IL11 is a crucial determinant of cardiovascular fibrosis

Schafer, S; Viswanathan, S; Widjaja, AA; Lim, WW; Moreno-Moral, A; DeLaughter, DM; Ng, B; Patone, G; Chow, K; Khin, E; Tan, J; Chothani, SP; Ye, L; Rackham, OJL; Ko, NSJ; Sahib, NE; Pua, CJ; Zhen, NTG; Xie, C; Wang, M; Maatz, H; Lim, S; Saar, K; Blachut, S; Petretto, E; Schmidt, S; Putoczki, T; Guimaraes-Camboa, N; Wakimoto, H; van Heesch, S; Sigmundsson, K; Lim, SL; Soon, JL; Chao, VTT; Chua, YL; Tan, TE; Evans, SM; Loh, YJ; Jamal, MH; Ong, KK; Chua, KC; Ong, BH; Chakaramakkil, MJ; Seidman, JG; Seidman, CE; Hubner, N; Sin, KYK; Cook, SA

Author(s): Schafer, S; Viswanathan, S; Widjaja, AA; Lim, WW; Moreno-Moral, A; DeLaughter, DM; Ng, B; Patone, G; Chow, K; Khin, E; Tan, J; Chothani, SP; Ye, L; Rackham, OJL; Ko, NSJ; Sahib, NE; Pua, CJ; Zhen, NTG; Xie, C; Wang, M; Maatz, H; Lim, S; Saar, K; Blachut, S; Petretto, E; Schmidt, S; Putoczki, T; Guimaraes-Camboa, N; Wakimoto, H; van Heesch, S; Sigmundsson, K; Lim, SL; Soon, JL; Chao, VTT; Chua, YL; Tan, TE; Evans, SM; Loh, YJ; Jamal, MH; Ong, KK; Chua, KC; Ong, BH; Chakaramakkil, MJ; Seidman, JG; Seidman, CE; Hubner, N; Sin, KYK; Cook, SA;
Details: Publication Year 2017-12-07,Volume 552,Issue #7683,Page 110-115
Journal Title: Nature
Publication Type: Journal Article
Abstract: Fibrosis is a final common pathology in cardiovascular disease(1). In the heart, fibrosis causes mechanical and electrical dysfunction(1,2) and in the kidney, it predicts the onset of renal failure(3). Transforming growth factor beta1 (TGFB1) is the principal pro-fibrotic factor(4,5) but its inhibition is associated with side effects due to its pleiotropic roles(6,7). We hypothesised that downstream effectors of TGFB1 in fibroblasts could be attractive therapeutic targets and lack upstream toxicities. Using integrated imaging-genomics analyses of primary human fibroblasts, we found that Interleukin 11 (IL11) upregulation is the dominant transcriptional response to TGFB1 exposure and required for its profibrotic effect. IL11 and its receptor (IL11RA) are expressed specifically in fibroblasts where they drive non-canonical, ERK-dependent autocrine signalling that is required for fibrogenic protein synthesis. In mice, fibroblast-specific Il11 transgene expression or Il11 injection causes heart and kidney fibrosis and organ failure whereas genetic deletion of Il11ra1 is protective against disease. Thus, inhibition of IL11 prevents fibroblast activation across organs and species in response to a range of important pro-fibrotic stimuli. These data reveal a central role of IL11 in fibrosis and we propose inhibition of IL11 as a new therapeutic strategy to treat fibrotic diseases.
Publisher: Springer Nature
Research Division(s): Inflammation
PubMed ID: 29160304
Publisher's Version: https://doi.org/10.1038/nature24676
Terms of Use/Rights Notice: Refer to copyright notice on published article.

Creation Date: 2018-01-15 09:30:26

Last Modified: 2018-01-15 10:12:45