Institute of Medical Science, Ajou University School of Medicine, Suwon, Gyeonggi-do 16499, Republic of Korea.
Department of Physiology, Ajou University School of Medicine, Suwon, Gyeonggi-do 16499, Republic of Korea.
Endocrinology. 2024 Jan 16;165(3). doi: 10.1210/endocr/bqae011.
Histone deacetylase 11 (HDAC11) has been implicated in the pathogenesis of metabolic diseases characterized by chronic low-grade inflammation, such as obesity. However, the influence of HDAC11 on inflammation and the specific effect of HDAC11 on the palmitic acid (PA)-induced NLR family pyrin domain containing 3 (NLRP3) inflammasome activation are poorly understood. The effect of PA treatment on HDAC11 activity and the NLRP3 inflammasome was investigated in human peripheral blood mononuclear cells and THP-1 cells. The PA-induced responses of key markers of NLRP3 inflammasome activation, including NLRP3 gene expression, caspase-1 p10 activation, cleaved IL-1β production, and extracellular IL-1β release, were assessed as well. The role of HDAC11 was explored using a specific inhibitor of HDAC11 and by knockdown using small interfering (si)HDAC11 RNA. The relationship between HDAC11 and yes-associated protein (YAP) in the PA-induced NLRP3 inflammasome was investigated in THP-1 cells with HDAC11 or YAP knockdown. Following PA treatment, HDAC11 activity and protein levels increased significantly, concomitant with activation of the NLRP3 inflammasome. Notably, PA-induced the upregulation of NLRP3, caspase-1 p10 activation, the production of cleaved IL-1β, and the release of IL-1β into the extracellular space, all of which were attenuated by FT895 treatment and by HDAC11 knockdown. In THP-1 cells, PA induced the expression of YAP and its interaction with NLRP3, resulting in NLRP3 inflammasome activation, whereas both were inhibited by FT895 and siHDAC11 RNA. These findings demonstrate a pivotal role for HDAC11 in the PA-induced activation of the NLRP3 inflammasome. HDAC11 inhibition thus represents a promising therapeutic strategy for mitigating NLRP3 inflammasome-related inflammation in the context of obesity.
组蛋白去乙酰化酶 11（HDAC11）已被牵连到以慢性低度炎症为特征的代谢疾病的发病机制中，例如肥胖症。然而，HDAC11 对炎症的影响以及 HDAC11 对软脂酸（PA）诱导的 NLR 家族 pyrin 结构域包含 3（NLRP3）炎性小体激活的具体作用仍知之甚少。在人外周血单核细胞和 THP-1 细胞中研究了 PA 处理对 HDAC11 活性和 NLRP3 炎性小体的影响。还评估了 PA 诱导的 NLRP3 炎性小体激活的关键标志物的反应，包括 NLRP3 基因表达、半胱天冬酶-1 p10 激活、切割的 IL-1β 产生和细胞外 IL-1β 释放。使用 HDAC11 的特异性抑制剂和使用小干扰（si）HDAC11 RNA 进行的 HDAC11 敲低来探索 HDAC11 的作用。在 THP-1 细胞中，使用 HDAC11 或 YAP 敲低研究了 PA 诱导的 NLRP3 炎性小体中 HDAC11 和 yes 相关蛋白（YAP）之间的关系。在用 PA 处理后，HDAC11 活性和蛋白水平显着增加，同时激活了 NLRP3 炎性小体。值得注意的是，PA 诱导了 NLRP3、半胱天冬酶-1 p10 激活、切割的 IL-1β 的产生和 IL-1β 向细胞外空间的释放的上调，所有这些都被 FT895 处理和 HDAC11 敲低所减弱。在 THP-1 细胞中，PA 诱导了 YAP 的表达及其与 NLRP3 的相互作用，导致 NLRP3 炎性小体的激活，而 FT895 和 siHDAC11 RNA 都抑制了这一作用。这些发现表明 HDAC11 在 PA 诱导的 NLRP3 炎性小体激活中起着关键作用。因此，HDAC11 抑制可能是减轻肥胖症中 NLRP3 炎性小体相关炎症的一种有前途的治疗策略。
