Han Bing, Choukér Alexander, Moser Dominique
Laboratory of Translational Research 'Stress and Immunity', Department of Anesthesiology, LMU Hospital, Ludwig-Maximilians-Universität in Munich, Germany.
Heliyon. 2024 May 11;10(10):e31156. doi: 10.1016/j.heliyon.2024.e31156. eCollection 2024 May 30.
Pyroptosis is a programmed and inflammation-inducing cell death that occurs predominantly in macrophages. It is characterized by the inflammasome-mediated activation of caspase-1, leading to cell lysis. During pyroptosis, pro-inflammatory mediators such as IL-1β are released extracellularly to further recruit and activate other immune cells. Thus, pyroptosis plays a crucial role in the prevention of the spread of pathogens. The clinically applied synthetic glucocorticoid, hydrocortisone (HC), has strong immunoregulatory properties. It may act as an immunosuppressive agent by negatively regulating pro-inflammatory gene transcription but has also shown immune-sensitizing properties. The conditions that determine the immunosuppressive or immune-sensitizing actions of HC during an infection are not fully clear. We hypothesized that the outcome may differ depending on the onset and duration of its administration. Therefore, we investigated the impact of acute (treatment upon infection) and chronic (24 h pre-treatment before infection) HC treatment on pyroptosis induction and execution in THP-1 macrophage-like cells. The focus was on pyroptosis-associated signaling pathways, inflammasome assembly and activation, IL-1β, and cell death. Physiological HC concentration and HC deprivation were used as controls. Compared to the physiological concentration, cells displayed augmented inflammasome activation and IL-1β release following acute HC treatment. Conversely, the whole pyroptosis machinery was suppressed by chronic HC administration. These investigations demonstrate pro-inflammatory actions of acute HC exposure and the immunosuppressive effects of chronic treatment. These differential effects on pyroptosis emphasize the importance of individualized HC medication in patients upon infection, and suggest the inclusion of IL-1β as a marker for current immune capacities.
细胞焦亡是一种程序性且可诱导炎症的细胞死亡，主要发生在巨噬细胞中。其特征是炎性小体介导的半胱天冬酶-1激活，导致细胞裂解。在细胞焦亡过程中，白细胞介素-1β等促炎介质会释放到细胞外，以进一步募集和激活其他免疫细胞。因此，细胞焦亡在预防病原体传播中起关键作用。临床应用的合成糖皮质激素氢化可的松（HC）具有强大的免疫调节特性。它可能通过负向调节促炎基因转录而作为免疫抑制剂，但也表现出免疫致敏特性。在感染期间决定HC免疫抑制或免疫致敏作用的条件尚不完全清楚。我们假设结果可能因给药的起始时间和持续时间而异。因此，我们研究了急性（感染时治疗）和慢性（感染前24小时预处理）HC治疗对THP-1巨噬细胞样细胞中细胞焦亡诱导和执行的影响。重点是细胞焦亡相关信号通路、炎性小体组装和激活、白细胞介素-1β以及细胞死亡。使用生理HC浓度和HC缺失作为对照。与生理浓度相比，急性HC治疗后细胞的炎性小体激活和白细胞介素-1β释放增强。相反，慢性HC给药会抑制整个细胞焦亡机制。这些研究证明了急性HC暴露的促炎作用和慢性治疗的免疫抑制作用。这些对细胞焦亡的不同影响强调了感染患者个体化HC用药的重要性，并建议将白细胞介素-1β作为当前免疫能力的标志物。
