IL-11 is a crucial determinant of cardiovascular fibrosis
Sebastian Schafer, Sivakumar Viswanathan, Anissa A. Widjaja, Wei-Wen Lim, Aida Moreno-Moral, Daniel M. DeLaughter, Benjamin Ng, Giannino Patone, Kingsley Chow, Ester Khin, Jessie Tan, Sonia P. Chothani, Lei Ye, Owen J. L. Rackham, Nicole S. J. Ko, Norliza E. Sahib, Chee Jian Pua, Nicole T. G. Zhen, Chen Xie, Mao Wang, Henrike Maatz, Shiqi Lim, Kathrin Saar, Susanne Blachut, Enrico Petretto, Sabine Schmidt, Tracy Putoczki, Nuno Guimarães-Camboa, Hiroko Wakimoto, Sebastiaan van Heesch, Kristmundur Sigmundsson, See L. Lim, Jia L. Soon, Victor T. T. Chao, Yeow L. Chua, Teing E. Tan, Sylvia M. Evans, Yee J. Loh, Muhammad H. Jamal, Kim K. Ong, Kim C. Chua, Boon-Hean Ong, Mathew J. Chakaramakkil, Jonathan G. Seidman, Christine E. Seidman, Norbert Hubner, Kenny Y. K. Sin, and Stuart A. Cook
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.