A study published in Nature provides new insights into the molecular mechanisms of fibrosis, a common pathology in cardiovascular and renal diseases that leads to impaired organ function, such as mechanical and electrical dysfunction in the heart, and which currently has no specific treatment. Stuart Cook and colleagues show that the cytokine IL-11 is crucial in the pathogenesis of cardiovascular fibrosis. “We found that IL-11 is the dominant transcriptional response to transforming growth factor β1 (TGFβ1) stimulation in fibroblasts and that IL-11 is needed for the profibrotic action of TGFβ1 and other profibrotic factors,” says Cook.
Although TGFβ1 is known to be an important profibrotic factor, targeting either TGFβ1 or its receptor has severe adverse effects because TGFβ1 has pleiotropic roles and important functions not only in fibroblasts, but also in many other cell types, including immune cells. Therefore, “we developed an imaging–genomic target discovery platform to search for new druggable targets acting downstream of TGFβ1 that we hoped would be just as effective as inhibiting TGFβ1, but lacking its associated toxicities,” explains Cook.
The research team used an approach that involved automated quantification of myofibroblast numbers and extracellular matrix production (characteristic features of fibrosis), together with RNA sequencing in cultures of primary human fibroblasts with or without stimulation with TGFβ1. The dominant transcriptional response to TGFβ1 exposure was upregulation of IL11. Both IL11 and its receptor IL11RA were expressed specifically in fibroblasts, a finding that was confirmed in in vivo single-cell RNA sequencing assays.
Next, the investigators demonstrated that IL-11 is needed for the profibrotic effect of TGFβ1. Neutralizing anti-IL-11 antibodies, ligand traps (generated by fusing IL-11RA and gp130), and blockade of IL-11RA (with receptor-blocking antibodies or with small interfering RNA) all diminished the profibrotic effect of TGFβ1 in different fibrosis assays. Activation of IL-11 signalling in cardiac fibroblasts had effects mainly at the protein level, through the activation of noncanonical, ERK-dependent autocrine signalling, but had negligible effects on the transcriptome.
In mice, fibroblast-specific expression of Il11 or injection of mouse recombinant IL-11 induced heart and kidney fibrosis and eventual organ failure. By contrast, deletion of Il11ra1 protected against development of the fibrosis in mouse models of cardiac or kidney disease. In addition to TGFβ1, the researchers tested the response of cardiac fibroblasts to other profibrotic factors, including endothelin 1, angiotensin II, and platelet-derived growth factor. IL-11 was required for fibroblast activation with all the profibrotic stimuli.
“inhibition of IL-11 prevented fibroblast activation in the heart and kidneys in response to a range of profibrotic stimuli”
In summary, inhibition of IL-11 prevented fibroblast activation in the heart and kidneys in response to a range of profibrotic stimuli, indicating that IL-11 has an essential role in fibrosis. According to Cook, there are two main reasons why the importance of IL-11 in fibrosis has passed unnoticed until now. “One reason is that IL-11 was mischaracterized by a previous paper in which the authors proposed IL-11 to be antifibrotic,” explains Cook. This study used recombinant human IL-11 in mouse models; however, Cook and colleagues found that human IL-11 is largely ineffective in mouse cardiac fibroblasts. “Another reason is that the action of IL-11 is at the level of profibrotic protein translation,” says Cook. “Many people use gene transcription as a primary read-out of function, but the effects of IL-11 in fibroblasts cannot be detected this way.”
The research team is now in the process of developing products to target IL-11 in fibrotic diseases. “We strongly believe that inhibiting IL-11 will be effective in treating a range of conditions in the heart, lung, liver, kidney, skin, and eye,” says Cook. “Heart failure (systolic and diastolic) and arrhythmias such as atrial fibrillation are high on the list of target diseases.”
Schafer, S. et al. IL11 is a crucial determinant of cardiovascular fibrosis. Nature http://dx.doi.org/10.1038/nature24676 (2017)
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Fernández-Ruiz, I. IL-11 is a potential therapeutic target in cardiovascular fibrosis. Nat Rev Cardiol 15, 1 (2018). https://doi.org/10.1038/nrcardio.2017.197