Picroside II prevents HSC activation and liver fibrosis in Mdr2-/- mice
by polarizing M1 macrophages and balancing immune responses
Abstract
Background and Purpose: Macrophages are central immune characters in
hepatic fibrosis by reconstructing the fibrotic immune microenvironment.
Picroside II (PIC II) has exerted a therapeutic potential on liver
injury. However, the mechanisms by which macrophage initiates immune
cascades and further contributes to liver fibrosis and whether this
process can be influenced by PIC II remains unclear. Experimental
Approach: In this research, the RNA sequencing of multidrug-resistance
protein 2 knockout (Mdr2-/-) mice was applied. Then aHSCs were incubated
with the medium from M1 macrophages and NK cells, with the extra
formation of neutrophils extracellular traps (NETs) being tested. In
addition, we intraperitoneal injected PIC II and then intravenously
injected the clodronate liposome to evaluate the therapeutic effect of
PIC II and macrophage deletion in Mdr2-/- mice. Key Results: We observed
the increase of CXCL16+ M1 macrophages in Mdr2-/- liver, accompanied by
the recruitment of CXCR6+ NK cells and NETs formation. PIC II promoted
the CXCL16+ macrophage recruited NK cells via CXCL16/CXCR6 axis, which
subsequently affecting the JAK1/STAT1 signaling in aHSCs. And fibrotic
liver was relieved to some extent when PIC II combined with macrophage
depletion. Conclusion and Implications: Mechanistically, PIC II
activated M1 macrophage to recruit NK cells via CXCL16-CXCR6 axis and
subsequently regulated the JAK1/STAT1 signaling to restrain aHSCs. PIC
II also alleviated fibrosis by attenuating the formation of NETs.
Notably, these PIC II-associated hepatoprotective effects were largely
reversed by macrophage depletion in Mdr2-/- mice. Collectively, our
research suggests that PIC II is potential for halting the liver
fibrosis.