Life sciences · 2025
Diamine oxidase acts as a novel risk factor in abnormal inflammation via mediating "cytosolic ROS-autophagy-IFN-γ" axis in NK cells.
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He Dongmei, Dai Weihong, Cui Yiqin, Gao Rui, Yang Xue, Li Wei, Zhou Jing, Yin Shuangqin, Kuang Tianyin, Zhu Junyu, Luo Li, Wang Rixing, Qu Ye, Yun Caihong, Liu Lizhu, Diao Xiaoyan, Ma Xiaoyuan, Liang Huaping, Wang Fangjie
Аннотация
AIMS: Diamine oxidase (DAO), a well-established biomarker for intestinal damage, histamine intolerance or tumorigenesis, has rarely been reported in immune regulation. This study aimed to identify DAO as a critical enhancer of abnormal inflammation by promoting interferon-gamma (IFN-γ) production from natural killer (NK) cells.
MAIN METHODS: Clinical bioinformatics analyzed aoc1 (DAO-coding gene) expression in PBMCs from patients with inflammatory diseases. Murine models (LPS-induced systemic inflammation, sepsis, DSS-induced colitis) using DAO-/- mice, alongside DAO-/- NK92 cells and DAO inhibitor DIZE, were employed for phenotypic validation. Cellular profiling, bone marrow chimeras, reciprocal transplantation, RNA-sequence, non-targeted metabolomics, and flow cytometry were utilized to dissect DAO's mechanisms in NK cells.
KEY FINDINGS: DAO deficiency protected mice from inflammatory pathology by suppressing IFN-γ production. NK cells were identified as the primary target cells during the process, with DAO acting intracellularly to promote IFN-γ via a reactive oxygen species (ROS)-autophagy axis. DAO-derived ROS, distinct from mitochondrial or NOX2 sources, enhanced autophagic flux during NK activation, enabling IFN-γ biosynthesis. DAO did not affect NK homeostasis, including maturation, proliferation, or receptor expressions.
SIGNIFICANCE: DAO is a novel risk factor in inflammatory diseases, driving IFN-γ production through ROS-autophagy signaling in NK cells. Targeting DAO may offer therapeutic strategies for conditions involving dysregulated IFN-γ responses, including sepsis, colitis, and autoimmune disorders.
MAIN METHODS: Clinical bioinformatics analyzed aoc1 (DAO-coding gene) expression in PBMCs from patients with inflammatory diseases. Murine models (LPS-induced systemic inflammation, sepsis, DSS-induced colitis) using DAO-/- mice, alongside DAO-/- NK92 cells and DAO inhibitor DIZE, were employed for phenotypic validation. Cellular profiling, bone marrow chimeras, reciprocal transplantation, RNA-sequence, non-targeted metabolomics, and flow cytometry were utilized to dissect DAO's mechanisms in NK cells.
KEY FINDINGS: DAO deficiency protected mice from inflammatory pathology by suppressing IFN-γ production. NK cells were identified as the primary target cells during the process, with DAO acting intracellularly to promote IFN-γ via a reactive oxygen species (ROS)-autophagy axis. DAO-derived ROS, distinct from mitochondrial or NOX2 sources, enhanced autophagic flux during NK activation, enabling IFN-γ biosynthesis. DAO did not affect NK homeostasis, including maturation, proliferation, or receptor expressions.
SIGNIFICANCE: DAO is a novel risk factor in inflammatory diseases, driving IFN-γ production through ROS-autophagy signaling in NK cells. Targeting DAO may offer therapeutic strategies for conditions involving dysregulated IFN-γ responses, including sepsis, colitis, and autoimmune disorders.