Please use this identifier to cite or link to this item: https://doi.org/10.1126/scitranslmed.aba8146
Title: Redefining IL11 as a regeneration-limiting hepatotoxin and therapeutic target in acetaminophen-induced liver injury
Authors: Widjaja, Anissa A 
Dong, Jinrui 
Adami, Eleonora 
Viswanathan, Sivakumar
Ng, Benjamin
Pakkiri, Leroy S
Chothani, Sonia P
Singh, Brijesh K 
Lim, Wei Wen 
Zhou, Jin
Shekeran, Shamini G
Tan, Jessie 
Lim, Sze Yun
Goh, Joyce
Wang, Mao
Holgate, Robert
Hearn, Arron
Felkin, Leanne E
Yen, Paul M
Dear, James W
Drum, Chester L 
Schafer, Sebastian 
Cook, Stuart A 
Keywords: Science & Technology
Life Sciences & Biomedicine
Cell Biology
Medicine, Research & Experimental
Research & Experimental Medicine
INTERLEUKIN-11 RECEPTOR
PROTECTS
MICE
APOPTOSIS
FAILURE
ADULT
Issue Date: 9-Jun-2021
Publisher: AMER ASSOC ADVANCEMENT SCIENCE
Citation: Widjaja, Anissa A, Dong, Jinrui, Adami, Eleonora, Viswanathan, Sivakumar, Ng, Benjamin, Pakkiri, Leroy S, Chothani, Sonia P, Singh, Brijesh K, Lim, Wei Wen, Zhou, Jin, Shekeran, Shamini G, Tan, Jessie, Lim, Sze Yun, Goh, Joyce, Wang, Mao, Holgate, Robert, Hearn, Arron, Felkin, Leanne E, Yen, Paul M, Dear, James W, Drum, Chester L, Schafer, Sebastian, Cook, Stuart A (2021-06-09). Redefining IL11 as a regeneration-limiting hepatotoxin and therapeutic target in acetaminophen-induced liver injury. SCIENCE TRANSLATIONAL MEDICINE 13 (597). ScholarBank@NUS Repository. https://doi.org/10.1126/scitranslmed.aba8146
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.
Source Title: SCIENCE TRANSLATIONAL MEDICINE
URI: https://scholarbank.nus.edu.sg/handle/10635/226666
ISSN: 19466234
19466242
DOI: 10.1126/scitranslmed.aba8146
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