Human Amniotic Membrane Mesenchymal Stem Cell-Synthesized PGE[sub.2] Exerts an Immunomodulatory Effect on Neutrophil Extracellular Trap in a PAD-4-Dependent Pathway through EP2 and EP4

• Published in: Cells (Basel, Switzerland) Vol. 11; no. 18
• Main Authors: Estúa-Acosta, Gibrán Alejandro, Buentello-Volante, Beatriz, Magaña-Guerrero, Fátima Sofía, Flores, José Eduardo-Aguayo, Vivanco-Rojas, Oscar, Castro-Salas, Ilse, Zarco-Ávila, Karla, García-Mejía, Mariana A, Garfias, Yonathan
• Format: Journal Article
• Language: English
• Published: MDPI AG 01-09-2022
• Subjects: Amnion; Amniotic sac; Health aspects; Neutrophils; Stem cells; Mexico
• ISSN: 2073-4409; 2073-4409
• DOI: 10.3390/cells11182831

Human amniotic membrane mesenchymal stem cells (hAM-MSC) secrete a myriad of components with immunosuppressive activities. In the present research, we aimed to describe the effect of prostaglandin E[sub.2] (PGE[sub.2] ) secreted by hAM-MSCs on neutrophil extracellular trap (NET) release and to characterize the role of its receptors (EP2/EP4) in PAD-4 and NFκB activity in neutrophils. Human peripheral blood neutrophils were ionomycin-stimulated in the presence of hAM-MSC conditioned medium (CM) treated or not with the selective PGE[sub.2] inhibitor MF-63, PGE[sub.2] , EP2/EP4 agonists, and the selective PAD-4 inhibitor GSK-484. NET release, PAD-4, and NFκB activation were analyzed. Ionomycin induced NET release, which was inhibited in the presence of hAM-MSC-CM, while CM from hAM-MSCs treated with MF-63 prevented NET release inhibition. PGE[sub.2] and EP2/EP4 agonists, and GSK-484 inhibited NET release. EP2/EP4 agonists and GSK-484 inhibited H3-citrullination but did not affect PAD-4 protein expression. Finally, PGE[sub.2] and EP2/EP4 agonists and GSK-484 increased NFκB phosphorylation. Taken together, these results suggest that hAM-MSC exert their immunomodulatory activities through PGE[sub.2,] inhibiting NET release in a PAD-4-dependent pathway. This research proposes a new mechanism by which hAM-MSC exert their activities when modulating the innate immune response and inhibiting NET release.