Back to Search
Start Over
Small Heterodimer Partner Deficiency Increases Inflammatory Liver Injury Through C-X-C motif chemokine ligand 2-Driven Neutrophil Recruitment in Mice
- Source :
- Toxicological Sciences. 163:254-264
- Publication Year :
- 2018
- Publisher :
- Oxford University Press (OUP), 2018.
-
Abstract
- Although detailed pathophysiological mechanisms of fulminant hepatitis remain elusive, immune cell recruitment with excessive cytokine production is a well-recognized hallmark of the disease. We determined the function of orphan nuclear receptor small heterodimer partner (SHP) in concanavalin A (ConA)-induced hepatitis model. Male C57BL/6 J mice were injected intravenously with either a lethal dose (25 mg/kg) or a sub-lethal dose (15 mg/kg) of ConA. For the C-X-C motif chemokine ligand (CXCL) 2 neutralization study, mice were intravenously administered anti-mouse CXCL2 antibody (100 μg/mouse). Thirty-six hours following lethal dose of ConA administration, 47% wild type (WT) mice were alive, whereas >85% of Shp knockout (KO) were dead. Shp KO mice were highly susceptible to ConA-induced liver injury and exhibited increased liver necrosis upon sub-lethal dose of ConA administration. FACS analysis and immunohistochemical staining showed significantly higher neutrophil infiltration in Shp KO mice, as compared with WT mice. We found that also in the WT situation, Shp expression gradually decreased, while Cxcl2 expression increased until 6 h, and vice versa at 24 h upon ConA-treatment, indicating an inverse correlation between Shp and Cxcl2 expression during ConA-induced hepatitis. Furthermore, in vivo neutralization of CXCL2 with neutralizing antibody reduces ConA-induced plasma ALT and AST levels, hepatocyte death and neutrophil infiltration in Shp KO mice. Collectively, these results confirm that lacking of SHP results in CXCL2-dependent neutrophil infiltration in ConA-induced liver damage. SHP plays a protective, anti-inflammatory role in liver during acute liver inflammation.
- Subjects :
- Male
0301 basic medicine
Chemokine
medicine.medical_treatment
Chemokine CXCL2
Receptors, Cytoplasmic and Nuclear
chemical and pharmacologic phenomena
Toxicology
Hepatitis
03 medical and health sciences
Liver Function Tests
Concanavalin A
medicine
Animals
Mice, Knockout
Liver injury
biology
Chemistry
Lethal dose
medicine.disease
Molecular biology
Mice, Inbred C57BL
Disease Models, Animal
CXCL2
030104 developmental biology
Cytokine
medicine.anatomical_structure
Liver
Neutrophil Infiltration
Hepatocyte
biology.protein
Small heterodimer partner
Subjects
Details
- ISSN :
- 10960929 and 10966080
- Volume :
- 163
- Database :
- OpenAIRE
- Journal :
- Toxicological Sciences
- Accession number :
- edsair.doi.dedup.....0312c26ef79e2e263e2bca71a3e42ea1