IL-11 is a therapeutic target in idiopathic pulmonary fibrosis

Abstract

Abstract:Idiopathic pulmonary fibrosis (IPF) remains a progressive disease despite best medical management. We previously identified IL-11 as a critical factor for cardiovascular fibrosis and examine here its role in pulmonary fibrosis. IL-11 is consistently upregulated in IPF genomic datasets, which we confirmed by histology. Pulmonary fibroblasts stimulated with IL-11 transform into invasive myofibroblasts whereas fibroblasts from Il11ra deleted mice did not respond to pro-fibrotic stimuli. In the mouse, injection of recombinant Il-11 or fibroblast-specific expression of Il-11 caused pulmonary fibrosis. We then generated a neutralising IL-11 binding antibody that blocks lung fibroblast activation across species. In a mouse model of IPF, anti-IL-11 therapy attenuated lung fibrosis and specifically blocked Erk activation. These data prioritise IL-11 as an accessible drug target in IPF. One Sentence Summary:Non-canonical IL-11 signalling is a central hallmark of idiopathic pulmonary fibrosis and represents a novel target for antibody therapies. Main Text:Idiopathic pulmonary fibrosis (IPF) is a progressive fibrotic lung disease that is characterised by epithelial injury and activation of invasive fibroblasts that deposit and remodel extracellular matrix (ECM) destroying tissue integrity (1, 2). Aging, genetic and environmental factors are known to trigger IPF but the underlying pathological mechanisms remain poorly characterised (2). Anti-inflammatory agents do not improve clinical outcomes (3-5), emphasizing the central role of fibroblast biology in IPF. Two anti-fibrotic drugs, nintedanib (6) and pirfenidone (7), are approved for the treatment of IPF but have notable toxicities (2) and despite best medical practice IPF remains a fatal disease and an unmet clinical need. Unfortunately recent clinical trials in IPF have not shown efficacy and new approaches based on a better understanding of disease biology are needed (8).Transforming growth factor-beta 1 (TGFβ1) is considered the principal pro-fibrotic cytokine and plays an important role in lung fibrosis (9), but TGFβ1-targeting therapies have marked side effects due to the pleiotropic roles of TGFβ1 in diverse cell types (8, 10). We recently screened for fibroblast-specific mediators of TGFβ1 activity in human cardiac fibroblasts and identified interleukin-11 (IL-11) as a crucial fibroblast-specific factor for cardiovascular fibrosis (11). In the lung there is conflicting literature for IL-11 that suggests it may either promote (12) or protect (13, 14) against lung damage, inflammation and/or fibrosis. Likely because of these discrepancies, the study of IL-11 biology in the lung has not progressed over the past decades. In recent genome wide studies IL-11 was found to be the most upregulated gene in fibroblasts from patients with IPF (15) but this chance observation was not explored further. Here we examined the hypothesis that IL-11 may be important for lung fibroblast activation and the pathobiology of IPF.. CC-BY-ND 4.0 International license It is made avai...

Interleukin 11 expression causes murine inflammatory bowel disease

“…We recently identified IL11 as a critical driver of fibroblast activation in the cardiovascular system, liver and lung downstream of a variety of pro-fibrotic factors including TGFB1 [8][9][10].…”

“…However, we recently showed that the IL11 effect, both in vitro in fibroblasts and in vivo at the tissue level, is also dependent on non-canonical signaling via extracellular signalregulated kinase (ERK) [8][9][10]. To investigate both canonical and non-canonical signaling pathways after Il11 expression, we performed western blotting of phosphorylated (p) STAT3 or ERK1/2 and total protein levels and derived indices of kinase activation by normalising phosphorylation amounts to total protein levels (Fig 3 and Supplementary Figure 3).…”

“…We have previously described a model of Il11 expression in fibroblasts (Il11 Fib ) that drives fibrosis in the heart, kidney, and lung [8,9]. To examine further the effect of Il11 expression in stromal cells on the colon, we studied colonic phenotypes in this second model of Il11 expression from the stromal niche (Fig 7a).…”

“…To model fibroblasts-selective secretion of IL11 in vivo, we crossed the heterozygous Rosa26-IL11 mice with Col1a2-CreER mice [34] to generate double heterozygous Col1a2-CreER:Rosa26-Il11 mice (referred to as Il11 Fib ) [9]. For Cre-mediated Il11 transgene induction, Il11 Fib mice were intraperitoneal injected with 50 mg kg -1 tamoxifen at 6 weeks of age for 10 consecutive days and the animals were sacrificed on day 21.…”

“…Both these cellular transitions are characterized by extracellular matrix (ECM) production, cell proliferation, invasion and migration. They can also be triggered by the same extracellular cues including TGFB family members [1,7].We recently identified IL11 as a critical driver of fibroblast activation in the cardiovascular system, liver and lung downstream of a variety of pro-fibrotic factors including TGFB1 [8][9][10].In a study from 1999, IL11 was also found to be secreted by vascular SMCs (VSMCs) in response to pathogenic stimuli, including interleukin 1 alpha (IL1A), TGFB and tumor necrosis factor (TNF) [11]. Although IL11 is upregulated in systemic sclerosis [6], TNFresistant ulcerative colitis [12,13] and asthma [14] and despite SMCs being a source of IL11[11], the effect of IL11 function in SMC biology has not been studied.…”