The landscape of mitophagy in sepsis reveals PHB1 as an NLRP3 inflammasome inhibitor

Shipeng Chen; Jinqi Ma; Ping Yin; Fang Liang

doi:10.3389/fimmu.2023.1188482

The landscape of mitophagy in sepsis reveals PHB1 as an NLRP3 inflammasome inhibitor

Front Immunol. 2023 Jun 8:14:1188482. doi: 10.3389/fimmu.2023.1188482. eCollection 2023.

Authors

Shipeng Chen^{1

2}, Jinqi Ma³, Ping Yin³, Fang Liang¹

Affiliations

¹ Department of Hematology and Critical Care Medicine, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China.
² Cancer Research Institute, Central South University, Changsha, Hunan, China.
³ Department of Blood Transfusion, The Third Xiangya Hospital, Central South University, Changsha, Hunan, China.

Abstract

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 via mitophagy in inflammatory diseases such as sepsis.

Keywords: NLRP3 inflammasome; PHB1; immunity; mitophagy; sepsis.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Humans
Inflammasomes* / metabolism
Mitophagy
NLR Family, Pyrin Domain-Containing 3 Protein / genetics
NLR Family, Pyrin Domain-Containing 3 Protein / metabolism
Sepsis*

Substances

Inflammasomes
NLR Family, Pyrin Domain-Containing 3 Protein

Grants and funding

This work was supported by National Key R&D Program of China (No.2020YFC2005000), National Natural Science Foundation of China (No. 81700127), Natural Science Foundation of Hunan Province (No. 2020JJ5860, 2021JJ31017), Clinical Medical Technology Innovation Guide Project of Hunan Province (No. 2021SK53715), the Fundamental Research Funds for the Central Universities of Central South University (2022ZZTS0935).