Hepatocyte-specific deletion of IL1-RI attenuates liver injury by blocking IL-1 driven autoinflammation

Background & Aims: Interleukin (IL)-1-type cytokines including IL-1 alpha, IL-1 beta and interleukin-1 receptor antagonist (IL-1Ra) are among the most potent molecules of the innate immune system and exert biological activities through the ubiquitously expressed interleukin-1 receptor type 1 (IL-1R1). The role of IL-1R1 in hepatocytes during acute liver failure (ALF) remains undetermined. Methods: The role of IL-1R1 during ALF was investigated using a novel transgenic mouse model exhibiting deletion of all signaling-capable IL-1R isoforms in hepatocytes (Il1r1(Hep-/-)). Results: ALF induced by D-galactosamine (D-GalN) and lipopolysaccharide (LPS) was significantly attenuated in Il1r1(Hep-/-) mice leading to reduced mortality. Conditional deletion of Il1r1 decreased activation of injurious c-Jun N-terminal kinases (JNK)/c-Jun signaling, activated nuclear factor-kappa B (NF-kappa B) p65, inhibited extracellular signal-regulated kinase (ERK) and prevented caspase 3-mediated apoptosis. Moreover, Il1r1(Hep-/-) mice exhibited reduced local and systemic inflammatory cytokine and chemokine levels, especially TNF-alpha, IL1 alpha/beta, IL-6, CC-chemokine ligand 2 (CCL2), C-X-C motif ligand 1 (CXCL-1) and CXCL-2, and a reduced neutrophil recruitment into the hepatic tissue in response to injury. NLRP3 inflammasome expression and caspase 1 activation were suppressed in the absence of the hepatocellular IL-1R1. Inhibition of IL-1R1 using IL-1 alpha (anakinra) attenuated the severity of liver injury, while IL-1 alpha administration exaggerated it. These effects were lost ex vivo and at later time points, supporting a role of IL-1R1 in inflammatory signal amplification during acute liver injury. Conclusion: IL-1R1 in hepatocytes plays a pivotal role in an IL1-driven auto-amplification of cell death and inflammation in the onset of ALF. (C) 2018 European Association for the Study of the Liver. Published by Elsevier B.V. All rights reserved.