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

1
Department of Physiology and Pharmacology “V. Erspamer”, Sapienza University of Rome, Piazzale Aldo Moro 5, 00185 Rome, Italy
2
Department of Clinical Medicine and Surgery, University of Naples “Federico II”, 80131 Naples, Italy
3
Department of Physiology, Michigan State University, East Lansing, MI 48824, USA
4
Department of Psychiatry, Giustino Fortunato University, 12, 82100 Benevento, Italy
*
Author to whom correspondence should be addressed.
Academic Editor: Pollen K. Yeung
Metabolites 2021, 11(9), 592; https://doi.org/10.3390/metabo11090592
Received: 5 August 2021 / Revised: 29 August 2021 / Accepted: 30 August 2021 / Published: 2 September 2021
(This article belongs to the Section Pharmacology and Drug Metabolism)
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. View Full-Text
Keywords: um-PEA; COVID19; NLRP3; murine alveolar macrophages; spike protein um-PEA; COVID19; NLRP3; murine alveolar macrophages; spike protein
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MDPI and ACS Style

Del Re, A.; Corpetti, C.; Pesce, M.; Seguella, L.; Steardo, L.; Palenca, I.; Rurgo, S.; De Conno, B.; Sarnelli, G.; Esposito, G. Ultramicronized Palmitoylethanolamide Inhibits NLRP3 Inflammasome Expression and Pro-Inflammatory Response Activated by SARS-CoV-2 Spike Protein in Cultured Murine Alveolar Macrophages. Metabolites 2021, 11, 592. https://doi.org/10.3390/metabo11090592

AMA Style

Del Re A, Corpetti C, Pesce M, Seguella L, Steardo L, Palenca I, Rurgo S, De Conno B, Sarnelli G, Esposito G. Ultramicronized Palmitoylethanolamide Inhibits NLRP3 Inflammasome Expression and Pro-Inflammatory Response Activated by SARS-CoV-2 Spike Protein in Cultured Murine Alveolar Macrophages. Metabolites. 2021; 11(9):592. https://doi.org/10.3390/metabo11090592

Chicago/Turabian Style

Del Re, Alessandro, Chiara Corpetti, Marcella Pesce, Luisa Seguella, Luca Steardo, Irene Palenca, Sara Rurgo, Barbara De Conno, Giovanni Sarnelli, and Giuseppe Esposito. 2021. "Ultramicronized Palmitoylethanolamide Inhibits NLRP3 Inflammasome Expression and Pro-Inflammatory Response Activated by SARS-CoV-2 Spike Protein in Cultured Murine Alveolar Macrophages" Metabolites 11, no. 9: 592. https://doi.org/10.3390/metabo11090592

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