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

Abstract

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.