2. Academic Validation
  3. Type 2 cytokine signaling in macrophages protects from cellular senescence and organismal aging

Type 2 cytokine signaling in macrophages protects from cellular senescence and organismal aging

  • Immunity. 2024 Jan 17:S1074-7613(24)00026-8. doi: 10.1016/j.immuni.2024.01.001.
Zhao Zhou 1,  Jingfei Yao 1,  Dongmei Wu 2,  Xun Huang 3,  Yushuang Wang 1,  Xinmeng Li 1,  Qiang Lu 1,  Yifu Qiu 4
Affiliations

Affiliations

  • 1 Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China.
  • 2 Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China.
  • 3 Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China; Academy for Advanced Interdisciplinary Studies, Peking University, Beijing 100871, China.
  • 4 Institute of Molecular Medicine, Beijing Key Laboratory of Cardiometabolic Molecular Medicine, College of Future Technology, Peking University, Beijing 100871, China; Peking-Tsinghua Center for Life Sciences, Peking University, Beijing 100871, China. Electronic address: yifu.qiu@pku.edu.cn.
PMID: 38262419 DOI: 10.1016/j.immuni.2024.01.001
Abstract

Accumulation of senescent cells in organs and tissues is a hallmark of aging and known to contribute to age-related diseases. Although aging-associated immune dysfunction, or immunosenescence, is known to contribute to this process, the underlying mechanism remains elusive. Here, we report that type 2 cytokine signaling deficiency accelerated aging and, conversely, that the interleukin-4 (IL-4)-STAT6 pathway protected macrophages from senescence. Mechanistically, activated STAT6 promoted the expression of genes involved in DNA repair both via homologous recombination and Fanconi anemia pathways. Conversely, STAT6 deficiency induced release of nuclear DNA into the cytoplasm to promote tissue inflammation and organismal aging. Importantly, we demonstrate that IL-4 treatment prevented macrophage senescence and improved the health span of aged mice to an extent comparable to senolytic treatment, with further additive effects when combined. Together, our findings support that type 2 cytokine signaling protects macrophages from immunosenescence and thus hold therapeutic potential for improving healthy aging.

Keywords

DNA repair; IL-4; STAT6; aging; immunosenescence; inflammaging; macrophage; type 2 cytokine.

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