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.
Hepatology
; 57(1): 373-84, 2013 Jan.
Article
in En
| MEDLINE
| ID: mdl-22821628
ABSTRACT
UNLABELLED 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. CONCLUSION:
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.
Full text:
1
Database:
MEDLINE
Main subject:
T-Lymphocytes
/
Neutrophil Infiltration
/
HMGB1 Protein
/
Hepatitis, Animal
/
Macrophages
Type of study:
Risk_factors_studies
Limits:
Animals
Language:
En
Year:
2013
Type:
Article