IL-11 neutralising therapies target hepatic stellate cell-induced liver inflammation and fibrosis in NASH

Widjaja, A. A.; Singh, B. K.; Adami, E.; Viswanathan, S.; D'Agostino, G. A.; Dong, J. R.; Ng, B.; Tan, J.; Paleja, B. S.; Tripathi, M.; Lim, S. Y.; Chothani, S.; Lim, W. W.; Rabes, A.; Sombetzki, M.; Bruinstroop, E.; Sinha, R. A.; Albani, S.; Yen, P. M.; Schafer, S.; Cook, S. A.

doi:10.1101/470062

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bioRxiv · 10.1101/470062

IL-11 neutralising therapies target hepatic stellate cell-induced liver inflammation and fibrosis in NASH

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Abstract

The transformation of hepatic stellate cells (HSCs) into myofibroblasts is the defining pathobiology in non-alcoholic steatohepatitis (NASH). Here we show that key NASH factors induce IL-11, which drives an autocrine and ERK-dependent activation loop to initiate and maintain HSC-to-myofibroblast transformation, causing liver fibrosis. IL-11 is upregulated in NASH and Il11ra1-deleted mice are strongly protected from liver fibrosis, inflammation and steatosis in murine NASH. Therapeutic inhibition of IL11RA or IL-11 with novel neutralizing antibodies robustly inhibits NASH pathology in preclinical models and reverses established liver fibrosis by promoting HSC senescence and favourable matrix remodelling. When given early in NASH, IL-11 inhibition prevents liver inflammation and steatosis, reverses severe hepatocyte damage and reduces hepatic immune cells and TGF{beta}1 levels. Our findings show an unappreciated and central role for IL-11 in HSCs and prioritise IL-11 signalling as a new therapeutic target in NASH while revealing an unexpected pro-inflammatory function for IL-11 in stromal immunity.

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Widjaja, A. A., Singh, B. K., Adami, E., Viswanathan, S., D'Agostino, G. A., Dong, J. R., Ng, B., Tan, J., Paleja, B. S., Tripathi, M., Lim, S. Y., Chothani, S., Lim, W. W., Rabes, A., Sombetzki, M., Bruinstroop, E., Sinha, R. A., Albani, S., Yen, P. M., Schafer, S., Cook, S. A.. 2018-11-14. IL-11 neutralising therapies target hepatic stellate cell-induced liver inflammation and fibrosis in NASH. https://doi.org/10.1101/470062

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