Department of Obstetrics and Gynecology, Xiangya Hospital, Central South University, Changsha 410008, China.
Clinical Medicine Eight-Year Program, Xiangya School of Medicine, Central South University, Changsha 410013, China.
Mediators Inflamm. 2023 Jan 27;2023:2252255. doi: 10.1155/2023/2252255. eCollection 2023.
Sepsis, which could cause a systemic inflammatory response, is a life-threatening disease with a high morbidity and mortality rate. There is evidence that brain injury may be related to severe systemic infection induced by sepsis. The brain injury caused by sepsis could increase the risk of mortality in septic patients, which seriously affects the septic patient's prognosis of survival. Although there remains a focus on sepsis research, clinical measures to prevent and treat brain injury in sepsis are not yet available, and the high mortality rate is still a big health burden. Therefore, it is necessary to investigate the new molecules or regulated pathways that can effectively inhibit the progress of sepsis.
NLR family pyrin domain-containing 3 (NLRP3) increased in the procession of sepsis and functioned as the key regulator of pyroptosis. Heat shock factor 1 (HSF1) can protect organs from multiorgan dysfunction syndrome induced by lipopolysaccharides in mice, and NLRP3 could be inhibited by HSF1 in many organs. However, whether HSF1 regulated NLRP3 in sepsis-induced brain injury, as well as the detailed mechanism of HSF1 in brain injury, remains unknown in the sepsis model. In this research, we try to explore the relationship between HSF1 and NLRP3 in a sepsis model and try to reveal the mechanism of HSF1 inhibiting the process of brain injury.
In this study, we used wild-type mice and mice for research and PC12 cells for research. Real-time PCR and Western blot were used to analyze the expression of HSF1, NLRP3, cytokines, and pyrolytic proteins. EthD-III staining was chosen to detect the pyroptosis of the hippocampus and PC12 cells.
The results showed that HSF1 is negatively related to pyroptosis. The pyroptosis in cells of brain tissue was significantly increased in the mouse model compared to mice. In PC12 cells, siRNA can upregulate pyroptosis while HSF1-transfected plasmid could inhibit the pyroptosis. HSF1 could negatively regulate the NLRP3 pathway in PC12 cells, while siRNA enhanced the pyroptosis in PC12 cells, which could be reversed by siRNA.
These results imply that HSF1 could alleviate sepsis-induced brain injury by inhibiting pyroptosis through the NLRP3-dependent pathway in brain tissue and PC12 cells, suggesting HSF1 as a potential molecular target for treating brain injury in sepsis clinical studies.
脓毒症可引起全身炎症反应，是一种发病率和死亡率都很高的危及生命的疾病。有证据表明，脑损伤可能与脓毒症引起的严重全身感染有关。脓毒症引起的脑损伤会增加脓毒症患者的死亡率，严重影响脓毒症患者的生存预后。尽管人们对脓毒症的研究仍在继续，但目前还没有预防和治疗脓毒症相关脑损伤的临床措施，高死亡率仍是一个巨大的健康负担。因此，有必要研究新的分子或调控途径，以有效抑制脓毒症的进展。
NLR 家族pyrin 结构域包含蛋白 3（NLRP3）在脓毒症的发展过程中增加，并作为细胞焦亡的关键调节因子。热休克因子 1（HSF1）可保护器官免受脂多糖诱导的多器官功能障碍综合征，在许多器官中，NLRP3 可被 HSF1 抑制。然而，HSF1 是否在脓毒症诱导的脑损伤中调节 NLRP3，以及 HSF1 在脑损伤中的详细机制，在脓毒症模型中尚不清楚。在这项研究中，我们试图在脓毒症模型中探讨 HSF1 与 NLRP3 之间的关系，并试图揭示 HSF1 抑制脑损伤过程的机制。
本研究采用野生型小鼠和 小鼠进行研究，采用 PC12 细胞进行研究。实时 PCR 和 Western blot 用于分析 HSF1、NLRP3、细胞因子和焦亡蛋白的表达。EthD-III 染色用于检测海马和 PC12 细胞的焦亡。
结果表明，HSF1 与焦亡呈负相关。与 小鼠相比， 小鼠脑组织细胞的焦亡明显增加。在 PC12 细胞中，siRNA 可上调焦亡，而 HSF1 转染质粒可抑制焦亡。HSF1 可在 PC12 细胞中负调控 NLRP3 通路，而 siRNA 增强了 PC12 细胞的焦亡，而 siRNA 可逆转这一现象。
这些结果表明，HSF1 通过 NLRP3 依赖的途径抑制脑组织和 PC12 细胞中的脓毒症诱导的脑损伤，减轻脓毒症诱导的脑损伤，提示 HSF1 可能成为脓毒症脑损伤临床研究的潜在分子靶点。
