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- Title
Agalactosyl IgG induces liver fibrogenesis via Fc gamma receptor 3a on human hepatic stellate cells.
- Authors
Ho, Cheng‐Hsun; Chang, Ting‐Tsung; Lin, Hsien‐Chang; Wang, Sheng‐Fan
- Abstract
The relevance of aberrant serum IgG N‐glycosylation in liver fibrosis has been identified; however, its causal effect remains unclear. Because hepatic stellate cells (HSCs) contribute substantially to liver fibrosis, we investigated whether and through which mechanisms IgG N‐glycosylation affects the fibrogenic properties of HSCs. Analysis of serum IgG1N‐glycome from 151 patients with chronic hepatitis B or liver cirrhosis revealed a positive correlation between Ishak fibrosis grading and IgG1 with agalactosyl N‐glycoforms on the crystallizable fragment (Fc). Fc gamma receptor (FcγR) IIIa was observed in cultured human HSCs and HSCs in human liver tissues, and levels of FcγRIIIa in HSCs correlated with the severity of liver fibrosis. Additionally, agalactosyl IgG treatment caused HSCs to have a fibroblast‐like morphology, enhanced migration and invasion capabilities, and enhanced expression of the FcγRIIIa downstream tyrosine‐protein kinase SYK. Furthermore, agalactosyl IgG treatment increased fibrogenic factors in HSCs, including transforming growth factor (TGF)‐β1, total collagen, platelet‐derived growth factor subunit B and its receptors, pro‐collagen I‐α1, α‐smooth muscle actin, and matrix metalloproteinase 9. These effects were more pronounced in HSCs that stably expressed FCGR3A and were reduced in FCGR3A knockout cells. Agalactosyl IgG and TGF‐β1 each increased FCGR3A in HSCs. Furthermore, serum TGF‐β1 concentrations in patients were positively correlated with agalactosyl IgG1 levels and liver fibrosis severity, indicating a positive feedback loop involving agalactosyl IgG, HSC‐FcγRIIIa, and TGF‐β1. In conclusion, agalactosyl IgG promotes fibrogenic characteristics in HSCs through FcγRIIIa. © 2024 The Pathological Society of Great Britain and Ireland.
- Subjects
LIVER cells; FC receptors; PLATELET-derived growth factor; HEPATIC fibrosis; IMMUNOGLOBULIN G
- Publication
Journal of Pathology, 2024, Vol 263, p508
- ISSN
0022-3417
- Publication type
Article
- DOI
10.1002/path.6303