Pleiotropic effects of BAFF on the senescence-associated secretome and growth arrest

Senescent cells release a variety of cytokines, proteases, and growth factors collectively known as the senescence-associated secretory phenotype (SASP). Sustained SASP contributes to a pattern of chronic inflammation associated with aging and implicated in many age-related diseases. Here, we investigated the expression and function of the immunomodulatory cytokine BAFF (B-cell activating factor; encoded by the TNFSF13B gene), a SASP protein, in multiple senescence models. We first characterized BAFF production across different senescence paradigms, including senescent human diploid fibroblasts (WI-38, IMR-90) and monocytic leukemia cells (THP-1), and tissues of mice induced to undergo senescence. We then identified IRF1 (interferon regulatory factor 1) as a transcription factor required for promoting TNFSF13B mRNA transcription in senescence. We discovered that suppressing BAFF production decreased the senescent phenotype of both fibroblasts and monocyte-like cells, reducing IL6 secretion and SA-beta-Gal staining. Importantly, however, the influence of BAFF on the senescence program was cell type-specific: in monocytes, BAFF promoted the early activation of NF-kappa B and general SASP secretion, while in fibroblasts, BAFF contributed to the production and function of TP53 (p53). We propose that BAFF is elevated across senescence models and is a potential target for senotherapy.

Automated summary

Senescent cells release the senescence-associated secretory phenotype (SASP), which is a collection of cytokines, proteases, and growth factors associated with chronic inflammation and age-related diseases. This study explored the expression and role of the immunomodulatory cytokine BAFF in different senescence models. BAFF production was found to be elevated in various senescence paradigms, and the transcription factor IRF1 was identified as necessary for TNFSF13B mRNA transcription. Inhibition of BAFF production reduced the senescent phenotype and secretion of IL6 in fibroblasts and monocyte-like cells, with cell type-specific effects on NF-kappa B activation and TP53 function.