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

Leslie, J. et al. (2020) c-Rel orchestrates energy-dependent epithelial and macrophage reprogramming in fibrosis. Nature Metabolism, 2, pp. 1350-1367. (doi: 10.1038/s42255-020-00306-2) (PMID:33168981) (PMCID:PMC7116435)

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.

• Item Type: Articles
• Additional Information: This work was funded by a UK Medical Research Council PhD studentship to J.L. and program grants MR/K0019494/1 (to D.A.M., J.M. and F.O.) and MR/R023026/1 (to D.A.M., J.M., L.A.B. and F.O.). An Arthritis Research UK grant (20812) supports F.O., D.A.M., J.L. and J.C.W. A CRUK program grant (C18342/A23390) supports J.L. and D.A.M. The cross-council Lifelong Health and Wellbeing initiative, funded by the MRC (L016354) funds D.A.M. and F.O. C.N. is supported by CRUK Beatson Institute Core funding (A171196). T.G.B. is funded by the Wellcome Trust (WT107492Z) and a CRUK/AECC/AIRC Accelerator Award (A26813). M.Y.W.Z. has a personal Ph.D award from Newton-Mosharafa fund. P.C., L.S. and L.-A.T. are financed by Methusalem funding, FWO, ERC Proof of Concept (ERC-713758) and an Advanced ERC Research Grant (EU-ERC743074). The IVIS spectrum was purchased under a Wellcome Trust Equipment Grant (087961) awarded to D.A.M. and others. We thank the Newcastle University bioimaging
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Worrell, Dr Julie
• Authors: Leslie, J., Macia, M. G., Luli, S., Worrell, J. C., Reilly, W. J., Paish, H. L., Knox, A., Barksby, B. S., Gee, L. M., Zaki, M. Y. W., Collins, A. L., Burgoyne, R. A., Cameron, R., Bragg, C., Xu, X., Chung, G. W., Brown, C. D. A., Blanchard, A. D., Nanthakumar, C. B., Karsdal, M., Robinson, S. M., Manas, D. M., Sen, G., French, J., White, S. A., Murphy, S., Trost, M., Zakrzewski, J. L., Klein, U., Schwabe, R. F., Mederacke, I., Nixon, C., Bird, T., Teuwen, L.-A., Schoonjans, L., Carmeliet, P., Mann, J., Fisher, A. J., Sheerin, N. S., Borthwick, L. A., Mann, D. A., and Oakley, F.
• College/School: College of Medical Veterinary and Life Sciences > School of Infection & Immunity
• Journal Name: Nature Metabolism
• Publisher: Nature Research
• ISSN: 2522-5812
• Published Online: 09 November 2020