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Type 2 cytokine signaling in macrophages protects from cellular senescence and organismal aging
Immunity ( IF 25.5 ) Pub Date : 2024-01-22 , 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 2
Immunity ( IF 25.5 ) Pub Date : 2024-01-22 , 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 2
Affiliation
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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.
中文翻译：
巨噬细胞中的 2 型细胞因子信号传导可防止细胞衰老和生物体衰老
衰老细胞在器官和组织中的积累是衰老的标志，已知会导致与年龄相关的疾病。尽管已知与衰老相关的免疫功能障碍或免疫衰老会导致这一过程，但其潜在机制仍然难以捉摸。在这里，我们报道了 2 型细胞因子信号缺陷加速衰老，相反，白细胞介素 4 （IL-4）-STAT6 通路保护巨噬细胞免于衰老。从机制上讲，激活的 STAT6 通过同源重组和 Fanconi 贫血通路促进参与 DNA 修复的基因的表达。相反，STAT6 缺陷诱导核 DNA 释放到细胞质中，从而促进组织炎症和生物体衰老。重要的是，我们证明 IL-4 治疗可以防止巨噬细胞衰老并改善老年小鼠的健康寿命，其程度与 senolytic 治疗相当，联合使用时具有进一步的累加效应。总之，我们的研究结果支持 2 型细胞因子信号传导保护巨噬细胞免受免疫衰老，从而具有改善健康老龄化的治疗潜力。
更新日期：2024-01-22
中文翻译：
巨噬细胞中的 2 型细胞因子信号传导可防止细胞衰老和生物体衰老
衰老细胞在器官和组织中的积累是衰老的标志，已知会导致与年龄相关的疾病。尽管已知与衰老相关的免疫功能障碍或免疫衰老会导致这一过程，但其潜在机制仍然难以捉摸。在这里，我们报道了 2 型细胞因子信号缺陷加速衰老，相反，白细胞介素 4 （IL-4）-STAT6 通路保护巨噬细胞免于衰老。从机制上讲，激活的 STAT6 通过同源重组和 Fanconi 贫血通路促进参与 DNA 修复的基因的表达。相反，STAT6 缺陷诱导核 DNA 释放到细胞质中，从而促进组织炎症和生物体衰老。重要的是，我们证明 IL-4 治疗可以防止巨噬细胞衰老并改善老年小鼠的健康寿命，其程度与 senolytic 治疗相当，联合使用时具有进一步的累加效应。总之，我们的研究结果支持 2 型细胞因子信号传导保护巨噬细胞免受免疫衰老，从而具有改善健康老龄化的治疗潜力。
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