2. Academic Validation
  3. Targeting macrophagic RasGRP1 with catechin hydrate ameliorates sepsis-induced multiorgan dysfunction

Targeting macrophagic RasGRP1 with catechin hydrate ameliorates sepsis-induced multiorgan dysfunction

  • Phytomedicine. 2024 May 12:130:155733. doi: 10.1016/j.phymed.2024.155733.
Zhixi Li 1,  Yongjing Yu 1,  Yue Bu 2,  Chang Liu 1,  Enran Liu 3,  Jiaqi Jin 4,  Guangmin Chen 5,  Chenglong Li 6,  Hongyu Wang 7,  Hui Li 3,  Lei Han 3,  Yan Zhang 3,  Weidong Gong 3,  Juan Luo 3,  Haichuan Xiao 3,  Ziyong Yue 8
Affiliations

Affiliations

  • 1 Department of Anesthesiology, Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin 150001, PR China; Heilongjiang Province Key Laboratory of Research on Anesthesiology and Critical Care Medicine, 246 Xuefu Road, Harbin 150001, PR China; The Key Laboratory of Myocardial Ischemia Organization, Chinese Ministry of Education, 246 Xuefu Road, Harbin 150001, PR China.
  • 2 Department of Anesthesiology, Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin 150001, PR China; Heilongjiang Province Key Laboratory of Research on Anesthesiology and Critical Care Medicine, 246 Xuefu Road, Harbin 150001, PR China; Department of Pain Medicine, Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin 150001, PR China.
  • 3 Department of Anesthesiology, Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin 150001, PR China; Heilongjiang Province Key Laboratory of Research on Anesthesiology and Critical Care Medicine, 246 Xuefu Road, Harbin 150001, PR China.
  • 4 The Key Laboratory of Myocardial Ischemia Organization, Chinese Ministry of Education, 246 Xuefu Road, Harbin 150001, PR China; Department of Neurology, Xuanwu Hospital, Capital Medical University, 45 Changchun Road, Beijing 100053, PR China.
  • 5 Department of Anesthesiology, First Affiliated Hospital of Harbin Medical University, 199 Dazhi Road, Harbin 150001, PR China.
  • 6 Department of Anesthesiology, Fourth Affiliated Hospital of Harbin Medical University, 37 Yiyuan Road, Harbin 150001, PR China.
  • 7 Department of Cardiology, First Affiliated Hospital of Harbin Medical University, 199 Dazhi Road, Harbin 150001, PR China.
  • 8 Department of Anesthesiology, Second Affiliated Hospital of Harbin Medical University, 246 Xuefu Road, Harbin 150001, PR China; Heilongjiang Province Key Laboratory of Research on Anesthesiology and Critical Care Medicine, 246 Xuefu Road, Harbin 150001, PR China. Electronic address: yueziyong@hrbmu.edu.cn.
PMID: 38759314 DOI: 10.1016/j.phymed.2024.155733
Abstract

Background: The proinflammatory response induced by macrophages plays a crucial role in the development of sepsis and the resulting multiorgan dysfunction. Identifying new regulatory targets for macrophage homeostasis and devising effective treatment strategies remains a significant challenge in contemporary research.

Purpose: This study aims to identify new regulatory targets for macrophage homeostasis and develop effective strategies for treating sepsis.

Study design and methods: Macrophage infiltration in septic patients and in lungs, kidneys, and brains of caecum ligation and puncture (CLP)-induced septic mice was observed using CIBERSORT and immunofluorescence (IF). Upon integrating the MSigDB database and GSE65682 dataset, differently expressed macrophage-associated genes (DEMAGs) were identified. Critical DEMAGs were confirmed through machine learning. The protein level of the critical DEMAG was detected in PBMCs of septic patients, RAW264.7 cells, and mice lungs, kidneys, and brains using ELISA, western blot, immunohistochemistry, and IF. siRNA was applied to investigate the effect of the critical DEMAG in RAW264.7 cells. A natural product library was screened to find a compound targeting the critical DEMAG protein. The binding of compounds and proteins was analyzed through molecular docking, molecular dynamics simulations, CETSA, and MST analysis. The therapeutic efficacy of the compounds against sepsis was then evaluated through in vitro and in vivo experiments.

Results: Macrophage infiltration was inversely correlated with survival in septic patients. The critical differentially expressed molecule RasGRP1 was frequently observed in the PBMCs of septic patients, LPS-induced RAW264.7 cells, and the lungs, kidneys, and brains of septic mice. Silencing RasGRP1 alleviated proinflammatory response and oxidative stress in LPS-treated RAW264.7 cells. Catechin Hydrate (CH) was identified as an inhibitor of RasGRP1, capable of maintaining macrophage homeostasis and mitigating lung, kidney, and brain damage during sepsis.

Conclusion: This study demonstrates that RasGRP1, a novel activator of macrophage proinflammatory responses, plays a crucial role in the excessive inflammation and oxidative stress associated with sepsis. CH shows potential for treating sepsis by inhibiting RasGRP1.

Keywords

Acute kidney injury; Acute lung injury; Inflammation; Macrophage; Sepsis; Sepsis-associated encephalopathy.

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