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

TL;DR

Removing GRSF1 in macrophages increases inflammation and causes nearby fibroblasts to show signs of cellular aging.

Contribution

This study reveals a new role for GRSF1 in modulating macrophage-driven inflammation and its paracrine effects on fibroblasts.

Findings

GRSF1-deficient macrophages secrete more IL6 and TNF-α, promoting inflammation.

Conditioned media from these macrophages induce senescence-like gene expression in fibroblasts.

Red ginseng extract reduces these inflammatory responses in fibroblasts.

Abstract

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.

The online version contains supplementary material available at 10.1038/s41598-025-11385-0.

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