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IL-11 is a crucial determinant of cardiovascular fibrosis
Open accessAbstract
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.
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“Microbiota driven intestinal fibrosis may be mediated by induction of the IL-33 receptor ST2 on epithelial cells157 or the pro-fibrotic action of tumor necrosis factor-like cytokine 1A (TL1A)158”
From Fibrosis: from mechanisms to medicines (2020) · cites this paper as [157]
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Metadata
- Authors
- 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. L., Ko, N. S. J., Sahib, N. E., Pua, C. J., Zhen, N. T. G., 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. 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. K., & Cook, S. A.
- Affiliations
- National University of Singapore (SG)
- National Heart Centre Singapore (SG)
- Harvard University (US)
- Max Delbrück Center (DE)
- The University of Melbourne (AU)
- KK Women's and Children's Hospital (SG)
- Brigham and Women's Hospital (US)
- Corresponding author
- Cook, Stuart A.
- ORCID
- Viswanathan, Sivakumar
- Widjaja, Anissa A.
- Lim, Wei-Wen
- DeLaughter, Daniel M.
- Ng, Benjamin
- Patone, Giannino
- Chow, Kingsley
- Chothani, Sonia P.
- Ye, Lei
- Rackham, Owen J. L.
- Pua, Chee Jian
- Xie, Chen
- Wang, Mao
- Maatz, Henrike
- Saar, Kathrin
- Blachut, Susanne
- Petretto, Enrico
- Schmidt, Sabine
- Putoczki, Tracy
- Wakimoto, Hiroko
- Chao, Victor T. T.
- Chua, Yeow L.
- Loh, Yee J.
- Jamal, Muhammad H.
- Ong, Boon-Hean
- Chakaramakkil, Mathew J.
- Seidman, Jonathan G.
- Seidman, Christine E.
- Sin, Kenny Y. K.
- Cook, Stuart A.
- Venue
- Nature
- Published
- 2017-11-13
- Volume
- 552
- Issue
- 7683
- Pages
- 110-115
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC5807082
- OpenAlex
- W2770331207
- Cited by
- 639
- References
- 42
- Citations by year
- 2026: 75 · 2025: 74 · 2024: 79 · 2023: 81 · 2022: 87 · 2021: 81 · 2020: 80 · 2019: 50 · 2018: 28 · 2017: 3
- FWCI
- 33.92
- Type
- journal article
- Language
- en
- Open access
- green
- www.ncbi.nlm.nih.gov
- Licence
- www.springer.com/tdm (tdm)
- Locations
- Nature (publishedVersion)
- PubMed (publishedVersion)
- PubMed Central (acceptedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (acceptedVersion)
- National University of Singapore (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- ePrints Soton (University of Southampton) (submittedVersion)
- Spiral (Imperial College London) (submittedVersion)
- Funders
- National Institutes of Health (DP1OD006428)
- National Heart, Lung, and Blood Institute (R01HL070867, DP1HL117649, R01HL080494)
- Topics
- Health Sciences › Medicine › Cardiology and Cardiovascular Medicine › Cardiac Fibrosis and Remodeling
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › TGF-β signaling in diseases
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Congenital heart defects research
- Keywords
- interleukin-11, IL-11 receptor, myocardial fibrosis, renal fibrosis, TGF-β1, fibroblast activation, ERK signaling, autocrine signaling, fibrotic diseases, therapeutic target, organ failure, renal failure, heart failure
- MeSH terms
- Animals, Cardiovascular System, Cells, Cultured, Female, Fibroblasts, Fibrosis, Heart, Humans, Kidney, Male, Middle Aged, Myocardium, Protein Biosynthesis, Interleukin-11, Mice, Knockout, Transgenes, Autocrine Communication, Mice, Interleukin-11 Receptor alpha Subunit, Transforming Growth Factor beta1, Organ Dysfunction Scores
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