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<p>Immunosenescence, the age-associated decline in immune function, is accompanied by altered macrophage phenotypes and increased chronic inflammation. Here, we examined the role of the mitochondrial RNA-binding protein GRSF1 in regulating macrophage-driven inflammation and its impact on neighboring fibroblasts. We found that macrophages differentiated from GRSF1-deficient THP-1 monocytes, particularly M(IL-4 + IL-13) macrophages, displayed elevated <i>IL6</i> mRNA expression levels and TNF-α secretion, without inducing overt senescence in macrophages themselves. Conditioned media from these macrophages triggered robust senescence-associated transcriptional changes in fibroblasts, including increased expression of <i>IL6</i>, <i>TNF</i>, <i>DPP4</i>, and <i>IL8</i>, as well as elevated SA-β-gal activity. Notably, expression of NF-κB-regulated long noncoding RNAs, such as <i>ANRIL</i> and <i>PACER</i>, was also induced in fibroblasts, suggesting the engagement of an NF-κB-linked inflammatory program. These transcriptional responses were mitigated by red ginseng extract, an anti-inflammatory compound known to suppress TNF-α signaling. Collectively, our findings suggest that GRSF1 depletion in macrophages contributes to a paracrine inflammatory niche that promotes senescence-associated gene expression in surrounding cells.</p>

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GRSF1 loss in THP-1 macrophages promotes senescence-associated transcription in neighboring fibroblasts

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年8月14日

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  • Younggi Lee,
  • Seokwoo Jo,
  • Mi-Hee Lim,
  • Sangik Hwang,
  • Sohyeon Jang,
  • Kyuseok Kim,
  • Sung-Jin Yoon,
  • Jian Sima,
  • M. Laura Idda,
  • Kyoung Mi Kim,
  • Myriam Gorospe,
  • Chungoo Park,
  • Ji Heon Noh

摘要

Immunosenescence, the age-associated decline in immune function, is accompanied by altered macrophage phenotypes and increased chronic inflammation. Here, we examined the role of the mitochondrial RNA-binding protein GRSF1 in regulating macrophage-driven inflammation and its impact on neighboring fibroblasts. We found that macrophages differentiated from GRSF1-deficient THP-1 monocytes, particularly M(IL-4 + IL-13) macrophages, displayed elevated IL6 mRNA expression levels and TNF-α secretion, without inducing overt senescence in macrophages themselves. Conditioned media from these macrophages triggered robust senescence-associated transcriptional changes in fibroblasts, including increased expression of IL6, TNF, DPP4, and IL8, as well as elevated SA-β-gal activity. Notably, expression of NF-κB-regulated long noncoding RNAs, such as ANRIL and PACER, was also induced in fibroblasts, suggesting the engagement of an NF-κB-linked inflammatory program. These transcriptional responses were mitigated by red ginseng extract, an anti-inflammatory compound known to suppress TNF-α signaling. Collectively, our findings suggest that GRSF1 depletion in macrophages contributes to a paracrine inflammatory niche that promotes senescence-associated gene expression in surrounding cells.