11/12/2019
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`A scar-y movie, starring IL-11 | Science Translational Medicine
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`A scar-y movie, starring IL-11
`
`Kevin R. King
`+ See all authors and a¨liations
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`Science Translational Medicine  29 Nov 2017:
`Vol. 9, Issue 418, eaar2443
`DOI: 10.1126/scitranslmed.aar2443
`
`Article
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`Abstract
`IL-11 is found to be a critical mediator of TGFβ1-induced scarring and ¦brosis in the heart and
`kidney.
`
`Fibrosis is considered a largely irreversible process leading to functional decline in a wide range of
`tissues. In the heart, ¦brosis impairs contractile function and electrical conduction causing
`progressive heart failure and fatal arrhythmias. It is also thought to impair cardiac regeneration.
`Transforming growth factor β1 (TGFβ1) is credited with fueling ¦brosis; however, it also has many
`non¦brotic roles that make it an unattractive target for direct inhibition. Therefore, Schafer and
`colleagues set out to identify ¦brosis-selective targets downstream of TGFβ1 signaling and
`discovered a surprising role for interleukin-11 (IL-11), a cytokine best known for its role in
`hematopoiesis.
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`The team began with a screen in which human ¦broblasts were stimulated with TGFβ1 to promote a
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`myo¦broblastic phenotype characterized by upregulation of ¦brosis-related genes and secretion of
`Singapore Exhibit 2002
`extracellular matrix (ECM), the hallmarks of ¦brosis. RNA-seq pro¦ling of the stimulated ¦broblasts
`Lassen v. Singapore et al.
`identi¦ed IL-11 as a gene highly induced by TGFβ1. In a genetic mouse model of cardiac ¦brosis,
`PGR2019-00053
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`A scar-y movie, starring IL-11 | Science Translational Medicine
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`single cell RNA-seq analysis found the most common IL-11–expressing cell type to be ECM-
`producing ¦broblasts. The authors also found that ¦broblasts expressed the IL-11 receptor, IL-11RA,
`suggesting the possibility of an autocrine signaling loop. When stimulated with recombinant IL-11,
`¦broblasts increased ECM production, motility, contraction, and invasion. Moreover, IL-11 “ligand
`traps,” IL-11RA–neutralizing antibodies, or siRNA each decreased TGFβ1-induced ¦brosis in multiple
`assays.
`
`Surprisingly, stimulation of ¦broblasts with IL-11 increased ECM production without altering gene
`expression. The authors therefore designed a series of experiments that led them to propose a
`transcription-independent mechanism in which IL-11 interacts with IL-11RA shed from cellular
`surfaces and signals in trans to induce ECM production and ¦brosis. Exploration of the intracellular
`mechanism revealed that TGFβ1 activated the ERK kinase in an IL-11–dependent fashion and that
`blocking ERK reduced IL-11-induced ¦brotic phenotypes. In vivo, IL-11 was spontaneously increased
`in multiple preclinical models of cardiovascular and renal ¦brosis including angiotensin II infusion,
`transverse aortic constriction in the heart, and folate-induced kidney damage. Administration of
`recombinant IL-11 or expression of IL-11 from a collagen promoter in vivo caused widespread
`¦broblast activation, increased histologic evidence of ¦brosis, and end organ damage with cardiac
`and renal dysfunction. Meanwhile, mice de¦cient in the IL-11 receptor were protected from ¦brosis
`in the same models, pointing to its potential as a target for therapeutic inhibition.
`
`The mechanism by which IL-11 and its receptor signal in trans, and how this relates to ERK-
`dependent ¦brosis, remains unclear. Nevertheless, this study provides many lines of evidence that
`bring IL-11 into focus as a potential therapeutic target to inhibit ¦brosis; a fundamental
`pathophysiologic process a©icting nearly every tissue and underlying a wide range of clinically
`important diseases.
`
`Highlighted Article
`
`S. Schafer, S. Viswanathan, A. A. Widjaja, W.-W. Lim, A. Moreno-Moral, D. M. DeLaughter, B. Ng, G. Patone, K. Chow,
`E. Khin, J. Tan, S. P. Chothani, L. Ye, O. J. L. Rackham, N. S. J. Ko, N. E. Sahib, C. J. Pua, N. T. G. Zhen, C. Xie, M.
`Wang, H. Maatz, S. Lim, K. Saar, S. Blachut, E. Petretto, S. Schmidt, T. Putoczki, N. Guimarães-Camboa, H.
`Wakimoto, S. van Heesch, K. Sigmundsson, S. L. Lim, J. L. Soon, V. T. T. Chao, Y. L. Chua, T. E. Tan, S. M. Evans, Y. J.
`Loh, M. H. Jamal, K. K. Ong, K. C. Chua, B.-H. Ong, M. J. Chakaramakkil, J. G. Seidman, C. E. Seidman, N. Hubner, K.
`Y. K. Sin, S. A. Cook, IL11 is a crucial determinant of cardiovascular ¦brosis. Nature 10.1038/nature24676 (2017).
`
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`Copyright © 2017, American Association for the Advancement of Science
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`11/12/2019
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`A scar-y movie, starring IL-11 | Science Translational Medicine
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`The αvβ1 integrin plays a critical in vivo role in tissue
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`Science Translational Medicine
`Vol 9, Issue 418
`29 November 2017
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`Table of Contents
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