Cytoplasmic OH scavenger TA293 attenuates cellular senescence and fibrosis by activating macrophages through oxidized phospholipids/TLR4

Life Sci. 2019 Mar 15:221:284-292. doi: 10.1016/j.lfs.2019.02.038. Epub 2019 Feb 19.

Abstract

Aims: Elucidation of the biological roles of the mitochondrial and cytoplasmic hydroxyl radical (cyto OH) is hampered by the absence of site-specific OH scavengers. Earlier findings using cyto OH scavenger, TA293, indicated that cyto OH causes cellular senescence, and senescence-associated secretory phenotype (SASP) factors secreted from cells cause macrophage infiltration, inflammation, and apoptosis. However, we found that macrophage infiltration occurs before senescent cells appear. We therefore aimed to elucidate how cyto OH-induces macrophage activation and investigate the mechanism by which activated macrophages cause oxidative stress, inflammation, and apoptosis.

Main methods: In vivo imaging of pyocyanin- and TA293-treated, macrophage-depleted Toll-like receptor 4-knockout (TLR4-/-) OKD48- and IDOL-Tg mouse models were used to visualize oxidative stress and inflammation. SA-β-gal and TUNEL staining were used to detect cellular senescence and apoptosis. The mRNA expression of SASP factors were quantified by qRT-PCR. Activation mechanism of cyto OH-mediated macrophages was studied by an ex vivo analysis that created macrophage-activated oxidized phospholipids (OxPLs) using TLR4-/- mice.

Key findings: Cyto OH produced OxPLs that acted as TLR4 ligands, resulting in macrophage activation. Macrophages were not involved in oxidative stress in tissues or with oxidative damage caused by cyto OH, but significantly exacerbated cellular senescence, inflammation, apoptosis, and fibrosis.

Significance: We present a novel mechanism by which cyto OH-induced macrophage activation exacerbates cellular senescence, inflammation, apoptosis, and fibrosis independently from the known cyto OH-induced cellular senescence pathway. Notably, through suppression of this pathway, TA293 shows promise as a therapeutic agent to prevent fibrosis caused by cyto OH-induced oxidative stress.

Keywords: Cytoplasmic hydroxyl radical; Inflammation; Macrophage; Oxidative stress; Oxidized phospholipid; TLR4.

MeSH terms

  • Animals
  • Apoptosis
  • Cellular Senescence / drug effects*
  • Coumarins / metabolism*
  • Coumarins / pharmacology
  • Cytoplasm
  • Cytosol
  • Fibrosis / drug therapy*
  • Fibrosis / metabolism
  • Inflammation
  • Macrophage Activation / drug effects
  • Macrophage Activation / physiology
  • Macrophages
  • Male
  • Mice
  • Mice, Inbred C57BL
  • Mice, Transgenic
  • Mitochondria
  • Oxidation-Reduction
  • Oxidative Stress
  • Phospholipids
  • Signal Transduction
  • Toll-Like Receptor 4 / drug effects

Substances

  • Coumarins
  • Phospholipids
  • TA293 compound
  • TLR4 protein, human
  • Tlr4 protein, mouse
  • Toll-Like Receptor 4