Key Laboratory of Animal Physiology and Biochemistry, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, PR China.
MOE Joint International Research Laboratory of Animal Health and Food Safety, College of Veterinary Medicine, Nanjing Agricultural University, Nanjing, 210095, PR China.
Cell Death Dis. 2022 Apr 19;13(4):372. doi: 10.1038/s41419-022-04841-6.
As a widely acknowledged FDA-approved dietary supplement or over-the-counter medicines, dehydroepiandrosterone (DHEA) exerts anti-inflammatory and immunomodulatory function. Pyroptosis is an important form of programmed cell death (PCD), and which acts a key role in the body's anti-infection and inflammatory responses. But the effects and mechanisms of DHEA on pyroptosis remain unclear. Here, we found that DHEA inhibited the NLRP3 inflammasome components expression by blocking inflammatory signals in lipopolysaccharide (LPS)-primed macrophages, and prevented the bacterial toxin nigericin (Nig)-induced NLRP3 inflammasome assembly. However, DHEA exacerbated NLRP3-independent cell death in Nig-treated inflammatory macrophages. During this process, DHEA induced the abnormal autophagy, which reflected as the blocking of autophagic flux and the accumulation of autophagy receptor p62 (SQSTM1) protein. In addition, DHEA caused a burst of reactive oxygen species (ROS) and activated extracellular signal-regulated kinase (ERK) phosphorylation in LPS plus Nig-stimulated macrophages but not in LPS-treated macrophages. Mechanistically, the present study certified that the activation of G protein-coupled estrogen receptor (GPER) signal mediated the cell death induced by DHEA in Nig-stimulated inflammatory macrophages, as GPER specific inhibitor G15 alleviated the abnormal autophagy and ultimately prevented the gasdermin D (GSDMD)-mediated pyroptosis induced by DHEA. Collectively, DHEA can exacerbate Nig-induced abnormal autophagy and pyroptosis via activation of GPER in LPS-primed macrophages, which prompts us the potential application value of DHEA in anti-infection or anti-tumor immunity.
脱氢表雄酮（DHEA）作为一种被广泛认可的美国食品和药物管理局批准的膳食补充剂或非处方药，具有抗炎和免疫调节功能。细胞焦亡是一种重要的程序性细胞死亡（PCD）形式，在机体抗感染和炎症反应中发挥关键作用。然而，DHEA 对细胞焦亡的作用和机制尚不清楚。在这里，我们发现 DHEA 通过阻断脂多糖（LPS）预处理的巨噬细胞中的炎症信号，抑制 NLRP3 炎性体成分的表达，并防止细菌毒素 Nigericin（Nig）诱导的 NLRP3 炎性体组装。然而，DHEA 在 Nig 处理的炎症巨噬细胞中加剧了 NLRP3 非依赖性细胞死亡。在此过程中，DHEA 诱导异常自噬，表现为自噬流阻断和自噬受体 p62（SQSTM1）蛋白积累。此外，DHEA 在 LPS 加 Nig 刺激的巨噬细胞中引起活性氧（ROS）爆发和细胞外信号调节激酶（ERK）磷酸化激活，但在 LPS 处理的巨噬细胞中没有。在机制上，本研究证实 G 蛋白偶联雌激素受体（GPER）信号的激活介导了 DHEA 在 Nig 刺激的炎症巨噬细胞中诱导的细胞死亡，因为 GPER 特异性抑制剂 G15 减轻了异常自噬，并最终阻止了 DHEA 诱导的 GSDMD 介导的细胞焦亡。总之，DHEA 通过激活 LPS 预处理的巨噬细胞中的 GPER 可加剧 Nig 诱导的异常自噬和细胞焦亡，提示我们 DHEA 在抗感染或抗肿瘤免疫方面具有潜在的应用价值。
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