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Updated: Nov 10, 2025
Alveolar Macrophage Phagocytosis and Bacteria Clearance in Mice
Published on: March 2, 2019
ABT-263 enhanced bacterial phagocytosis of macrophages in aged mouse through Beclin-1-dependent autophagy
Yu Zhang1, Li-Hua Tang2, Jia Lu2
1Department of Anesthesiology, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou, China.
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.
Insights
Senolytic drug ABT-263 improved sepsis survival in aged mice by enhancing macrophage function and autophagy. This senolytic compound rejuvenates immune cells, offering a potential therapeutic strategy for sepsis in older adults.
Area of Science:
- Immunology
- Gerontology
- Pharmacology
Background:
- Sepsis poses a critical threat to older adults due to age-related decline in immune function, particularly macrophage dysfunction.
- Aging impairs macrophage capabilities, including reduced chemokine production, phagocytosis, and autophagy.
- Senolytic compounds like ABT-263, a Bcl-2 inhibitor, show potential in clearing senescent cells and rejuvenating aged tissues.
Purpose of the Study:
- To investigate the senolytic compound ABT-263's effect on sepsis survival in aged mice.
- To explore the impact of ABT-263 on macrophage function and the underlying molecular mechanisms in aged mice during sepsis.
- To determine the role of autophagy in ABT-263's protective effects against sepsis in the elderly.
Main Methods:
- Aged and young C57BL/6 mice were treated with ABT-263 and subsequently induced with sepsis via cecal slurry injection.
- Peritoneal macrophages were isolated from aged mice to assess cell function and molecular changes.
- Autophagy was modulated using 3-methyladenine (autophagy inhibitor) and rapamycin (autophagy enhancer).
- Gene and protein expression related to autophagy was analyzed using RT-PCR and Western Blot; phagocytic ability was assessed using EGFP-expressing E. coli.
Main Results:
- ABT-263 treatment significantly improved sepsis survival rates in aged mice, an effect dependent on autophagy.
- Blocking autophagy abolished the protective effect of ABT-263, indicating autophagy's crucial role.
- ABT-263 enhanced macrophage phagocytic capacity by upregulating Trem-2 receptors.
- The compound inhibited Bcl-2 binding to Beclin-1, thereby inducing Beclin-1-dependent autophagy.
Conclusions:
- ABT-263 enhances macrophage function in aged mice by increasing Trem-2 receptors and promoting Beclin-1-dependent autophagy.
- These improvements in macrophage function and autophagy contribute to the protection of aged mice against sepsis.
- ABT-263 represents a promising therapeutic agent for combating sepsis in the elderly population by targeting cellular senescence and immune dysfunction.
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