ABT-263 enhanced bacterial phagocytosis of macrophages in aged mouse through Beclin-1-dependent autophagy.

Autor: Zhang Y; Department of Anesthesiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China., Tang LH; Department of Anesthesiology, The Second Hospital of Dalian Medical University, 467 Zhongshan Road, Dalian, ZIP: 116027, Liaoning, China., Lu J; Department of Anesthesiology, The Second Hospital of Dalian Medical University, 467 Zhongshan Road, Dalian, ZIP: 116027, Liaoning, China., Xu LM; Research Center, The Second Hospital of Dalian Medical University, Dalian, China., Cheng BL; Department of Anesthesiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China., Xiong JY; Department of Anesthesiology, The Second Hospital of Dalian Medical University, 467 Zhongshan Road, Dalian, ZIP: 116027, Liaoning, China. jyxiong0639@163.com.
Jazyk: angličtina
Zdroj: BMC geriatrics [BMC Geriatr] 2021 Apr 01; Vol. 21 (1), pp. 225. Date of Electronic Publication: 2021 Apr 01.
DOI: 10.1186/s12877-021-02173-2
Abstrakt: Background: Sepsis is a critical challenge for the older adults as the immune function is less responsive by aging. Although cell numbers seem preserved in the older adults, macrophages present age-related function decline, which including reduced chemokines, phagocytosis, and autophagy. ABT-263, an inhibitor of the anti-apoptotic protein Bcl-2, is reported had a senolytic effect which can selectively clear the senescent cells in vivo and rejuvenate the aged tissues.
Methods: We treated the aged (12-16 months) and young (4-6 months) C57BL/6 mouse with ABT-263, then gave the animals cecal slurry injection to induce sepsis to observe the effect of senolytic compound ABT-263 on the survival rate of sepsis. Additionally, we isolated peritoneal macrophages from the aged mouse to investigate the cell function and molecular mechanism. 3-methyladenine (3-MA), a phosphatidylinositol 3-kinases (PI3K) inhibitor, and rapamycin, an autophagy-enhancer, were used to block or mimic the autophagy, respectively. RT-PCR and Western Blot were used to detect autophagy related gene and protein changes in sepsis. EGFP-expressing E. coli was used as a marker to evaluate the phagocytic ability of macrophages.
Results: The results showed ABT-263 treatment improved the survival rate of sepsis in the aged mouse which related to autophagy, while blocking the autophagy can eliminate this effect. It is revealed that ABT-263 enhanced the phagocytic ability of the peritoneal macrophages by increasing the Trem-2 receptor. Additionally, ABT-263 blocked the binding of Bcl-2 to Beclin-1, thus induced Beclin-1-dependent autophagy.
Conclusion: ABT-263 enhanced the macrophage function in aged mouse by increasing the Trem-2 receptors and inducing a beclin-1-dependent autophagy, consequently, protected the aged mouse from sepsis.
Databáze: MEDLINE
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