Department of Hematology and Critical Care Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
Cancer Research Institute, Central South University, Changsha, Hunan, China.
Front Immunol. 2023 Jun 8;14:1188482. doi: 10.3389/fimmu.2023.1188482. eCollection 2023.
Mitophagy is a selective autophagy targeting damaged and potential cytotoxic mitochondria, which can effectively prevent excessive cytotoxic production from damaged mitochondria and alleviate the inflammatory response. However, the potential role of mitophagy in sepsis remains poorly explored. Here, we studied the role of mitophagy in sepsis and its immune heterogeneity. By performing mitophagy-related typing on 348 sepsis samples, three clusters (A, B, and C) were obtained. Cluster A had the highest degree of mitophagy accompanied by lowest disease severity, while cluster C had the lowest degree of mitophagy with the highest disease severity. The three clusters had unique immune characteristics. We further revealed that the expression of PHB1 in these three clusters was significantly different and negatively correlated with the severity of sepsis, suggesting that PHB1 was involved in the development of sepsis. It has been reported that impaired mitophagy leads to the over-activation of inflammasomes, which promotes sepsis development. Further analysis showed that the expressions of NLRP3 inflammasomes core genes in cluster C were significantly up-regulated and negatively correlated with PHB1. Next, we verified whether PHB1 downregulation caused the activation of inflammasomes and found that the PHB1 knockdown increased the levels of mtDNA in the cytoplasm and enhanced the activation of NLRP3 inflammasomes. In addition, mitophagy inhibitor treatment abolished PHB1 knockdown-mediated activation of NLRP3 inflammasomes, suggesting that PHB1 inhibited the activation of inflammasomes through mitophagy. In conclusion, this study reveals that a high degree of mitophagy may predict a good outcome of sepsis, and PHB1 is a key NLRP3 inflammasome regulator mitophagy in inflammatory diseases such as sepsis.
自噬是一种靶向损伤和潜在细胞毒性线粒体的选择性自噬，可以有效防止损伤线粒体产生过多的细胞毒性物质，并减轻炎症反应。然而，自噬在脓毒症中的潜在作用仍未得到充分探索。在这里，我们研究了自噬在脓毒症及其免疫异质性中的作用。通过对 348 例脓毒症样本进行自噬相关分型，得到了三个聚类（A、B 和 C）。聚类 A 具有最高程度的自噬，同时疾病严重程度最低，而聚类 C 具有最低程度的自噬，疾病严重程度最高。这三个聚类具有独特的免疫特征。我们进一步揭示，这三个聚类中 PHB1 的表达存在显著差异，且与脓毒症的严重程度呈负相关，提示 PHB1 参与了脓毒症的发生发展。有报道称，自噬受损会导致炎症小体过度激活，从而促进脓毒症的发展。进一步分析表明，聚类 C 中 NLRP3 炎症小体核心基因的表达显著上调，且与 PHB1 呈负相关。接下来，我们验证了 PHB1 下调是否导致炎症小体的激活，发现 PHB1 敲低增加了细胞质中线粒体 DNA 的水平，并增强了 NLRP3 炎症小体的激活。此外，自噬抑制剂处理消除了 PHB1 敲低介导的 NLRP3 炎症小体的激活，表明 PHB1 通过自噬抑制炎症小体的激活。总之，本研究揭示了高程度的自噬可能预示着脓毒症的良好预后，PHB1 是炎症性疾病（如脓毒症）中 NLRP3 炎症小体调节自噬的关键调节因子。
