Ultramicronized Palmitoylethanolamide Inhibits NLRP3 Inflammasome Expression and Pro-Inflammatory Response Activated by SARS-CoV-2 Spike Protein in Cultured Murine Alveolar Macrophages.

Alessandro Del Re,Chiara Corpetti,Giovanni Sarnelli,Giuseppe Esposito,Luisa Seguella,Irene Palenca,Barbara De Conno,Sara Rurgo,Marcella Pesce,Luca Steardo

doi:10.3390/metabo11090592

Abstract

Despite its possible therapeutic potential against COVID-19, the exact mechanism(s) by which palmitoylethanolamide (PEA) exerts its beneficial activity is still unclear. PEA has demonstrated analgesic, anti-allergic, and anti-inflammatory activities. Most of the anti-inflammatory properties of PEA arise from its ability to antagonize nuclear factor-κB (NF-κB) signalling pathway via the selective activation of the PPARα receptors. Acting at this site, PEA can downstream several genes involved in the inflammatory response, including cytokines (TNF-α, Il-1β) and other signal mediators, such as inducible nitric oxide synthase (iNOS) and COX2. To shed light on this, we tested the anti-inflammatory and immunomodulatory activity of ultramicronized(um)-PEA, both alone and in the presence of specific peroxisome proliferator-activated receptor alpha (PPAR-α) antagonist MK886, in primary cultures of murine alveolar macrophages exposed to SARS-CoV-2 spike glycoprotein (SP). SP challenge caused a significant concentration-dependent increase in proinflammatory markers (TLR4, p-p38 MAPK, NF-κB) paralleled to a marked upregulation of inflammasome-dependent inflammatory pathways (NLRP3, Caspase-1) with IL-6, IL-1β, TNF-α over-release, compared to vehicle group. We also observed a significant concentration-dependent increase in angiotensin-converting enzyme-2 (ACE-2) following SP challenge. um-PEA concentration-dependently reduced all the analyzed proinflammatory markers fostering a parallel downregulation of ACE-2. Our data show for the first time that um-PEA, via PPAR-α, markedly inhibits the SP induced NLRP3 signalling pathway outlining a novel mechanism of action of this lipid against COVID-19.

Highlights

From the first outbreak of the COVID-19 pandemic, SARS-CoV-2 has caused more than 3 million deaths to date [1]
Western Blot Analysis Reveal Reduction of Pro-Inflammatory Proteins Expression Arbitrated by ultramicronized PEA (um-PEA) in Alveolar Macrophages Challenged with spike glycoprotein (SP)
The effect of um-PEA was tested in cultured alveolar macrophages exposed to increasing concentration of SP for 24 h, in the presence and absence of specific PEA receptor PPAR-α antagonist MK886

Summary

Introduction

From the first outbreak of the COVID-19 pandemic, SARS-CoV-2 has caused more than 3 million deaths to date [1]. In the most severe cases, COVID-19 patients could develop a peculiar form of uncontrolled pulmonary inflammation known as acute respiratory distress syndrome (ARDS), which is primarily responsible for intensive care unit (ICU) admissions and the need for medical ventilation [4]. This condition is due to an over-activation of the innate immune response, mostly triggered by macrophages and mast cells, leading to an over-release of proinflammatory mediators, such as tumor necrosis factor-alpha (TNF-α), Interleukin-6 (IL-6), and Interleukin-1beta (IL-1β), which could determine extensive fibrosis and reduced lung capacity, which can in turn lead to patients’ death [5,6]. Drugs potentially manageable for home therapies able to target the most involved mediators in ARDS onset would be crucial in reducing the pressure on the intensive care units and hospitalizations

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