RT Journal Article
SR Electronic
T1 IL-11 neutralising therapies target hepatic stellate cell-induced liver inflammation and fibrosis in NASH
JF bioRxiv
FD Cold Spring Harbor Laboratory
SP 470062
DO 10.1101/470062
A1 Anissa A. Widjaja
A1 Brijesh K. Singh
A1 Eleonora Adami
A1 Sivakumar Viswanathan
A1 Giuseppe A. D’Agostino
A1 Jinrui Dong
A1 Benjamin Ng
A1 Jessie Tan
A1 Bhairav S. Paleja
A1 Madhulika Tripathi
A1 Sze Yun Lim
A1 Sonia P. Chothani
A1 Wei Wen Lim
A1 Anne Rabes
A1 Martina Sombetzki
A1 Eveline Bruinstroop
A1 Rohit A. Sinha
A1 Salvatore Albani
A1 Paul M. Yen
A1 Sebastian Schafer
A1 Stuart A. Cook
YR 2018
UL http://biorxiv.org/content/early/2018/11/14/470062.abstract
AB 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 TGFβ1 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.