Abstract

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.

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Author information

Author notes

    • Sebastian Schafer
    • , Sivakumar Viswanathan
    •  & Anissa A Widjaja

    These authors contributed equally.

Affiliations

  1. National Heart Centre Singapore, Singapore

    • Sebastian Schafer
    • , Wei-Wen Lim
    • , Benjamin Ng
    • , Kingsley Chow
    • , Jessie Tan
    • , Lei Ye
    • , Chee Jian Pua
    • , Nicole T G Zhen
    • , Chen Xie
    • , Shiqi Lim
    • , See L Lim
    • , Jia L Soon
    • , Victor T T Chao
    • , Yeow L Chua
    • , Teing E Tan
    • , Yee J Loh
    • , Muhammad H Jamal
    • , Kim K Ong
    • , Kim C Chua
    • , Boon-Hean Ong
    • , Mathew J Chakaramakkil
    • , Kenny Y K Sin
    •  & Stuart A Cook
  2. Duke–National University of Singapore Medical School, Singapore

    • Sebastian Schafer
    • , Sivakumar Viswanathan
    • , Anissa A Widjaja
    • , Aida Moreno-Moral
    • , Ester Khin
    • , Sonia P Chothani
    • , Owen J L Rackham
    • , Nicole S J Ko
    • , Norliza E Sahib
    • , Mao Wang
    • , Enrico Petretto
    • , Kristmundur Sigmundsson
    • , Jia L Soon
    • , Victor T T Chao
    • , Kenny Y K Sin
    •  & Stuart A Cook
  3. Department of Genetics, Harvard Medical School, Boston, MA 02115, USA

    • Daniel M DeLaughter
    • , Hiroko Wakimoto
    • , Jonathan G Seidman
    •  & Christine E Seidman
  4. Cardiovascular and Metabolic Sciences, Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Robert-Rossle Strasse 10, 13125 Berlin, Germany

    • Giannino Patone
    • , Henrike Maatz
    • , Kathrin Saar
    • , Susanne Blachut
    • , Sabine Schmidt
    • , Sebastiaan van Heesch
    •  & Norbert Hubner
  5. Inflammation Division, Walter and Eliza Hall Institute of Medical Research, VIC 3052, Australia; Department of Medical Biology, The University of Melbourne, Parkville, Victoria 3050, Australia

    • Tracy Putoczki
  6. Skaggs School of Pharmacy and Pharmaceutical Sciences, University of California San Diego, La Jolla, USA

    • Nuno Guimarães-Camboa
    •  & Sylvia M Evans
  7. Department of Medicine, University of California at San Diego, La Jolla, CA 92093, USA

    • Sylvia M Evans
  8. Department of Pharmacology, University of California at San Diego, La Jolla, CA 92093, USA

    • Sylvia M Evans
  9. Kandang Kerbau Women’s and Children’s Hospital, Singapore

    • Yee J Loh
    •  & Kim K Ong
  10. Division of Cardiovascular Medicine, Brigham and Women's Hospital, Boston, MA 02115, USA

    • Christine E Seidman
  11. Howard Hughes Medical Institute, Chevy Chase, MD 20815, USA

    • Christine E Seidman
  12. DZHK (German Centre for Cardiovascular Research), partner site Berlin, Germany

    • Norbert Hubner
  13. Charité-Universitätsmedizin, Berlin, Germany

    • Norbert Hubner
  14. Berlin Institute of Health (BIH), Berlin, Germany

    • Norbert Hubner
  15. National Heart and Lung Institute, Imperial College London, London, UK

    • Stuart A Cook
  16. MRC-London Institute of Medical Sciences, Hammersmith Hospital Campus, Du Cane Road, London, W12 0NN

    • Stuart A Cook

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Corresponding author

Correspondence to Stuart A Cook.

Supplementary information

PDF files

  1. 1.

    Supplementary Figure

    This file contains source data for all western blot experiments.

  2. 2.

    Life Sciences Reporting Summary

Excel files

  1. 1.

    Supplementary Table 1

    Detailed information about the quality of each RNA sample, RNA-seq library and sample information about each individual that has contributed primary cells for the therapeutic target discovery high-content imaging screening and transcriptome profiling.

  2. 2.

    Supplementary Table 2

    Therapeutic Target Screen results: 1) Differentially expressed genes between TGFB stimulated fibroblasts and non-stimulated fibroblasts, 2) Spearman correlation (SPcor) between delta of fibroblasts expression (stimulated/non-stimulated) and delta of SMA, 3) Jensen–Shannon divergence (JSD) between of each gene across all GTEx tissues and FANTOM primary cell types (see more details in methods), 4) Average expression levels (transcripts per million, TPM) in TGFB1 stimulated and non-stimulated (baseline only) fibroblasts. Log2 fold change, shrunken Log2-fold changes computed by DESeq2 package. BH adj.P, Benjamini-Hochberg (BH) adjusted p-value.

  3. 3.

    Supplementary Table 3

    Gene Ontology database gene set enrichment analysis (GSEA) results for the stimulated versus baseline fibroblasts (GSEA computed by ranking all the genes by DESeq output statistic). Only terms enriched with FDR < 0.05 are presented. NES denotes normalized enrichment score.