Translational Tissue Engineering Center, Wilmer Eye Institute and Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Department of Biomedical Sciences, Korea University College of Medicine, Seoul, South Korea.
J Clin Invest. 2020 Oct 1;130(10):5493-5507. doi: 10.1172/JCI134091.
Senescent cells (SnCs) are implicated in the pathogenesis of age-related diseases including osteoarthritis (OA), in part via expression of a senescence-associated secretory phenotype (SASP) that includes immunologically relevant factors and cytokines. In a model of posttraumatic OA (PTOA), anterior cruciate ligament transection (ACLT) induced a type 17 immune response in the articular compartment and draining inguinal lymph nodes (LNs) that paralleled expression of the senescence marker p16INK4a (Cdkn2a) and p21 (Cdkn1a). Innate lymphoid cells, γδ+ T cells, and CD4+ T cells contributed to IL-17 expression. Intra-articular injection of IL-17-neutralizing antibody reduced joint degeneration and decreased expression of the senescence marker Cdkn1a. Local and systemic senolysis was required to attenuate tissue damage in aged animals and was associated with decreased IL-17 and increased IL-4 expression in the articular joint and draining LNs. In vitro, we found that Th17 cells induced senescence in fibroblasts and that SnCs skewed naive T cells toward Th17 or Th1, depending on the presence of TGF-β. The SASP profile of the inflammation-induced SnCs included altered Wnt signaling, tissue remodeling, and cell-cycle pathways not previously implicated in senescence. These findings provide molecular targets and mechanisms for senescence induction and therapeutic strategies to support tissue healing in an aged environment.
衰老细胞（SnCs）被认为与年龄相关性疾病的发病机制有关，包括骨关节炎（OA），部分原因是表达了衰老相关分泌表型（SASP），其中包括免疫相关因子和细胞因子。在创伤后 OA（PTOA）模型中，前交叉韧带切断（ACLT）在关节腔和引流腹股沟淋巴结（LNs）中诱导了 17 型免疫反应，与衰老标志物 p16INK4a（Cdkn2a）和 p21（Cdkn1a）的表达相平行。固有淋巴样细胞、γδ+T 细胞和 CD4+T 细胞有助于 IL-17 的表达。关节内注射 IL-17 中和抗体可减少关节退变和衰老标志物 Cdkn1a 的表达。局部和全身衰老细胞溶解是减轻老年动物组织损伤所必需的，与关节和引流 LNs 中 IL-17 的减少和 IL-4 的增加有关。在体外，我们发现 Th17 细胞诱导成纤维细胞衰老，而 SnCs 使幼稚 T 细胞向 Th17 或 Th1 倾斜，这取决于 TGF-β的存在。炎症诱导的 SnCs 的 SASP 特征包括改变的 Wnt 信号通路、组织重塑和细胞周期途径，这些途径以前与衰老无关。这些发现为衰老诱导提供了分子靶点和机制，并为在老年环境中支持组织愈合提供了治疗策略。
