IL11 is a crucial determinant of cardiovascular fibrosis

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Item Type:	Article
Title:	IL11 is a crucial determinant of cardiovascular fibrosis
Creators Name:	Schafer, S., Viswanathan, S., Widjaja, A.A., Lim, W.W., Moreno-Moral, A., DeLaughter, D.M., Ng, B., Patone, G., Chow, K., Khin, E., Tan, J., Chothani, S.P., Ye, L., Rackham, O.J., Ko, N.S., Sahib, N.E., Pua, C.J., Zhen, N.T., Xie, C., Wang, M., Maatz, H., Lim, S., Saar, K., Blachut, S., Petretto, E., Schmidt, S., Putoczki, T., Guimarães-Camboa, N., Wakimoto, H., van Heesch, S., Sigmundsson, K., Lim, S.L., Soon, J.L., Chao, V.T., Chua, Y.L., Tan, T.E., Evans, S.M., Loh, Y.J., Jamal, M.H., Ong, K.K., Chua, K.C., Ong, B.H., Chakaramakkil, M.J., Seidman, J.G., Seidman, C.E., Hubner, N., Sin, K.Y. and Cook, S.A.
Abstract:	Fibrosis is a final common pathology in cardiovascular disease. In the heart, fibrosis causes mechanical and electrical dysfunction and in the kidney, it predicts the onset of renal failure. Transforming growth factor β1 (TGFβ1) is the principal pro-fibrotic factor but its inhibition is associated with side effects due to its pleiotropic roles. We hypothesised that downstream effectors of TGFβ1 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 TGFβ1 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.
Keywords:	Autocrine Communication, Cardiovascular System, Cells, Cultured, Fibroblasts, Fibrosis, Heart, Interleukin-11, Interleukin-11 Receptor Alpha Subunit, Kidney, Myocardium, Organ Dysfunction Scores, Protein Biosynthesis, Transforming Growth Factor Beta1, Transgenes, Animals, Mice
Source:	Nature
ISSN:	0028-0836
Publisher:	Nature Publishing Group
Volume:	552
Number:	7683
Page Range:	110-115
Date:	7 December 2017
Official Publication:	https://doi.org/10.1038/nature24676
External Fulltext:	View full text on PubMed Central
PubMed:	View item in PubMed

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