Inhibition of autophagy with 3-methyladenine is protective in a lethal model of murine endotoxemia and polymicrobial sepsis

Li, Qirui; Li, Lingyun; Fei, Xiaoyuan; Zhang, Yuanyue; Chen, Qi; Hua, Shuyao; Gong, Feili; Fang, Min

doi:10.1177/1753425918771170

Cited by 38 publications

(28 citation statements)

References 33 publications

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“…Interestingly, our study appears to contradict a recent study by Li and coworkers [25]. They found 3-MA protected the mice from sepsis while rapamycin worsen the outcome.…”

Section: Discussioncontrasting

confidence: 99%

Senolytic compound ABT-263 improved senescent macrophages function by inducing autophagy and protected the aged mouse from sepsis

Tang¹,

Lu²,

Xu³

et al. 2020

Preprint

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Sepsis is a critical challenge for the elderly population as the immune function is less responsive by aging. Although cell numbers seem preserved in the elderly, macrophages present age-related function decline, which including reduced chemokines, phagocytosis, and autophagy. an inhibitor of the anti-apoptotic protein Bcl2, is reported had a senolytic effect which can selectively clear the senescent cells in vivo and rejuvenate the aged tissues. Therefore, we treated the aged mouse with ABT-263 and used cecal slurry injection to induce sepsis to observe its effect on the survival rate of sepsis. Besides, 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. EGFP-expressing E. Coli was used as a marker to evaluate the phagocytic ability of macrophages. The results showed ABT-263 treatment improved the survival rate of sepsis in the aged mouse which related to autophagy. Additionally, It is revealed that ABT-263 induced autophagy and enhanced the phagocytic ability of the peritoneal macrophages. However, blocking the autophagy can eliminate this effect. In conclusion, ABT-263 enhanced the macrophage function by inducing autophagy, consequently, protected the aged mouse from sepsis. YZ took the lead in drafting this manuscript. YZ and LHT carried out the experiments and acquired the raw data. JL and LMX analysed and interpretation the data. BLC provided critical feedback and consultation. JYX conceived and planned the experiments. All authors read and approved the final manuscript.

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“…Interestingly, our study appears to contradict a recent study by Li and coworkers [25]. They found 3-MA protected the mice from sepsis while rapamycin worsen the outcome.…”

Section: Discussioncontrasting

confidence: 99%

Senolytic compound ABT-263 improved senescent macrophages function by inducing autophagy and protected the aged mouse from sepsis

Tang¹,

Lu²,

Xu³

et al. 2020

Preprint

View full text Add to dashboard Cite

show abstract

“…Interestingly, our study appears to contradict a recent study by Li and coworkers [25]. They found 3-MA protected the mice from sepsis while rapamycin worsens the outcome.…”

Section: Discussioncontrasting

confidence: 99%

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

Tang

Jia

et al. 2020

Preprint

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Background: Sepsis is a critical challenge for the elderly population as the immune function is less responsive by aging. Although cell numbers seem preserved in the elderly, 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.

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“…Intraperitoneal and i.v. injection of LPS have been shown to induce systemic inflammatory responses, MOF, and mortality in murine models (24,25). Consistent with LPS-induced MOF, intraperitoneal injection of sonicated bacteria supernatants elevated plasma TNF-α and IL-6 levels in mice ( Figure 3, A and B).…”

Section: Local Injection Of Pamps But Not Damps Cause Systemic Orgamentioning

confidence: 61%

Damage- and pathogen-associated molecular patterns play differential roles in late mortality after critical illness

Eppensteiner¹,

Kwun²,

Scheuermann³

et al. 2019

JCI Insight

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Inhibition of autophagy with 3-methyladenine is protective in a lethal model of murine endotoxemia and polymicrobial sepsis

Cited by 38 publications

References 33 publications

Senolytic compound ABT-263 improved senescent macrophages function by inducing autophagy and protected the aged mouse from sepsis

Senolytic compound ABT-263 improved senescent macrophages function by inducing autophagy and protected the aged mouse from sepsis

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

Damage- and pathogen-associated molecular patterns play differential roles in late mortality after critical illness

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