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 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... More
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 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.
