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通过NLRP3炎性小体激活COX-2/mPGES-1/PGE-2级联反应，促进广州管圆线虫诱导的嗜酸性粒细胞性脑膜脑炎。

Activation of the COX-2/mPGES-1/PGE-2 cascade through the NLRP3 inflammasome contributes to Angiostrongylus cantonensis-induced eosinophilic meningoencephalitis.

作者信息

Chen Ke-Min, Lu Cheng-You, Lai Shih-Chan

机构信息

Department of Parasitology, Chung Shan Medical University, Taichung, 402, Taiwan.

Department of Post-Baccalaureate Medicine, College of Medicine, National Chung Hsing University, Taichung, Taiwan.

出版信息

Parasitol Res. 2025 Jan 20;124(1):9. doi: 10.1007/s00436-025-08454-8.

DOI:10.1007/s00436-025-08454-8
PMID:39832004
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC11753341/
Abstract

Prostaglandin E2 (PGE-2) is synthesised by cyclooxygenase-2 (COX-2) and microsomal prostaglandin E synthase 1 (mPGES-1). PGE-2 exhibits pro-inflammatory properties in inflammatory conditions. However, there remains limited understanding of the COX-2/mPGES-1/PGE-2 pathway in Angiostrongylus cantonensis-induced meningoencephalitis. This study revealed several key findings regarding the activation of the COX-2/mPGES-1/PGE-2 pathway and its correlation with eosinophilic meningoencephalitis induced by A. cantonensis infection. Immunostaining revealed an increase in the expression of COX-2 and mPGES-1 in the subarachnoid space and glial cells compared to control subjects. Inhibition of the NLRP3 inflammasome by small interfering RNA (siRNA) blocked extracellular secretory proteins (ESPs) stimulated COX-2, mPGES-1 and PGE-2 in microglia. MCC950, an NLRP3 inhibitor, inhibited the levels of the COX-2, mPGES-1, and PGE-2 proteins induced by A. cantonensis in mice. Treatment of mice infected with A. cantonensis with the COX-2 inhibitor NS398 significantly reduced the levels of mPGES-1, PGE-2, and matrix metalloproteinase-9 (MMP-9) levels. Similarly, the mPGES-1 inhibitor MF63 significantly reduced PGE-2 and MMP-9 levels in A. cantonensis-infected mice. Administration of MCC950, NS398, or MF63 resulted in marked attenuation of blood-brain barrier (BBB) permeability and eosinophil counts in A. cantonensis-infected mice. These findings highlight the critical role of the COX-2/mPGES-1/PGE-2 pathway and its regulation by the NLRP3 inflammasome in the pathogenesis of eosinophilic meningoencephalitis induced by A. cantonensis infection. Furthermore, pharmacological interventions targeting this pathway, such as MCC950, NS398, and MF63, show promising therapeutic potential in mitigating associated inflammatory responses and disruption of the BBB. The results indicate that blocking NLRP3 using pharmacological (MCC950) and gene silencing (siNLRP3) methods emphasised the crucial involvement of NLRP3 in the COX-2/mPGES-1/PGE-2 pathway. This suggests that the activation of the COX-2/mPGES-1/PGE-2 axis in response to A. cantonensis infection may be mediated through a mechanism involving the NLRP3 inflammasome.

摘要

前列腺素E2（PGE-2）由环氧化酶-2（COX-2）和微粒体前列腺素E合酶1（mPGES-1）合成。在炎症条件下，PGE-2具有促炎特性。然而，人们对广州管圆线虫诱导的脑膜脑炎中COX-2/mPGES-1/PGE-2途径的了解仍然有限。本研究揭示了关于COX-2/mPGES-1/PGE-2途径的激活及其与广州管圆线虫感染诱导的嗜酸性脑膜脑炎相关性的几个关键发现。免疫染色显示，与对照组相比，蛛网膜下腔和神经胶质细胞中COX-2和mPGES-1的表达增加。小干扰RNA（siRNA）对NLRP3炎性小体的抑制作用阻断了细胞外分泌蛋白（ESP）刺激小胶质细胞中COX-2、mPGES-1和PGE-2的表达。NLRP3抑制剂MCC950可抑制广州管圆线虫诱导的小鼠体内COX-2、mPGES-1和PGE-2蛋白水平。用COX-2抑制剂NS398治疗感染广州管圆线虫的小鼠，可显著降低mPGES-1、PGE-2和基质金属蛋白酶-9（MMP-9）的水平。同样，mPGES-1抑制剂MF63可显著降低感染广州管圆线虫小鼠体内的PGE-2和MMP-9水平。给予MCC950、NS398或MF63可显著减轻感染广州管圆线虫小鼠的血脑屏障（BBB）通透性和嗜酸性粒细胞计数。这些发现突出了COX-2/mPGES-1/PGE-2途径及其受NLRP3炎性小体调节在广州管圆线虫感染诱导的嗜酸性脑膜脑炎发病机制中的关键作用。此外，针对该途径的药物干预，如MCC950、NS398和MF63，在减轻相关炎症反应和血脑屏障破坏方面显示出有前景的治疗潜力。结果表明，使用药物（MCC950）和基因沉默（siNLRP3）方法阻断NLRP3，强调了NLRP3在COX-2/mPGES-1/PGE-2途径中的关键作用。这表明，广州管圆线虫感染后COX-2/mPGES-1/PGE-2轴的激活可能是通过一种涉及NLRP3炎性小体的机制介导的。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e7c/11753341/3b1fe3408294/436_2025_8454_Fig10_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e7c/11753341/6ccc2a3c459a/436_2025_8454_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e7c/11753341/3b1fe3408294/436_2025_8454_Fig10_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e7c/11753341/af088706c4ad/436_2025_8454_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e7c/11753341/b03b2a86481d/436_2025_8454_Fig2_HTML.jpg
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https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e7c/11753341/af5ba77cda0c/436_2025_8454_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e7c/11753341/b5ca581b26fa/436_2025_8454_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e7c/11753341/5d4bf0cb9ada/436_2025_8454_Fig6_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e7c/11753341/6fe4384f05e3/436_2025_8454_Fig7_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e7c/11753341/9565e48e69d1/436_2025_8454_Fig8_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e7c/11753341/6ccc2a3c459a/436_2025_8454_Fig9_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/8e7c/11753341/3b1fe3408294/436_2025_8454_Fig10_HTML.jpg

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[5]
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[6]
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[10]
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