1. Academic Validation
  2. Neutrophil ALDH2 is a new therapeutic target for the effective treatment of sepsis-induced ARDS

Neutrophil ALDH2 is a new therapeutic target for the effective treatment of sepsis-induced ARDS

  • Cell Mol Immunol. 2024 Mar 12. doi: 10.1038/s41423-024-01146-w.
Changchang Xu # 1 2 3 4 Lin Zhang # 1 2 3 4 Shaoyu Xu 1 2 3 4 Zichen Wang 1 2 3 4 Qi Han 1 2 3 4 Ying Lv 1 2 3 4 Xingfang Wang 1 2 3 4 Xiangxin Zhang 1 2 3 4 Qingju Zhang 1 2 3 4 Ying Zhang 1 2 3 4 Simeng He 1 2 3 4 Qiuhuan Yuan 1 2 3 4 Yuan Bian 1 2 3 4 Chuanbao Li 1 2 3 4 Jiali Wang 1 2 3 4 Feng Xu 1 2 3 4 Yihai Cao 5 Jiaojiao Pang 6 7 8 9 Yuguo Chen 10 11 12 13
Affiliations

Affiliations

  • 1 Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China.
  • 2 Chest Pain Center, Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China.
  • 3 Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China.
  • 4 The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China.
  • 5 Department of Microbiology, Tumor and Cell Biology, Karolinska Institute, Stockholm, 171 65, Sweden.
  • 6 Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China. jiaojiaopang@email.sdu.edu.cn.
  • 7 Chest Pain Center, Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China. jiaojiaopang@email.sdu.edu.cn.
  • 8 Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China. jiaojiaopang@email.sdu.edu.cn.
  • 9 The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China. jiaojiaopang@email.sdu.edu.cn.
  • 10 Department of Emergency Medicine, Qilu Hospital of Shandong University, Jinan, China. chen919085@sdu.edu.cn.
  • 11 Chest Pain Center, Shandong Provincial Clinical Research Center for Emergency and Critical Care Medicine, Institute of Emergency and Critical Care Medicine of Shandong University, Qilu Hospital of Shandong University, Jinan, China. chen919085@sdu.edu.cn.
  • 12 Key Laboratory of Emergency and Critical Care Medicine of Shandong Province, Key Laboratory of Cardiopulmonary-Cerebral Resuscitation Research of Shandong Province, Shandong Provincial Engineering Laboratory for Emergency and Critical Care Medicine, Qilu Hospital of Shandong University, Jinan, China. chen919085@sdu.edu.cn.
  • 13 The Key Laboratory of Cardiovascular Remodeling and Function Research, Chinese Ministry of Education, Chinese Ministry of Health and Chinese Academy of Medical Sciences, The State and Shandong Province Joint Key Laboratory of Translational Cardiovascular Medicine, Qilu Hospital of Shandong University, Jinan, China. chen919085@sdu.edu.cn.
  • # Contributed equally.
Abstract

Acetaldehyde dehydrogenase 2 (ALDH2) mutations are commonly found in a subgroup of the Asian population. However, the role of ALDH2 in septic acute respiratory distress syndrome (ARDS) remains unknown. Here, we showed that human subjects carrying the ALDH2rs671 mutation were highly susceptible to developing septic ARDS. Intriguingly, ALDH2rs671-ARDS patients showed higher levels of blood cell-free DNA (cfDNA) and myeloperoxidase (MPO)-DNA than ALDH2WT-ARDS patients. To investigate the mechanisms underlying ALDH2 deficiency in the development of septic ARDS, we utilized ALDH2 gene knockout mice and ALDH2rs671 gene knock-in mice. In clinically relevant mouse sepsis models, ALDH2-/- mice and ALDH2rs671 mice exhibited pulmonary and circulating NETosis, a specific process that releases neutrophil extracellular traps (NETs) from neutrophils. Furthermore, we discovered that NETosis strongly promoted endothelial destruction, accelerated vascular leakage, and exacerbated septic ARDS. At the molecular level, ALDH2 increased K48-linked polyubiquitination and degradation of peptidylarginine deiminase 4 (PAD4) to inhibit NETosis, which was achieved by promoting PAD4 binding to the E3 ubiquitin ligase CHIP. Pharmacological administration of the ALDH2-specific activator Alda-1 substantially alleviated septic ARDS by inhibiting NETosis. Together, our data reveal a novel ALDH2-based protective mechanism against septic ARDS, and the activation of ALDH2 may be an effective treatment strategy for sepsis.

Keywords

ALDH2; ARDS; NETosis; Sepsis.

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