Journal Article

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

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

2021

Overview

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.

• Publisher: MDPI AG,MDPI
• Subject: ACE2 / Alveoli / Analgesics / Angiotensin / Angiotensin-converting enzyme 2 / Anti-inflammatory agents / Caspase-1 / Coronaviruses / COVID-19 / COVID19 / Cyclooxygenase-2 / Cytokines / Cytotoxicity / IL-1β / Immunomodulation / Infections / Inflammasomes / Inflammation / Intensive care / Interleukin 6 / Macrophages / MAP kinase / murine alveolar macrophages / NF-κB protein / Nitric-oxide synthase / NLRP3 / Palmitoylethanolamide / Peptidyl-dipeptidase A / Peroxisome proliferator-activated receptors / Protein expression / Proteins / Severe acute respiratory syndrome coronavirus 2 / Signal transduction / Spike glycoprotein / Spike protein / TLR4 protein / Toll-like receptors / Tumor necrosis factor-TNF / Tumor necrosis factor-α / um-PEA