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IL-11 is a crucial determinant of cardiovascular fibrosis.

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 ?1 (TGF?1) 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 TGF?1 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 TGF?1 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.

SUBMITTER: Schafer S

PROVIDER: S-EPMC5807082 | biostudies-literature | 2017 Dec

REPOSITORIES: biostudies-literature

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IL-11 is a crucial determinant of cardiovascular fibrosis.

Schafer Sebastian S Viswanathan Sivakumar S Widjaja Anissa A AA Lim Wei-Wen WW Moreno-Moral Aida A DeLaughter Daniel M DM Ng Benjamin B Patone Giannino G Chow Kingsley K Khin Ester E Tan Jessie J Chothani Sonia P SP Ye Lei L Rackham Owen J L OJL Ko Nicole S J NSJ Sahib Norliza E NE Pua Chee Jian CJ Zhen Nicole T G NTG Xie Chen C Wang Mao M Maatz Henrike H Lim Shiqi S Saar Kathrin K Blachut Susanne S Petretto Enrico E Schmidt Sabine S Putoczki Tracy T Guimarães-Camboa Nuno N Wakimoto Hiroko H van Heesch Sebastiaan S Sigmundsson Kristmundur K Lim See L SL Soon Jia L JL Chao Victor T T VTT Chua Yeow L YL Tan Teing E TE Evans Sylvia M SM Loh Yee J YJ Jamal Muhammad H MH Ong Kim K KK Chua Kim C KC Ong Boon-Hean BH Chakaramakkil Mathew J MJ Seidman Jonathan G JG Seidman Christine E CE Hubner Norbert N Sin Kenny Y K KYK Cook Stuart A SA

Nature 20171113 7683

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 inte ...[more]

PMID: 29160304

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Project description:Determining the mechanism of senescence-associated pulmonary fibrosis is crucial for designing more effective treatments for chronic lung diseases. This study aimed to determine the following: whether Sirt1 and serum vitamin D decreased with physiological aging, promoting senescence-associated pulmonary fibrosis by activating TGF-β1/IL-11/MEK/ERK signaling, whether Sirt1 overexpression prevented TGF-β1/IL-11/MEK/ERK signaling-mediated senescence-associated pulmonary fibrosis in vitamin D-deficient (Cyp27b1-/- ) mice, and whether Sirt1 downregulated IL-11 expression transcribed by TGF-β1/Smad2 signaling through deacetylating histone at the IL-11 promoter in pulmonary fibroblasts. Bioinformatics analysis with RNA sequencing data from pulmonary fibroblasts of physiologically aged mice was conducted for correlation analysis. Lungs from young and physiologically aged wild-type (WT) mice were examined for cell senescence, fibrosis markers, and TGF-β1/IL-11/MEK/ERK signaling proteins, and 1,25(OH)2 D3 and IL-11 levels were detected in serum. Nine-week-old WT, Sirt1 mesenchymal transgene (Sirt1Tg ), Cyp27b1-/- , and Sirt1Tg Cyp27b1-/- mice were observed the pulmonary function, aging, and senescence-associated secretory phenotype and TGF-β1/IL-11/MEK/ERK signaling. We found that pulmonary Sirt1 and serum vitamin D decreased with physiological aging, activating TGF-β1/IL-11/MEK/ERK signaling, and promoting senescence-associated pulmonary fibrosis. Sirt1 overexpression improved pulmonary dysfunction, aging, DNA damage, senescence-associated secretory phenotype, and fibrosis through downregulating TGF-β1/IL-11/MEK/ERK signaling in Cyp27b1-/- mice. Sirt1 negatively regulated IL-11 expression through deacetylating H3K9/14ac mainly at the region from -871 to -724 of IL-11 promoter, also the major binding region of Smad2 which regulated IL-11 expression at the transcriptional level, and subsequently inhibiting TGF-β1/IL-11/MEK/ERK signaling in pulmonary fibroblasts. This signaling in aging fibroblasts could be a therapeutic target for preventing senescence-associated pulmonary fibrosis induced by vitamin D deficiency.

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IL-11 is a crucial determinant of cardiovascular fibrosis.

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IL-11 is a crucial determinant of cardiovascular fibrosis.

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