@article{Schafer:2017:10.1038/nature24676,
author = {Schafer, S and Viswanathan, S and Widjaja, AA and Lim, W-W and Moreno-Moral, A and DeLaughter, DM and Ng, B and Patone, G and Chow, K and Khin, E and Tan, J and Chothani, SP and Ye, L and Rackham, OJL and Ko, NSJ and Sahib, NE and Pua, CJ and Zhen, NTG and Xie, C and Wang, M and Maatz, H and Lim, S and Saar, K and Blachut, S and Petretto, E and Schmidt, S and Putoczki, T and Guimarães-Camboa, N and Wakimoto, H and van, Heesch S and Sigmundsson, K and Lim, SL and Soon, JL and Chao, VTT and Chua, YL and Tan, TE and Evans, SM and Loh, YJ and Jamal, MH and Ong, KK and Chua, KC and Ong, B-H and Chakaramakkil, MJ and Seidman, JG and Seidman, CE and Hubner, N and Sin, KYK and Cook, SA},
doi = {10.1038/nature24676},
journal = {Nature},
pages = {110--115},
title = {IL-11 is a crucial determinant of cardiovascular fibrosis},
url = {http://dx.doi.org/10.1038/nature24676},
volume = {552},
year = {2017}
}

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TY  - JOUR
AB  - Fibrosis is a final common pathology in cardiovascular disease1. In the heart, fibrosis causes mechanical and electrical dysfunction1,2 and in the kidney, it predicts the onset of renal failure3. Transforming growth factor β1 (TGFB1) is the principal pro-fibrotic factor4,5 but its inhibition is associated with side effects due to its pleiotropic roles6,7. 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.
AU  - Schafer,S
AU  - Viswanathan,S
AU  - Widjaja,AA
AU  - Lim,W-W
AU  - Moreno-Moral,A
AU  - DeLaughter,DM
AU  - Ng,B
AU  - Patone,G
AU  - Chow,K
AU  - Khin,E
AU  - Tan,J
AU  - Chothani,SP
AU  - Ye,L
AU  - Rackham,OJL
AU  - Ko,NSJ
AU  - Sahib,NE
AU  - Pua,CJ
AU  - Zhen,NTG
AU  - Xie,C
AU  - Wang,M
AU  - Maatz,H
AU  - Lim,S
AU  - Saar,K
AU  - Blachut,S
AU  - Petretto,E
AU  - Schmidt,S
AU  - Putoczki,T
AU  - Guimarães-Camboa,N
AU  - Wakimoto,H
AU  - van,Heesch S
AU  - Sigmundsson,K
AU  - Lim,SL
AU  - Soon,JL
AU  - Chao,VTT
AU  - Chua,YL
AU  - Tan,TE
AU  - Evans,SM
AU  - Loh,YJ
AU  - Jamal,MH
AU  - Ong,KK
AU  - Chua,KC
AU  - Ong,B-H
AU  - Chakaramakkil,MJ
AU  - Seidman,JG
AU  - Seidman,CE
AU  - Hubner,N
AU  - Sin,KYK
AU  - Cook,SA
DO  - 10.1038/nature24676
EP  - 115
PY  - 2017///
SN  - 0028-0836
SP  - 110
TI  - IL-11 is a crucial determinant of cardiovascular fibrosis
T2  - Nature
UR  - http://dx.doi.org/10.1038/nature24676
UR  - https://www.nature.com/articles/nature24676
UR  - http://hdl.handle.net/10044/1/54929
VL  - 552
ER  - 

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