Transgenic interleukin 11 expression causes cross-tissue fibro-inflammation and an inflammatory bowel phenotype in mice.

Wei-Wen Lim,Nicole Ko,Chen Xie,Sze-Yun Lim,Anissa Widjaja,Liping Su,Benjamin Ng,Xiu-Yi Kwek,Stuart Alexander Cook,Sebastian Schafer,Stella Lim

doi:10.1371/journal.pone.0227505

Abstract

Interleukin 11 (IL11) is a profibrotic cytokine, secreted by myofibroblasts and damaged epithelial cells. Smooth muscle cells (SMCs) also secrete IL11 under pathological conditions and express the IL11 receptor. Here we examined the effects of SMC-specific, conditional expression of murine IL11 in a transgenic mouse (Il11SMC). Within days of transgene activation, Il11SMC mice developed loose stools and progressive bleeding and rectal prolapse, which was associated with a 65% mortality by two weeks. The bowel of Il11SMC mice was inflamed, fibrotic and had a thickened wall, which was accompanied by activation of ERK and STAT3. In other organs, including the heart, lung, liver, kidney and skin there was a phenotypic spectrum of fibro-inflammation, together with consistent ERK activation. To investigate further the importance of stromal-derived IL11 in the inflammatory bowel phenotype we used a second model with fibroblast-specific expression of IL11, the Il11Fib mouse. This additional model largely phenocopied the Il11SMC bowel phenotype. These data show that IL11 secretion from the stromal niche is sufficient to drive inflammatory bowel disease in mice. Given that IL11 expression in colonic stromal cells predicts anti-TNF therapy failure in patients with ulcerative colitis or Crohn's disease, we suggest IL11 as a therapeutic target for inflammatory bowel disease.

Highlights

Non-striated smooth muscle cells (SMCs) line the walls of hollow organs and the vasculature
We generated an Il11SMC mouse model that overexpresses Interleukin 11 (IL11) in myosin heavy chain 11 (Myh11)+ve SMCs: Conditional transgenic mice with mouse Il11 inserted into the Rosa26 locus (Rosa26-Il11-Tg) [8] were crossed with smooth muscle-specific Myh11-cre/ERT2 mice [15] (Fig 1a and 1b)
IL11 is highly upregulated in the colonic mucosa of patients with either ulcerative colitis or Crohn’s disease who do not respond to anti-tumor necrosis factor (TNF) therapy, with recent single cell RNA-seq studies localizing IL11 to inflammatory mucosal stromal cells [32,33,34]

Summary

Introduction

Non-striated smooth muscle cells (SMCs) line the walls of hollow organs and the vasculature. SMCs are not terminally differentiated and their cellular phenotype remains plastic. A variety of extracellular cues such as humoral factors, mechanical or oxidative stress and cellcell interactions can induce a spectrum of cellular states ranging from contractile SMCs to highly synthetic and proliferative SMCs [1]. Synthetic SMCs are associated with a wide variety.

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Conclusion