2. Academic Validation
  3. Oroxylin A-induced Trained Immunity Promotes LC3-associated Phagocytosis in Macrophage in Protecting Mice Against Sepsis

Oroxylin A-induced Trained Immunity Promotes LC3-associated Phagocytosis in Macrophage in Protecting Mice Against Sepsis

  • Inflammation. 2024 May 13. doi: 10.1007/s10753-024-02033-2.
Lijie Yin 1,  Ziqian Bing 1,  Yaojun Zheng 1,  Yuchen Pan 2,  Yue Dong 1,  Jiali Wang 1,  Renjie Luo 1,  Yue Zhao 3 4,  Huan Dou 5 6,  Yayi Hou 7 8
Affiliations

Affiliations

  • 1 The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China.
  • 2 Jiangsu International Laboratory of Immunity and Metabolism, The Department of Pathogenic Biology and Immunology, Xuzhou Medical University, Xuzhou, 221004, China.
  • 3 The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China. zhyue@nju.edu.cn.
  • 4 Jiangsu Key Laboratory of Molecular Medicine, Nanjing, 210093, China. zhyue@nju.edu.cn.
  • 5 The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China. douhuan@nju.edu.cn.
  • 6 Jiangsu Key Laboratory of Molecular Medicine, Nanjing, 210093, China. douhuan@nju.edu.cn.
  • 7 The State Key Laboratory of Pharmaceutical Biotechnology, Division of Immunology, Medical School, Nanjing University, Nanjing, 210093, China. yayihou@nju.edu.cn.
  • 8 Jiangsu Key Laboratory of Molecular Medicine, Nanjing, 210093, China. yayihou@nju.edu.cn.
PMID: 38739341 DOI: 10.1007/s10753-024-02033-2
Abstract

Sepsis is defined as a dysregulated host response to Infection that leads to multiorgan failure. Innate immune memory, i.e., "trained immunity", can result in stronger immune responses and provide protection against various infections. Many biological agents, including β-glucan, can induce trained immunity, but these stimuli may cause uncontrolled inflammation. Oroxylin A (OA) is an active flavonoid compound that is derived from Scutellaria baicalensis. OA is an agonist for inducing trained immunity in vivo and in vitro, and β-glucan was used as a positive control. The protective effects of OA-induced trained immunity were evaluated in mouse models that were established by either lipopolysaccharide (LPS) administration or caecal ligation and puncture (CLP). The expression of inflammatory factors and signaling pathway components involved in trained immunity was evaluated in vitro using qRT‒PCR, western blotting (WB) and enzyme-linked immunosorbent assay (ELISA). Flow cytometry and confocal microscopy were used to examine Reactive Oxygen Species (ROS) levels and phagocytosis in trained macrophages. A PCR array was used to screen genes that were differentially expressed in trained macrophages. Here, we revealed that OA alleviated sepsis via trained immunity. OA-treated macrophages displayed increased glycolysis and mTOR phosphorylation, and mTOR inhibitors suppressed OA-induced trained immunity by effectively reprogramming macrophages. The PCR array revealed key genes in the mTOR signaling pathway in OA-treated macrophages. Furthermore, OA targeted the Dectin-1-syk axis to promote LC3-associated phagocytosis (LAP) by trained macrophages, thereby enhancing the ability of these macrophages to protect against Infection. This ability could be transferred to a new host via the adoptive transfer of peritoneal macrophages. This study is the first to provide new insights into the potential of OA-induced trained immunity to be used as a strategy to protect mice against sepsis by promoting LAP by macrophages.

Keywords

LC3-associated phagocytosis; macrophage; oroxylin A; sepsis; trained immunity.

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