Cytoplasmic OH scavenger TA293 attenuates cellular senescence and fibrosis by activating macrophages through oxidized phospholipids/TLR4
| Autor: | Hidetsugu Takagaki, Shinichi Hatta, Takahiro Sakai, Michio Ui, Jun Imai |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
Male
0301 basic medicine Cytoplasm Apoptosis Mice Transgenic Inflammation medicine.disease_cause 030226 pharmacology & pharmacy General Biochemistry Genetics and Molecular Biology Mice 03 medical and health sciences chemistry.chemical_compound Cytosol 0302 clinical medicine Pyocyanin Coumarins Fibrosis medicine Animals Macrophage General Pharmacology Toxicology and Pharmaceutics Cellular Senescence Phospholipids TUNEL assay Macrophages General Medicine Macrophage Activation medicine.disease Mitochondria Cell biology Mice Inbred C57BL Toll-Like Receptor 4 Oxidative Stress 030104 developmental biology chemistry TLR4 medicine.symptom Oxidation-Reduction Oxidative stress Signal Transduction |
| Zdroj: | Life Sciences. 221:284-292 |
| ISSN: | 0024-3205 |
| DOI: | 10.1016/j.lfs.2019.02.038 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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