Scholarlink

<p>Phospholipase A<sub>2</sub> (PLA<sub>2</sub>) is a crucial enzyme in lipid metabolism and inflammatory signaling, playing a significant role in macrophage activation and neuroinflammation. However, its role in Japanese encephalitis virus (JEV)-mediated immune responses remains unclear. In this study, we show that PLA<sub>2</sub> and its associated receptors, lysophosphatidic acid receptors (LPAR1 and LPAR3), are significantly upregulated at 24&#xa0;h post-JEV infection, suggesting their involvement in JEV-induced inflammatory responses. To investigate the effect of PLA<sub>2</sub> inhibition, we used arachidonyl trifluoromethyl ketone (AACOCF<sub>3</sub>). Molecular docking using AutoDock Vina 1.1.2, supported by Protein Data Bank and AlphaFold structures, indicated that AACOCF<sub>3</sub> interacts with key inflammatory targets including gp91<sup>phox</sup> (− 7.9&#xa0;kcal/mol) and LPAR3 (− 7.8&#xa0;kcal/mol), suggesting its potential to modulate inflammatory and oxidative pathways. In vitro studies in JEV-infected macrophages demonstrated that AACOCF<sub>3</sub> reduced activation of calcium-dependent cytosolic (c) PLA<sub>2</sub> expression and phosphorylation, LPAR1, 3, MAPK signaling (JNK, ERK1/2, p38), and NF-κB protein levels, along with a reduction in JE viral RNA levels, likely reflecting indirect effects mediated through host pathway modulation. AACOCF<sub>3</sub> also decreased proinflammatory cytokines (IL-1β, TNF-α) and autophagy-related markers (pAkt, LC3-II/I, SQSTM1/p6<sub>2</sub>), and reduced expression of the ROS-generating enzyme gp91<sup>phox</sup> (NOX2), indicating partial attenuation of inflammatory and oxidative stress–associated pathways. Oxidative stress was assessed via gp91<sup>phox</sup> expression, and NF-κB was evaluated at protein level. These findings suggest that PLA<sub>2</sub> contributes to JEV-induced inflammatory signaling, and that its inhibition modulates host responses during infection in vitro, rather than exerting a definitive therapeutic effect.</p>

错误：搜索内容不能为空，请输入英文关键词
错误：关键词超出字数限制，请精简
高级检索

Targeting phospholipase A2 with arachidonyl trifluoromethyl ketone modulates macrophage activation during Japanese encephalitis virus infection

  • 期刊论文

  • 发表日期：

    2026年5月26日

查看全文
  • Alok Kumar,
  • Gajendra Singh,
  • Francesco Zonta,
  • Qiujie Zhu,
  • Anjali Singh,
  • Abhishek Saxena,
  • Devlina Ghosh

摘要

Phospholipase A2 (PLA2) is a crucial enzyme in lipid metabolism and inflammatory signaling, playing a significant role in macrophage activation and neuroinflammation. However, its role in Japanese encephalitis virus (JEV)-mediated immune responses remains unclear. In this study, we show that PLA2 and its associated receptors, lysophosphatidic acid receptors (LPAR1 and LPAR3), are significantly upregulated at 24 h post-JEV infection, suggesting their involvement in JEV-induced inflammatory responses. To investigate the effect of PLA2 inhibition, we used arachidonyl trifluoromethyl ketone (AACOCF3). Molecular docking using AutoDock Vina 1.1.2, supported by Protein Data Bank and AlphaFold structures, indicated that AACOCF3 interacts with key inflammatory targets including gp91phox (− 7.9 kcal/mol) and LPAR3 (− 7.8 kcal/mol), suggesting its potential to modulate inflammatory and oxidative pathways. In vitro studies in JEV-infected macrophages demonstrated that AACOCF3 reduced activation of calcium-dependent cytosolic (c) PLA2 expression and phosphorylation, LPAR1, 3, MAPK signaling (JNK, ERK1/2, p38), and NF-κB protein levels, along with a reduction in JE viral RNA levels, likely reflecting indirect effects mediated through host pathway modulation. AACOCF3 also decreased proinflammatory cytokines (IL-1β, TNF-α) and autophagy-related markers (pAkt, LC3-II/I, SQSTM1/p62), and reduced expression of the ROS-generating enzyme gp91phox (NOX2), indicating partial attenuation of inflammatory and oxidative stress–associated pathways. Oxidative stress was assessed via gp91phox expression, and NF-κB was evaluated at protein level. These findings suggest that PLA2 contributes to JEV-induced inflammatory signaling, and that its inhibition modulates host responses during infection in vitro, rather than exerting a definitive therapeutic effect.