Scholarlink

<p>Cellular senescence drives chronic sterile inflammation during aging via the senescence-associated secretory phenotype, yet the senescent cell types responsible are poorly defined. Macrophages share multiple features of senescence, including inflammatory secretion, yet whether macrophages can adopt a senescent state remains unclear. Here we identify p21⁺Trem2⁺ senescent macrophages as a major source of inflammaging, using primary mouse and human macrophage models of DNA damage and cholesterol-induced senescence characterized by multi-omic profiling. We found that senescent macrophages exhibit a distinctive p21-TREM2 expression profile and senescence-associated secretory phenotype, driven in part by type I interferon signaling via cytosolic mitochondrial DNA. We also found that senescent macrophage accumulation occurs in aging, metabolic dysfunction-associated steatotic liver disease mouse livers, and is enriched in human cirrhotic liver tissue. Finally, senolytic treatment targeting senescent macrophages reduced liver inflammation and steatosis in both aged mice and mice with metabolic dysfunction-associated steatotic liver disease. These findings establish macrophage senescence as a central driver of chronic inflammation in aging and metabolic liver disease, and a tractable therapeutic target.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

p21+TREM2+ senescent macrophages fuel inflammaging and metabolic dysfunction-associated steatotic liver disease

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2026年4月16日

查看全文
  • Ivan A. Salladay-Perez,
  • Itzetl Avila,
  • Lizeth Estrada,
  • Andreea C. Alexandru,
  • Cristian Ponce,
  • Anika Dhingra,
  • Grasiela Torres,
  • Christina Y. Deng,
  • Ronak Hegde,
  • Julia Gensheimer,
  • Abhijit Kale,
  • Indra Heckenbach,
  • Simon Hui,
  • Chantle Edillor,
  • Jose A. Soto,
  • Alexander J. Napior,
  • Isaiah Little,
  • Mark Larsen,
  • Jacob Rose,
  • Lia Farahi,
  • Edwin D. J. Lopez Gonzalez,
  • Matthew R. Krieger,
  • Kushan Chowdhury,
  • Mridul Sharma,
  • Yuming Jiang,
  • Kevin Williams,
  • Morten Scheibye-Knudsen,
  • Carla M. Koehler,
  • Jesse G. Meyer,
  • Julia J. Mack,
  • Charles Brenner,
  • Steven J. Bensinger,
  • Cyril Lagger,
  • João Pedro de Magalhães,
  • Birgit Schilling,
  • Rajat Singh,
  • Eric Verdin,
  • Aldons J. Lusis,
  • Anthony J. Covarrubias

摘要

Cellular senescence drives chronic sterile inflammation during aging via the senescence-associated secretory phenotype, yet the senescent cell types responsible are poorly defined. Macrophages share multiple features of senescence, including inflammatory secretion, yet whether macrophages can adopt a senescent state remains unclear. Here we identify p21⁺Trem2⁺ senescent macrophages as a major source of inflammaging, using primary mouse and human macrophage models of DNA damage and cholesterol-induced senescence characterized by multi-omic profiling. We found that senescent macrophages exhibit a distinctive p21-TREM2 expression profile and senescence-associated secretory phenotype, driven in part by type I interferon signaling via cytosolic mitochondrial DNA. We also found that senescent macrophage accumulation occurs in aging, metabolic dysfunction-associated steatotic liver disease mouse livers, and is enriched in human cirrhotic liver tissue. Finally, senolytic treatment targeting senescent macrophages reduced liver inflammation and steatosis in both aged mice and mice with metabolic dysfunction-associated steatotic liver disease. These findings establish macrophage senescence as a central driver of chronic inflammation in aging and metabolic liver disease, and a tractable therapeutic target.