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

Abstract

Acetaminophen (N-acetyl-p-aminophenol; APAP) toxicity is a common cause of liver damage. In the mouse model of APAP-induced liver injury (AILI), interleukin 11 (IL11) is highly up-regulated and administration of recombinant human IL11 (rhIL11) has been shown to be protective. Here, we demonstrate that the beneficial effect of rhIL11 in the mouse model of AILI is due to its inhibition of endogenous mouse IL11 activity. Our results show that species-matched IL11 behaves like a hepatotoxin. IL11 secreted from APAP-damaged human and mouse hepatocytes triggered an autocrine loop of NADPH oxidase 4 (NOX4)–dependent cell death, which occurred downstream of APAP-initiated mitochondrial dysfunction. Hepatocyte-specific deletion of Il11 receptor subunit alpha chain 1 (Il11ra1) in adult mice protected against AILI despite normal APAP metabolism and glutathione (GSH) depletion. Mice with germline deletion of Il11 were also protected from AILI, and deletion of Il1ra1 or Il11 was associated with reduced c-Jun N-terminal kinase (JNK) and extracellular signal–regulated kinase (ERK) activation and quickly restored GSH concentrations. Administration of a neutralizing IL11RA antibody reduced AILI in mice across genetic backgrounds and promoted survival when administered up to 10 hours after APAP. Inhibition of IL11 signaling was associated with the up-regulation of markers of liver regenerations: cyclins and proliferating cell nuclear antigen (PCNA) as well as with phosphorylation of retinoblastoma protein (RB) 24 hours after AILI. Our data suggest that species-matched IL11 is a hepatotoxin and that IL11 signaling might be an effective therapeutic target for APAP-induced liver damage.

Similarities and differences between IL11 and IL11RA1 knockout mice for lung fibro-inflammation, fertility and craniosynostosis

“…It was surprising to observe differences in skull morphology and bone phenotypes between Il11 − / − and that published, and replicated by us, for Il11ra1 − / − genotypes, both maintained on C57BL/6J backgrounds. This said, it was recently shown that Ccl27 expression may be disrupted at the Il11ra1 locus in Il11ra1 − / − mice 19 although this is unrelated to the craniosynostosis phenotypes seen in humans with bi-allelic IL11RA LOF mutations. The fact that Il11 − / − mice do not have snout deformities implies that this is unrelated to the loss of IL11 signaling per se.…”

Molecular Dissection of Pro-Fibrotic IL11 Signaling in Cardiac and Pulmonary Fibroblasts

“…To study the functional relevance of TGFβ1-or IL11-induced ERK and/or STAT3 activation, we stimulated HCFs with TGFβ1 in the presence of neutralizing IL11 or IL11RA antibodies that were developed to inhibit fibroblast activation (in vitro) and fibrosis phenotypes (in vivo), agnostic of the underlying pathways (Widjaja et al, 2019;Widjaja et al, 2021). In TGFβ1-stimulated HCFs, inhibition of IL11 signaling using either anti-IL11 or anti-IL11RA prevented ERK phosphorylation (at the 24 h time point) but had no effect on STAT3 activity (Figure 1C).…”

The TGF-β/NADPH Oxidases Axis in the Regulation of Liver Cell Biology in Health and Disease

“…In the same line of evidence, therapeutic blocking NOX1/4 with GKT137831 ameliorated cholestatic fibrosis in Mdr2−/− mice [172]. Furthermore, GKT137831 treatment also prevented liver inflammation after CCl 4 injection [124] and protected from GSH depletion, caspase-3 cleavage and hepatocyte death in acetaminophen-induced liver injury [173]. In a phase 2 clinical trial, GKT137831 was found to be safe and well tolerated (https://clinicaltrials.gov/ct2/show/NCT02010242, accessed on 7 July 2021).…”