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Pig Liver Esterase Hydrolysis of 2-Arachidonoglycerol Exacerbates PRRSV-Induced Inflammation via PI3K-Akt-NF-κB
Yuelin Fu1,2, Huiwen Zhu1,2, Qiling Xiao1
1State Key Laboratory of Agriculture Microbiology, College of Veterinary Medicine, Huazhong Agricultural University, Wuhan 430070, China.
Abstract:
Inflammation is essential for host defense but requires strict regulation to prevent immunopathology. This study reveals how pig liver esterase (PLE) in alveolar macrophages (PAMs) modulates PRRSV-induced inflammation through endocannabinoid metabolism. We identified PLE6 as the dominant hydrolytically active subtype in PAMs. Functional studies demonstrated that PLE promotes pro-inflammatory cytokine expression during PRRSV infection, while its substrate 2-arachidonoylglycerol (2-AG) exerts anti-inflammatory effects. Animal experiments confirmed that PLE inhibition reduces pulmonary inflammation and tissue damage in PRRSV-infected piglets. Transcriptomic and mechanistic analyses revealed that PLE hydrolyzes 2-AG to activate the PI3K-Akt-NF-κB pathway, particularly through enhanced phosphorylation of Akt and p65. These findings establish a novel pathological mechanism where PLE-mediated 2-AG degradation disrupts endocannabinoid homeostasis, amplifying PRRSV-induced inflammation. The study provides therapeutic insights for targeting endocannabinoid hydrolysis to control inflammatory diseases.
Insights
Pig liver esterase (PLE) in lung macrophages amplifies inflammation during PRRSV infection by degrading the anti-inflammatory endocannabinoid 2-AG. Inhibiting PLE reduces lung inflammation and damage in piglets.
Area of Science:
- Immunology
- Biochemistry
- Veterinary Medicine
Background:
- Inflammation is crucial for host defense but must be tightly regulated to prevent immunopathology.
- Porcine reproductive and respiratory syndrome virus (PRRSV) infection triggers significant pulmonary inflammation.
- Alveolar macrophages play a key role in regulating lung inflammation during viral infections.
Purpose of the Study:
- To investigate the role of pig liver esterase (PLE) in alveolar macrophages (PAMs) in modulating PRRSV-induced inflammation.
- To elucidate the mechanism by which PLE affects endocannabinoid metabolism and inflammatory signaling pathways.
- To evaluate the therapeutic potential of targeting PLE for controlling PRRSV-induced lung inflammation.
Main Methods:
- Identification and characterization of PLE subtypes in PAMs.
- In vitro functional assays to assess PLE activity and its effect on cytokine expression.
- In vivo animal experiments using PRRSV-infected piglets treated with a PLE inhibitor.
- Transcriptomic analysis and mechanistic studies involving the PI3K-Akt-NF-κB signaling pathway.
Main Results:
- PLE6 was identified as the dominant active PLE subtype in PAMs.
- PLE promotes pro-inflammatory cytokine expression, while its substrate 2-arachidonoylglycerol (2-AG) has anti-inflammatory effects.
- Inhibition of PLE significantly reduced pulmonary inflammation and tissue damage in PRRSV-infected piglets.
- PLE hydrolyzes 2-AG, leading to the activation of the PI3K-Akt-NF-κB pathway via enhanced Akt and p65 phosphorylation.
Conclusions:
- PLE-mediated degradation of 2-AG disrupts endocannabinoid homeostasis, exacerbating PRRSV-induced inflammation.
- This study reveals a novel pathological mechanism linking endocannabinoid metabolism to viral-induced inflammation.
- Targeting endocannabinoid hydrolysis, specifically PLE activity, offers a potential therapeutic strategy for inflammatory lung diseases like PRRSV.
