Pleiotrophic function of BAFF to promote a senescence-associated secretome and growth arrest

Senescent cells release a variety of cytokines, proteases and growth factors collectively defined as the Senescent Secretory Associated Phenotype (SASP). Sustained SASP induces a pattern of chronic inflammation associated with aging and implicated in multiple age-related diseases. Here, we investigated the expression and function of the immunomodulatory cytokine BAFF (B-cell activating factor), a SASP factor, in multiple senescence models. First, we characterized BAFF production across different senescence models, including senescent human diploid fibroblasts (WI-38, IMR-90) and monocytic leukemia cells (THP-1), and tissues of mice induced to undergo senescence. We identified IRF1 (interferon response factor 1) as a transcription factor required for promoting BAFF mRNA transcription in senescence, and found that suppressing BAFF production decreased the senescent phenotype in both monocytes and fibroblasts. Importantly, 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). Overall, BAFF silencing affected shared senescence-associated phenotypes including IL6 secretion, SA-beta-Gal staining, and γ-H2AX accumulation. We propose that BAFF is a novel biomarker of senescence and a potential target for senotherapy. Gene expression analysis of BAFF siRNA vs. Ctrl siRNA transfected cells in senescence.

衰老细胞可释放多种细胞因子、蛋白酶及生长因子，这类物质集合被统一称为衰老分泌相关表型（Senescent Secretory Associated Phenotype, SASP）。持续存在的SASP会诱导与衰老相关的慢性炎症状态，并与多种年龄相关性疾病的发生发展密切相关。本研究针对免疫调节性细胞因子BAFF（B细胞活化因子，B-cell activating factor）——一种SASP因子——在多种衰老模型中的表达与功能展开了探究。
首先，我们对不同衰老模型中的BAFF产生特征进行了系统表征，所涉及的模型包括衰老型人二倍体成纤维细胞（WI-38、IMR-90）、单核细胞白血病细胞（THP-1）以及诱导衰老的小鼠组织。我们鉴定出干扰素应答因子1（IRF1, interferon response factor 1）是衰老过程中促进BAFF mRNA转录的必需转录因子；同时发现抑制BAFF的产生可降低单核细胞与成纤维细胞的衰老表型。
值得注意的是，BAFF对衰老程序的调控作用具有细胞类型特异性：在单核细胞中，BAFF可促进NF-κB的早期活化与整体SASP分泌；而在成纤维细胞中，BAFF则参与TP53（p53）的表达与功能发挥。总体而言，BAFF沉默会影响多种共有的衰老相关表型，包括IL6分泌、SA-β-半乳糖苷酶（SA-beta-Gal）染色以及γ-H2AX聚集。我们提出，BAFF是一种新型衰老生物标志物，同时也是衰老治疗（senotherapy）的潜在靶点。本研究同时包含了衰老状态下转染BAFF小干扰RNA（siRNA）与对照小干扰RNA（Ctrl siRNA）的细胞的基因表达分析。