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

Yu Zhang,Bao-Li Cheng,Li-Hua Tang,Jun-Yu Xiong,Jia Lu,Li-Ming Xu

doi:10.1186/s12877-021-02173-2

Abstract

BackgroundSepsis 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.MethodsWe 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.ResultsThe 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.ConclusionABT-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.

Highlights

Sepsis is a critical challenge for the older adults as the immune function is less responsive by aging
ABT-263 treatment improved the survival rate of the aged sepsis mouse which may relate to the regulation of autophagy
When the aged mice treated with ABT-263, the survival rate of cecal slurry injection (CSI)-induced sepsis increased compared to the control group (10/14 vs. 6/14, P = 0.038)

Summary

Introduction

Sepsis is a critical challenge for the older adults as the immune function is less responsive by aging. 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. The significant pathophysiologic difference lies between the of young and aged population, the majority of sepsis studies were based on ABT-263, an inhibitor of the anti-apoptotic protein Bcl-2, was first known because of its high efficacy against. It is reported that the ABT-263 had the senolytic effect which can selectively clear the senescent cells (SCs) in vivo and rejuvenate the aged tissues [5, 6]. It is interesting to know whether this senolytic drug has positive effect on the immune function and the acute critical infectious disease like sepsis on the older adults. We further investigated blocking or inducing autophagy with 3-Methyladenine (3-MA) and Rapamycin (Rap), respectively, on the effect of ABT-263 treatment and the possible mechanism

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