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

Life Sciences
Takahiro SakaiShinichi Hatta

Abstract

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. 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. Cyto OH produced OxPLs that acted as TLR4 ligands, resu...Continue Reading

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Citations

Apr 25, 2020·Cells·Pratap Karki, Konstantin G Birukov
Aug 3, 2021·Trends in Immunology·Jonathan J LiangClare E Bryant

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