Inhibiting Interleukin 11 Signaling Reduces Hepatocyte Death and Liver Fibrosis, Inflammation, and Steatosis in Mouse Models of Non-Alcoholic Steatohepatitis

Abstract

BACKGROUND & AIMS:

We studied the role of interleukin 11 (IL11) signaling in the pathogenesis of nonalcoholic steatohepatitis using hepatic stellate cells (HSCs), hepatocytes, and mouse models of non-alcoholic steatohepatitis (NASH).

METHODS:

We stimulated mouse and human fibroblasts, HSCs, or hepatocytes with IL11 and other cytokines and analyzed them by imaging, immunoblot, and functional assays and ELISAs. Mice were given injections of IL11. Mice with disruption of the interleukin 11 receptor subunit alpha gene (Il11ra1-/-) mice and Il11ra1+/+ mice were fed a high-fat methionine- and choline-deficient diet (HFMCD) or a Western diet with liquid fructose (WDF) to induce steatohepatitis; control mice were fed normal chow. db/db mice were fed with MCD for 12 weeks and C57BL/6 NTac were fed with HFMCD for 10 weeks or WDF for 16 weeks. Some mice were given intraperitoneal injections of anti-IL11 (X203), anti-IL11RA (X209), or a control antibody at different timepoints on the diets. Livers and blood were collected; blood samples were analyzed by biochemistry and liver tissues were analyzed by histology, RNA-seq, immunoblots, immunohistochemistry, hydroxyproline, and mass cytometry time of flight assays.

RESULTS:

HSCs incubated with cytokines produced IL11, resulting in activation (phosphorylation) of ERK and expression of markers of fibrosis. Livers of mice given injections of IL11 became damaged, with increased markers of fibrosis and inflammation. Following the HFMCD or WDF, livers from Il11ra1-/- mice had reduced steatosis, fibrosis, expression of markers of inflammation and steatohepatitis, and lower levels of serum lipids and glucose compared to and Il11ra1+/+ mice on the same diets. Depending on the time of administration of anti-IL11 or anti-IL11RA to wild-type mice on the HFMCD or WDF, or to db/db mice on the MCD, the antibodies prevented, stopped, or reversed development of fibrosis and steatosis. Blood samples from Il11ra1+/+ mice fed the HFMCD or WDF and given injections of anti-IL11 or anti-IL11RA, as well as from Il11ra1-/- mice fed the diets, had lower serum levels of lipids and glucose than mice not injected with antibody or with disruption of Il11ra1.

CONCLUSIONS:

Neutralizing antibodies that block IL11 signaling reduce fibrosis, steatosis, hepatocyte death, inflammation and hyperglycemia in mice with diet-induced steatohepatitis. These antibodies improve the cardiometabolic profile of mice and might be developed for treatment of NASH.

 2019 May 8. pii: S0016-5085(19)40858-5. doi: 10.1053/j.gastro.2019.05.002. [Epub ahead of print]