Background
Acute liver injury (ALI) caused by sepsis is a fearful disease with high mortality and poor prognosis. This study aimed to explore the roles and mechanism of Maresin 1 (MaR1) in lipopolysaccharide/d-galactosamine (LPS/D-GalN)-induced ALI.
Conclusion
MaR1 could ameliorate inflammation during LPS/D-GalN induced ALI by suppressing mitogen-activated protein kinase /NF-κB signaling and NLRP3 inflammasome-induced pyroptosis, activating macrophage M1/M2 polarization and Nrf2/HO-1 signaling. This provides new evidence for the potential of developing MaR1 for ALI treatment.
Methods
We established an ALI mouse model induced by LPS/D-GalN. Each group was treated with or without LPS/D-GalN or MaR1. For the vitro experiments, RAW264.7, NCTC1469 cells, and bone marrow-derived macrophages (BMDMs) were stimulated with LPS. The effects of MaR1 on the reactive oxygen species (ROS), pyroptosis and inflammatory response in macrophages were investigated.
Results
MaR1 significantly inhibited an excessive inflammatory response and proinflammatory markers during LPS/D-GalN-induced ALI. MaR1 markedly decreased the levels of ROS, tumor necrosis factor-α, and interleukin-1β (IL-1β) in macrophages, and limited hepatocyte apoptosis in vitro. Upon exploring the mechanisms underlying the protective role of MaR1, we found MaR1 markedly upregulated the nuclear factor erythroid 2-related factor 2 (Nrf2) and heme oxygenase-1 (HO-1), and considerably reduced the phosphorylation of p38, ERK, and nuclear factor-kappa B (NF-κB)-p65. Knocking down Nrf2 decreased the effect of MaR1. Furthermore, we observed that MaR1 reduced inflammatory injury by inhibiting M1 macrophages and promoting M2 macrophage polarization. Finally, we observed that MaR1 could inhibit the production of gasdermin D N-terminus (GSDMD-N) in vivo. In vitro, MaR1 could significantly suppressed the expression of NLR family pyrin domain containing 3 (NLRP3) inflammasome, GSDMD-N, and IL-1β caused by LPS and nigericin stimulation in BMDMs.