title: High-mobility group box 1 (HMGB1)-Toll-like receptor (TLR)4-interleukin (IL)-23-IL-17A axis in drug-induced damage-associated lethal hepatitis: Interaction of γδ T cells with macrophages.
abstract: Acetaminophen overdose causes acute liver inflammation with neutrophil infiltration; however, the mechanism of damage-associated inflammation has not been elucidated. In this study we found that the HMGB1-TLR4-IL-23-IL-17A axis played a crucial role in acetaminophen-induced infiltration of neutrophils and liver injury. Notably, interleukin (IL)-17A and IL-23 significantly increased after acetaminophen challenge. A neutralizing antibody against IL-17A attenuated the recruitment of neutrophils, accompanied by reduced liver injury. Only IL-17A(+) CD3(+) γδ T cell receptor (TCR)(+) cells were significantly increased in the liver, and depletion of γδ T cells, but not CD4(+) T cells or natural killer (NK)T cells significantly reduced IL-17A production, attenuated liver injury, and decreased the number of neutrophils in the liver. Furthermore, a neutralizing IL-23 p19 antibody or p40-deficiency significantly decreased the levels of IL-17A and infiltration of neutrophils. After in vitro stimulation, the percentage of IL-17A-producing γδ T cells and the levels of supernatant IL-17A from total hepatic lymphocytes or purified γδ T cells markedly increased in the presence with IL-23. Importantly, IL-23 and IL-17A were reduced after inhibition of macrophages and could not be induced in Toll-like receptor TLR4(-/-) mice after acetaminophen challenge. Meanwhile, serum high-mobility group box 1 (HMGB1), a damage-associated molecule released from necrotic hepatocytes, increased after acetaminophen challenge, and the HMGB1 inhibitor glycyrrhizin markedly reduced the production of IL-23 and IL-17A and the recruitment of hepatic neutrophils. HMGB1 stimulated the production of IL-23 by TLR4(+/+) but not by TLR4(-/-) macrophages.
  
  
  CONCLUSIONS
  The HMGB1-TLR4-IL-23 pathway in macrophages makes the generation of IL-17-producing γδ T cells, which mediates neutrophil infiltration and damage-induced liver inflammation.
authors: Institute of Immunology, School of Life Sciences, University of Science and Technology of China, Hefei, China.
authors: Xuefu
authors: X
authors: Wang
authors: Rui
authors: R
authors: Sun
authors: Haiming
authors: H
authors: Wei
authors: Zhigang
authors: Z
authors: Tian
mesh_terms: D000082:Acetaminophen; D018712:Analgesics, Non-Narcotic; D000818:Animals; D024243:HMGB1 Protein / Q000097:blood*; D006520:Hepatitis, Animal / Q000139:chemically induced / Q000276:immunology* / Q000378:metabolism; D022781:Hepatocytes / Q000378:metabolism; D020381:Interleukin-17 / Q000378:metabolism; D053759:Interleukin-23 / Q000378:metabolism; D008099:Liver / Q000276:immunology; D008264:Macrophages / Q000378:metabolism*; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D020556:Neutrophil Infiltration; D013601:T-Lymphocytes / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000378:metabolism
chemical_list: D018712:Analgesics, Non-Narcotic; D024243:HMGB1 Protein; C098680:Il17a protein, mouse; D020381:Interleukin-17; D053759:Interleukin-23; C493487:Tlr4 protein, mouse; D051197:Toll-Like Receptor 4; D000082:Acetaminophen