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Nature. 2017 Dec 7;552(7683):110-115. doi: 10.1038/nature24676. Epub 2017 Nov 13.

IL-11 is a crucial determinant of cardiovascular fibrosis.

Author information

1
National Heart Centre Singapore, Singapore.
2
Duke-National University of Singapore Medical School, Singapore.
3
Department of Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA.
4
Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rossle Strasse 10, 13125 Berlin, Germany.
5
Inflammation Division, Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia.
6
Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3050, Australia.
7
Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, California, USA.
8
Department of Medicine, University of California at San Diego, La Jolla, California 92093, USA.
9
Department of Pharmacology, University of California at San Diego, La Jolla, California 92093, USA.
10
Kandang Kerbau Women's and Children's Hospital, Singapore.
11
Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, Massachusettes 02115, USA.
12
Howard Hughes Medical Institute, Chevy Chase, Maryland 20815, USA.
13
DZHK (German Centre for Cardiovascular Research), partner site, Berlin, Germany.
14
Charité-Universitätsmedizin, Berlin, Germany.
15
Berlin Institute of Health (BIH), Berlin, Germany.
16
National Heart and Lung Institute, Imperial College London, London, UK.
17
MRC-London Institute of Medical Sciences, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN, UK.

Abstract

Fibrosis is a 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 hypothesized that downstream effectors of TGFβ1 in fibroblasts could be attractive therapeutic targets and lack upstream toxicity. Here we show, using integrated imaging-genomics analyses of primary human fibroblasts, that upregulation of interleukin-11 (IL-11) is the dominant transcriptional response to TGFβ1 exposure and required for its pro-fibrotic effect. IL-11 and its receptor (IL11RA) are expressed specifically in fibroblasts, in which they drive non-canonical, ERK-dependent autocrine signalling that is required for fibrogenic protein synthesis. In mice, fibroblast-specific Il11 transgene expression or Il-11 injection causes heart and kidney fibrosis and organ failure, whereas genetic deletion of Il11ra1 protects against disease. Therefore, inhibition of IL-11 prevents fibroblast activation across organs and species in response to a range of important pro-fibrotic stimuli. These results reveal a central role of IL-11 in fibrosis and we propose that inhibition of IL-11 is a potential therapeutic strategy to treat fibrotic diseases.

PMID:
29160304
PMCID:
PMC5807082
DOI:
10.1038/nature24676
[Indexed for MEDLINE]
Free PMC Article

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