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.
【저자키워드】 COVID19, Spike protein, NLRP3, um-PEA, murine alveolar macrophages, 【초록키워드】 COVID-19, Anti-inflammatory, nitric oxide, IL-6, TLR4, cytokine, ACE-2, proinflammatory, SARS-CoV-2 spike glycoprotein, pathway, Alpha, receptors, receptor, angiotensin-converting enzyme-2, mechanism of action, alveolar macrophage, TNF-α, NF-κB, marker, IL-1β, immunomodulatory activity, Inflammatory response, COX2, MAPK, Activation, therapeutic potential, activities, upregulation, downregulation, selective, MOST, downstream, nuclear, murine, tested, analyzed, caused, involved, inhibit, reduced, demonstrated, increase in, several gene, anti-inflammatory property, inflammatory pathway, primary culture, 【제목키워드】 SARS-CoV-2, spike, response, palmitoylethanolamide,