Fibroblast‐specific IL11 signaling drives chronic inflammation in murine fibrotic lung disease

Ng, Benjamin; Dong, Jinqiao; Sivakumar, V.; Widjaja, Anissa A.; Paleja, Bhairav; Adami, Eleonora; Ko, Nicole S. J.; Mao, Wang; Lim, Si Ching; Tan, Jessie; Chothani, Sonia; Albani, Salvatore; Schäfer, Sebastian; Cook, Stuart A.

doi:10.1096/fj.202001045rr

Cited by 58 publications

(56 citation statements)

References 40 publications

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“…Furthermore, inhibition of IL11 in the heart does not appear to feedback onto TGFβ signalling, given that SMAD2/3 activation was unaltered. This is in line with previous results in the cardiac fibroblast, 3 but in contrast to lung fibrosis 4,23 …”

Section: Discussionsupporting

confidence: 93%

Antibody‐mediated neutralization of IL11 signalling reduces ERK activation and cardiac fibrosis in a mouse model of severe pressure overload

Lim

Corden

et al. 2021

Clin Exp Pharma Physio

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Interleukin‐11 (IL11) is important for fibroblast‐to‐myofibroblast transformations. Here, we examined the signalling and phenotypic effects of inhibiting IL11 signalling using neutralizing antibodies against IL11 or its cognate receptor (IL11RA) in a mouse model of acute and severe pressure overload. C57BL/6J mice underwent ascending aortic constriction (AAC) surgery and were randomized to anti‐IL11, anti‐IL11RA, or isotype control antibodies (20 mg/kg, bi‐weekly for 2 weeks). AAC surgery induced the expression of IL11, IL11RA and extracellular matrix (ECM) genes that was associated with cardiac hypertrophy and aortic remodelling. Inhibition of IL11 signalling reduced AAC‐induced cardiac fibrosis and ECM gene expression as well as ERK1/2 phosphorylation but had no effect on cardiac hypertrophy. STAT3 was phosphorylated in the hearts of AAC‐treated mice but this was unrelated to IL11 activity, which we confirmed in mouse cardiac fibroblasts in vitro. These data highlight that blocking IL11 signalling reduces cardiac fibrosis due to severe pressure overload and suggests ERK, but not STAT3, activity as the relevant underlying signalling pathway.

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Section: Discussionsupporting

confidence: 93%

Antibody‐mediated neutralization of IL11 signalling reduces ERK activation and cardiac fibrosis in a mouse model of severe pressure overload

Lim

Corden

et al. 2021

Clin Exp Pharma Physio

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“…Notably, lung IL6 levels in Il11 -/mice were lower than wild type control levels in the absence of lung injury. These data show that Il11 -/mice are protected from BLM-induced lung fibrosis and inflammation, similar to Il11ra1 -/mice, while confirming the importance of IL11stimulated ERK activation for these phenotypes 14,15 .…”

Section: Reduced Expression Of Several Inflammatory Response Genes (Ssupporting

confidence: 69%

Similarities and differences between IL11 and IL11RA1 knockout mice for lung fibro-inflammation, fertility and craniosynostosis

Widjaja

Sivakumar

et al. 2020

Preprint

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Genetic loss of function (LOF) in IL11RA infers IL11 signaling as important for fertility, fibrosis, inflammation and craniosynostosis. The impact of genetic LOF in IL11 has not been characterized. We generated IL11-knockout (Il11-/-) mice, which are born in normal Mendelian ratios, have normal hematological profiles and are protected from bleomycin-induced lung fibro-inflammation. Noticeably, baseline IL6 levels in the lungs of Il11-/- mice are lower than those of wild-type mice and are not induced by bleomycin damage, placing IL11 upstream of IL6. Lung fibroblasts from Il11-/- mice are resistant to pro-fibrotic stimulation and show evidence of reduced autocrine IL11 activity. Il11-/- female mice are infertile. Unlike Il11ra1-/- mice, Il11-/- mice do not have a craniosynostosis-like phenotype and exhibit mildly reduced body weights. These data highlight similarities and differences between LOF in IL11 or IL11RA while establishing further the role of IL11 signaling in fibrosis and stromal inflammation.

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“…6 and 8). Expression of IL11RA on parenchymal and stromal cells, but not immune cells 14 , suggests that the beneficial effects on inflammation associated with IL11 inhibition are indirect, as seen recently by proinflammatory fibroblasts 48 .…”

Section: Discussionmentioning

confidence: 93%

Interleukin-11 is important for vascular smooth muscle phenotypic switching and aortic inflammation, fibrosis and remodeling in mouse models

Lim

Corden

et al. 2020

Sci Rep

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Transforming growth factor beta-1 (TGFβ1) is a major driver of vascular smooth muscle cell (VSMC) phenotypic switching, an important pathobiology in arterial disease. We performed RNA-sequencing of TGFβ1-stimulated human aortic or arterial VSMCs which revealed large and consistent upregulation of Interleukin 11 (IL11). IL11 has an unknown function in VSMCs, which highly express the IL11 receptor alpha, suggestive of an autocrine loop. In vitro, IL11 activated ERK signaling, but inhibited STAT3 activity, and caused VSMC phenotypic switching to a similar extent as TGFβ1 or angiotensin II (ANGII) stimulation. Genetic or therapeutic inhibition of IL11 signaling reduced TGFβ1- or ANGII-induced VSMC phenotypic switching, placing IL11 activity downstream of these factors. Aortas of mice with Myh11-driven IL11 expression were remodeled and had reduced contractile but increased matrix and inflammatory genes expression. In two models of arterial pressure loading, IL11 was upregulated in the aorta and neutralizing IL11 antibodies reduced remodeling along with matrix and pro-inflammatory gene expression. These data show that IL11 plays an important role in VSMC phenotype switching, vascular inflammation and aortic pathobiology.

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Fibroblast‐specific IL11 signaling drives chronic inflammation in murine fibrotic lung disease

Cited by 58 publications

References 40 publications

Antibody‐mediated neutralization of IL11 signalling reduces ERK activation and cardiac fibrosis in a mouse model of severe pressure overload

Antibody‐mediated neutralization of IL11 signalling reduces ERK activation and cardiac fibrosis in a mouse model of severe pressure overload

Similarities and differences between IL11 and IL11RA1 knockout mice for lung fibro-inflammation, fertility and craniosynostosis

Interleukin-11 is important for vascular smooth muscle phenotypic switching and aortic inflammation, fibrosis and remodeling in mouse models

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