, explaining reduced fibrosis in RelΔLysM mice. Pharmacological inhibition of c-Rel attenuated multi-organ fibrosis in both murine and human fibrosis. In conclusion, activation of c-Rel/Pfkfb3 in damaged tissue instigates a paracrine signalling network among epithelial, myeloid and mesenchymal cells to stimulate fibrogenesis. Targeting the c-Rel–Pfkfb3 axis has potential for therapeutic applications in fibrotic disease.
Original languageEnglish
Pages (from-to)1350-1367
JournalNature Metabolism
Volume2
Issue number11
DOIs
Publication statusPublished - 9 Nov 2020

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