Matrine suppresses NLRP3 inflammasome activation via regulating PTPN2/JNK/SREBP2 pathway in sepsis

  • Phytomedicine. 2023 Jan:109:154574. doi: 10.1016/j.phymed.2022.154574.
Xu Wang  1 ,  Fu-Peng Wu  2 ,  Yu-Ran Huang  1 ,  Hai-Dong Li  1 ,  Xin-Yue Cao  1 ,  Yan You  1 ,  Zhe-Feng Meng  3 ,  Ke-Yu Sun  4 ,  Xiao-Yan Shen  5
Affiliations
  • 1. Minhang Hospital and Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China.
  • 2. Department of Emergency, Minhang Hospital, Fudan University, Shanghai, China.
  • 3. Minhang Hospital, Fudan University, Shanghai, China. Electronic address: [email protected].
  • 4. Department of Emergency, Minhang Hospital, Fudan University, Shanghai, China. Electronic address: [email protected].
  • 5. Minhang Hospital and Department of Pharmacology, School of Pharmacy, Fudan University, Shanghai, China. Electronic address: [email protected].
PMID: 36610161 DOI: 10.1016/j.phymed.2022.154574
Abstract

Background: Sepsis is defined as life-threatening organ dysfunction caused by a dysregulated host response to Infection. Abnormal activation of NOD-like Receptor thermal protein domain associated protein 3 (NLRP3) inflammasome plays a vital role in the pathogenesis of sepsis. Matrine is proved to show good anti-inflammatory properties, whereas its effect and the underlying molecular machinery on sepsis remains unclear.

Purpose: The aim of this study is to evaluate the effect and mechanism of Matrine on sepsis.

Study design: THP-1 cells and J774A.1 cells were stimulated by lipopolysaccharide (LPS) with nigericin or adenosine triphosphate (ATP) to establish an in vitro model. Cecal ligation and puncture (CLP)-induced sepsis mouse model was used. Matrine was given by gavage.

Methods: To investigate the NLRP3 inflammasome activation, phorbol myristate acetate (PMA)-induced THP-1 cells were first primed with LPS and then stimulated by matrine, followed by treatment with nigericin or ATP. The concentration of interleukin 1β (IL-1β) and interleukin 18 (IL-18) in the Cell Culture supernatant was detected. The mechanism was explored by cell death assay, immunoblots and immunofluorescence in vitro. C57BL/6 mice were intragastrically administered with matrine for 5 days before CLP. The therapeutic effect of matrine was evaluated by symptoms, pathological analysis, ELISA and RT-qPCR.

Results: Our results revealed that matrine inhibited IL-1β and IL-18 secretion, suppressed Caspase-1 activation, reduced cell death, and blocked ASC speck formation upon NLRP3 inflammasome activation. Furthermore, matrine restrains NLRP3 inflammasome activation as well as Pyroptosis through regulating the protein tyrosine Phosphatase non-receptor type 2 (PTPN2)/JNK/SREBP2 signaling. Matrine also prominently improved the symptoms and pathological changes with reduced levels of TNF-α, IL-1β, and IL-6 in the lung tissues and serum in a dose-dependent manner.

Conclusion: Matrine effectively alleviates the symptoms of CLP-induced sepsis in mice, restrains NLRP3 inflammasome activation by regulating PTPN2/JNK/SREBP2 signaling pathway, and may become a promising therapeutic agent for sepsis treatment.

Keywords
CLP-induced sepsis; Macrophages; Matrine; PTPN2/JNK/SREBP2; Pyroptosis.
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