IL-11 in cardiac and renal fibrosis: Late to the party but a central player

Abstract

Fibrosis is a pathophysiological hallmark of cardiorenal disease. In the heart, fibrosis leads to contractile dysfunction and arrhythmias; in the kidney, it is the final common pathway for many diseases and predicts end-stage renal failure. Despite this, there are currently no specific anti-fibrotic treatments available for cardiac or renal disease. Recently and unexpectedly, IL-11 was found to be of major importance for cardiorenal fibroblast activation and fibrosis. In mouse models, IL-11 overexpression caused fibrosis of the heart and kidney while genetic deletion of Il11ra1 protected against fibrosis and preserved organ function. Neutralizing antibodies against IL-11 or IL-11RA have been developed that have anti-fibrotic activity in human fibroblasts and protect against fibrosis in murine models of disease. While IL-11 biology has been little studied and, we suggest, largely misunderstood, its autocrine activity in myofibroblasts appears non-redundant for fibrosis, which offers new opportunities to better understand and potentially target cardiorenal fibrosis.

Figure 1

Overview of heart and kidney diseases defined by fibrosis and the consequent effects on organ function

Figure 2

In fibroblasts, IL‐11 acts at a point of signalling convergence downstream of multiple and diverse stimuli and is the nexus between pro‐fibrotic initiating factors and organ fibrosis. ANG II, angiotensin II; bFGF, basic FGF; CTGF, connective tissue growth factor; ET‐1, endothelin 1; OSM, oncostatin M

Figure 3

Putative IL‐11 signalling pathways in fibroblasts. In contrast to TGFβ (and other upstream pro‐fibrotic stimuli), IL‐11 has a negligible effect on transcription in fibroblasts. Instead, IL‐11 signals via ERK to enhance translation of pro‐fibrotic proteins while also possibly employing EPRS activation to translate proline rich proteins where ribosomes can stall on proline repeat regions (PRRs). ACTA2, actin α2 (aka smooth muscle actin); COL1A2, collagen type 1 α2; eIF4E, eurkaryotic translation initiation factor 4E; EPRS, glutamyl‐prolyl‐tRNA synthetase; gp130, glycoprotein 130; IL‐11RA: IL‐11 receptor α; MNK, MAPK‐interacting serine/threonine‐protein kinase 1; p90RSK, p90 ribosomal S6 kinase; POSTN, periostin; TGFβ Rec, TGF β receptor