Pleiotropic effects of BAFF on the senescence-associated secretome and growth arrest
Martina Rossi, Carlos Anerillas, Maria Laura Idda, Rachel Munk, Chang Hoon Shin, Stefano Donegà, Dimitrios Tsitsipatis, Allison B. Herman, Jennifer L. Martindale, Xiaoling Yang, Yulan Piao, Krystyna Mazan-Mamczarz, Jinshui Fan, Luigi Ferrucci, Peter F. Johnson, Supriyo De, Kotb Abdelmohsen, Myriam Gorospe
Abstract
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-β-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-κB 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.