Redefining IL11 as a regeneration-limiting hepatotoxin and therapeutic target in acetaminophen-induced liver injury

Acetaminophen (APAP) toxicity is a leading cause of liver failure. In the mouse model of APAP-induced liver injury (AILI), IL11 is upregulated and the administration of recombinant human interleukin 11 (rhIL11) is protective. Here we show that the beneficial effect of rhIL11 in the mouse is due to its unexpected and paradoxical inhibition of endogenous mouse IL11 activity. Contrary to the accepted paradigm, IL11 is a hepatotoxin and is secreted from APAP damaged hepatocytes to drive an autocrine loop of NOX4-dependent cell death. Mice with hepatocyte-specific Il11ra1 deletion are protected from AILI despite normal APAP metabolism and glutathione depletion. Mice null for IL11 are also protected. Neutralizing IL11RA antibodies reduce AILI in male and female mice across genetic backgrounds and promote survival. Inhibition of IL11 signalling in AILI is associated with liver regeneration. Our data challenge the idea that IL11 is hepato-protective and suggest IL11 signaling as a therapeutic target in AILI