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 cellsvia 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.
Keywords: Liver fibrosis; picroside Ⅱ; M1 macrophage; hepatic
stellate cell; natural killer cell; neutrophil; CXCL16.