Research ArticleLIVER INJURY

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

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Science Translational Medicine  09 Jun 2021:
Vol. 13, Issue 597, eaba8146
DOI: 10.1126/scitranslmed.aba8146

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A matter of species specificity

Acetaminophen (APAP) overdose can cause liver injury; effective therapies for treating APAP poisoning beyond 8 hours after ingestion are lacking. Recombinant human interleukin 11 (rhIL11) protected rodents from liver injury; however, recent studies produced results that question the underlying mechanism. Here, Widjaja et al. used a mouse model of APAP-induced liver injury and showed that species-matched IL11 was detrimental in mice, causing hepatocyte cell death. Genetic IL11 deletion protected mice from liver damage and administration of an antibody targeting IL11 receptor reduced APAP-induced toxicity even when administered 10 hours after APAP. The results suggest that IL11 might be detrimental for hepatocytes. Additional studies will clarify the translational potential of targeting IL11 for treating liver injury.


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.

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