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

• Published in: Cellular & molecular immunology Vol. 21; no. 5; pp. 510 - 526
• Main Authors: Xu, Changchang, Zhang, Lin, Xu, Shaoyu, Wang, Zichen, Han, Qi, Lv, Ying, Wang, Xingfang, Zhang, Xiangxin, Zhang, Qingju, Zhang, Ying, He, Simeng, Yuan, Qiuhuan, Bian, Yuan, Li, Chuanbao, Wang, Jiali, Xu, Feng, Cao, Yihai, Pang, Jiaojiao, Chen, Yuguo
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 01.05.2024; Nature Publishing Group
• Subjects: 631/250/1932; 631/250/1933; 631/250/254; 631/250/256/1980; 631/80/304; Acetaldehyde dehydrogenase; Aldehyde dehydrogenase; Aldehyde dehydrogenase (NAD); Aldehyde Dehydrogenase, Mitochondrial - genetics; Aldehyde Dehydrogenase, Mitochondrial - metabolism; Animal models; Animals; Antibodies; Biomedical and Life Sciences; Biomedicine; Blood levels; Disease Models, Animal; Extracellular Traps - metabolism; Female; Humans; Immunology; Leukocytes (neutrophilic); Male; Medical Microbiology; Medicin och hälsovetenskap; Mice; Mice, Inbred C57BL; Mice, Knockout; Microbiology; Mutation; Neutrophils; Neutrophils - immunology; Neutrophils - metabolism; Peroxidase; Peroxidase - metabolism; Protein-arginine deiminase; Protein-Arginine Deiminase Type 4 - metabolism; Respiratory distress syndrome; Respiratory Distress Syndrome - etiology; Respiratory Distress Syndrome - pathology; Sepsis; Sepsis - complications; Therapeutic targets; Ubiquitin-protein ligase; Ubiquitination; Vaccine; Sepsis; NETosis; ALDH2; ARDS
• ISSN: 2042-0226; 1672-7681; 2042-0226
• DOI: 10.1038/s41423-024-01146-w

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 ALDH2 rs671 mutation were highly susceptible to developing septic ARDS. Intriguingly, ALDH2 rs671 -ARDS patients showed higher levels of blood cell-free DNA (cfDNA) and myeloperoxidase (MPO)-DNA than ALDH2 WT -ARDS patients. To investigate the mechanisms underlying ALDH2 deficiency in the development of septic ARDS, we utilized Aldh2 gene knockout mice and Aldh2 rs671 gene knock-in mice. In clinically relevant mouse sepsis models, Aldh2 -/- mice and Aldh2 rs671 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.