Fibrosis is a 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 (TGFβ1) is the principal pro-fibrotic factor4,5, but its inhibition is associated with side effects due to its pleiotropic roles6,7. 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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Gene Expression Omnibus
We thank all patients for taking part in this research, which was performed with approval from the SingHealth Centralised IRB Review Board (CIRB; 2013/103/C). The research was supported by the National Medical Research Council (NMRC) Singapore STaR award (S.A.C.) (NMRC/STaR/0011/2012), the NMRC Centre Grant to the National Heart Centre Singapore (NHCS), Goh Foundation, Tanoto Foundation, NHLBI 5R01HL080494 (J.G.S., C.E.S.), HHMI (C.E.S.) and a grant from the Fondation Leducq (N.H., J.G.S., C.E.S., S.C.). We thank I. Kamer and R. Plehm, Max-Delbrück-Center for Molecular Medicine (MDC), for expert technical help with telemetry blood pressure measurements.
Extended data figures
Extended data tables
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.
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.
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.
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Bone Research (2019)