IL-33 signalling in liver immune cells enhances drug-induced liver injury and inflammation

• Published in: Inflammation research Vol. 67; no. 1; pp. 77 - 88
• Main Authors: Antunes, Maísa Mota, Araújo, Alan Moreira, Diniz, Ariane Barros, Pereira, Rafaela Vaz Sousa, Alvarenga, Débora Moreira, David, Bruna Araújo, Rocha, Renata Monti, Lopes, Maria Alice Freitas, Marchesi, Sarah Cozzer, Nakagaki, Brenda Naemi, Carvalho, Érika, Marques, Pedro Elias, Ryffel, Bernhard, Quesniaux, Valérie, Guabiraba Brito, Rodrigo, Filho, José Carlos Alves, Cara, Denise Carmona, Rezende, Rafael Machado, Menezes, Gustavo Batista
• Format: Journal Article
• Language: English
• Published: Cham Springer International Publishing 2018; Springer Nature B.V; Springer Verlag
• Subjects: Acetaminophen; Acetaminophen - toxicity; Allergology; Analgesics; Analgesics, Non-Narcotic - toxicity; Animals; Biomedical and Life Sciences; Biomedicine; Bisphosphonates; Bone marrow; Bone Marrow Transplantation; Chemical and Drug Induced Liver Injury - etiology; Chemical and Drug Induced Liver Injury - immunology; Chemical and Drug Induced Liver Injury - therapy; Chemokines; Chimeras; Chronic lymphocytic leukemia; Clodronic acid; Cytometry; Dermatology; DNA - metabolism; Drug development; Female; Flow cytometry; Hepatocytes; Hepatocytes - immunology; Immune system; Immunofluorescence; Immunology; Inflammation; Inflammation - immunology; Inflammatory response; Injury prevention; Interleukin-1 Receptor-Like 1 Protein - genetics; Interleukin-33 - blood; Interleukin-33 - genetics; Interleukin-33 - immunology; Leukocytes (neutrophilic); Life Sciences; Liposomes; Liver; Liver - cytology; Liver - immunology; Macrophages; Mice; Mice, Inbred BALB C; Mice, Knockout; Microscopy; Neurology; Neutrophils; Neutrophils - immunology; Original Research Paper; Overdose; Pharmacology/Toxicology; Rheumatology; Rodents; Signal Transduction; Signaling; ST2; Leukocytes; Liver necrosis; IL-33; Neutrophils; DAMPs; neutrophil; leucocyte
• ISSN: 1023-3830; 1420-908X
• DOI: 10.1007/s00011-017-1098-3

Objective and design
The aim of this study was to investigate the contribution of IL-33/ST2 axis in the onset and progression of acute liver injury using a mice model of drug-induced liver injury (DILI).
Material and treatments
DILI was induced by overdose administration of acetaminophen (APAP) by oral gavage in wild-type BALB/c, ST2-deficient mice and in different bone marrow chimeras. Neutrophils were depleted by anti-Ly6G and macrophages with clodronate liposomes (CLL).
Methods
Blood and liver were collected for biochemical, immunologic and genetic analyses. Mice were imaged by confocal intravital microscopy and liver non-parenchymal cells and hepatocytes were isolated for flow cytometry, genetic and immunofluorescence studies.
Results
Acetaminophen overdose caused a massive necrosis and accumulation of immune cells within the liver, concomitantly with IL-33 and chemokine release. Liver non-parenchymal cells were the major sensors for IL-33, and amongst them, neutrophils were the major players in amplification of the inflammatory response triggered by IL-33/ST2 signalling pathway.
Conclusion
Blockage of IL-33/ST2 axis reduces APAP-mediated organ injury by dampening liver chemokine release and activation of resident and infiltrating liver non-parenchymal cells.