Maresin 1 protects against lipopolysaccharide/d-galactosamine-induced acute liver injury by inhibiting macrophage pyroptosis and inflammatory response

Biochem Pharmacol. 2022 Jan:195:114863. doi: 10.1016/j.bcp.2021.114863. Epub 2021 Nov 30.

Abstract

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.

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.

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.

Keywords: Acute liver injury; LPS/D-GalN; Maresin 1; NF-κB; Pyroptosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Chemical and Drug Induced Liver Injury / etiology
  • Chemical and Drug Induced Liver Injury / prevention & control*
  • Cytokines / metabolism
  • Docosahexaenoic Acids / pharmacology*
  • Galactosamine
  • Heme Oxygenase-1 / metabolism
  • Inflammasomes / drug effects*
  • Inflammasomes / metabolism
  • Lipopolysaccharides
  • Liver / drug effects
  • Liver / metabolism
  • Liver / pathology
  • Macrophages / drug effects*
  • Mice
  • NF-E2-Related Factor 2 / metabolism
  • NF-kappa B / metabolism
  • Protective Agents / pharmacology
  • Pyroptosis / drug effects*
  • RAW 264.7 Cells
  • Reactive Oxygen Species / metabolism

Substances

  • 7,14-dihydroxydocosa-4,8,10,12,16,19-hexaenoic acid
  • Cytokines
  • Inflammasomes
  • Lipopolysaccharides
  • NF-E2-Related Factor 2
  • NF-kappa B
  • Nfe2l2 protein, mouse
  • Protective Agents
  • Reactive Oxygen Species
  • Docosahexaenoic Acids
  • Galactosamine
  • Heme Oxygenase-1