Sorbonne Université, CNRS UMR 8256 Biological Adaptation and Ageing (B2A), INSERM U1164, Institut de Biologie Paris Seine (IBPS), Paris 75005, France.
INSERM U1148, Laboratory for Vascular and Translational Sciences (LVTS), Université Sorbonne Paris Nord, Bobigny 93000, France.
Aging (Albany NY). 2024 Oct 3;16(19):12697-12725. doi: 10.18632/aging.206124.
The accumulation of senescent cells, characterized by a senescence-associated secretory phenotype (SASP), contributes to chronic inflammation and age-related diseases (ARD). During aging, macrophages can adopt a senescent-like phenotype and an altered function, which promotes senescent cell accumulation. In the context of aging and ARD, controlling the resolution of the inflammatory response and preventing chronic inflammation, especially by targeting macrophages, must be a priority. Aging being a dynamic process, we developed a model of murine peritoneal macrophage aging. Our results show that macrophages cultured for 7 or 14 days exhibit a senescence-like phenotype: proliferation decrease, the levels of cyclin-dependent kinase inhibitors p16 and p21 and of pro-inflammatory SASP components (MCP-1, IL-6, IL-1β, TNF-α, and MMP-9) increase, phagocytosis capacity decline and glycolytic activity is induced. In our model, chronic treatment with CB3, a thioredoxin-1 mimetic anti-inflammatory peptide, completely prevents p21 increase and enables day 14 macrophages to maintain proliferative activity.We describe a new model of macrophage aging with a senescence-like phenotype associated with inflammatory, metabolic and functional perturbations. This model is a valuable tool for characterizing macrophage aging mechanisms and developing innovative strategies with promising therapeutical purpose in limiting inflammaging and ARD.
衰老细胞的积累，其特征是衰老相关的分泌表型（SASP），导致慢性炎症和与年龄相关的疾病（ARD）。在衰老过程中，巨噬细胞可以采用类似衰老的表型和改变的功能，这促进了衰老细胞的积累。在衰老和 ARD 的背景下，控制炎症反应的解决和预防慢性炎症，特别是通过靶向巨噬细胞，必须是优先事项。衰老作为一个动态过程，我们开发了一种小鼠腹腔巨噬细胞衰老模型。我们的结果表明，培养 7 或 14 天的巨噬细胞表现出类似衰老的表型：增殖减少，细胞周期蛋白依赖性激酶抑制剂 p16 和 p21 的水平以及促炎 SASP 成分（MCP-1、IL-6、IL-1β、TNF-α 和 MMP-9）增加，吞噬能力下降，糖酵解活性被诱导。在我们的模型中，用 CB3（一种硫氧还蛋白-1 模拟抗炎肽）进行慢性治疗完全阻止了 p21 的增加，并使第 14 天的巨噬细胞能够保持增殖活性。我们描述了一种具有与炎症、代谢和功能紊乱相关的类似衰老表型的新型巨噬细胞衰老模型。该模型是研究巨噬细胞衰老机制和开发具有限制炎症和 ARD 治疗潜力的创新策略的有价值工具。
