A Benzenediamine Analog FC-99 Drives M2 Macrophage Polarization and Alleviates Lipopolysaccharide- (LPS-) Induced Liver Injury.

Wei Gong,Li Lu,Huan Dou,Haiyan Zhu,Yayi Hou

doi:10.1155/2019/7823069

Abstract

Macrophages have variable functional phenotypes, high diversity, and plasticity and are involved in the pathogenesis of sepsis-induced liver injury. Alteration of macrophage polarization through activated (M1) macrophage to alternatively activated (M2) macrophage has emerged as a potential therapeutic strategy. This study was designed to explore the effect of a benzenediamine analog FC-99 on macrophage polarization in vitro and lipopolysaccharide- (LPS-) induced liver injury followed by the underlying mechanisms. For in vitro experiments, FC-99 inhibited M1-related macrophage factors and promoted M2-related markers induced by IL-4 in the mouse macrophage cell line RAW264.7. Moreover, FC-99-induced macrophages polarized to M2 phenotype which could be repressed by a PPAR-γ inhibitor but not STAT6 siRNA knockdown, indicating FC-99-induced M2 macrophage polarization through PPAR-γ rather than STAT6 signal. In LPS-induced septic mice, FC-99 pretreated mice displayed lower expression of M1 markers together with the increased M2 marker CD206 and improvement of liver injury. These findings illustrated that FC-99 could promote M2 macrophage polarization via PPAR-γ signaling and seemed to be a potential therapeutic candidate for inflammatory liver injury.

Highlights

Sepsis and subsequent multiple organ dysfunction syndrome (MODS) have become a major challenge in surgical critical care due to high morbidity and mortality in the absence of adequate treatment [1]
FC-99 significantly suppressed the levels of Inflammation synthases (iNOS) and TNF-α induced by LPS (Figures 1(c) and 1(d)), exhibiting an anti-inflammatory activity as previously described [20]
These results suggested that FC-99 may promote M2 macrophage activation and inhibit M1 polarization

Summary

Introduction

Sepsis and subsequent multiple organ dysfunction syndrome (MODS) have become a major challenge in surgical critical care due to high morbidity and mortality in the absence of adequate treatment [1]. Liver dysfunction is an indicator of progression from sepsis to MODS. Effective prevention and treatment of sepsisinduced liver injury are urgently needed. Macrophage displays multiple functions such as presenting antigens, repairing tissue, and modulating inflammation through various effector populations [5, 6]. The ability to alter the function of macrophages is called “polarization.” Depending on different environmental stimuli, macrophage mainly exists in two opposite activated populations, classically activated (M1) macrophage and alternatively activated (M2) macrophage [7]. The M1 phenotype is proinflammatory and secretes numerous inflammatory cytokines such as inducible nitric oxide

Methods

Results

Conclusion