title: PPAR activation induces M1 macrophage polarization via cPLA₂-COX-2 inhibition, activating ROS production against Leishmania mexicana.
abstract: Defence against Leishmania depends upon Th1 inflammatory response and, a major problem in susceptible models, is the turnoff of the leishmanicidal activity of macrophages with IL-10, IL-4, and COX-2 upregulation, as well as immunosuppressive PGE2, all together inhibiting the respiratory burst. Peroxisome proliferator-activated receptors (PPAR) activation is responsible for macrophages polarization on Leishmania susceptible models where microbicide functions are deactivated. In this paper, we demonstrated that, at least for L. mexicana, PPAR activation, mainly PPAR γ , induced macrophage activation through their polarization towards M1 profile with the increase of microbicide activity against intracellular pathogen L. mexicana. PPAR activation induced IL-10 downregulation, whereas the production of proinflammatory cytokines such as TNF- α , IL-1 β , and IL-6 remained high. Moreover, PPAR agonists treatment induced the deactivation of cPLA2-COX-2-prostaglandins pathway together with an increase in TLR4 expression, all of whose criteria meet the M1 macrophage profile. Finally, parasite burden, in treated macrophages, was lower than that in infected nontreated macrophages, most probably associated with the increase of respiratory burst in these treated cells. Based on the above data, we conclude that PPAR agonists used in this work induces M1 macrophages polarization via inhibition of cPLA2 and the increase of aggressive microbicidal activity via reactive oxygen species (ROS) production.
authors.affiliation: Departamento de Infectómica y Patogénesis Molecular, Centro de Investigación y de Estudios Avanzados del IPN, Avenida Instituto Politécnico Nacional No. 2508, Colonia San Pedro Zacatenco, Delegación Gustavo A. Madero, 07360 México, DF, Mexico.
authors.forename: J A
authors.initials: JA
authors.lastname: Díaz-Gandarilla
authors.forename: C
authors.initials: C
authors.lastname: Osorio-Trujillo
authors.forename: V I
authors.initials: VI
authors.lastname: Hernández-Ramírez
authors.forename: P
authors.initials: P
authors.lastname: Talamás-Rohana
mesh_terms: D000818:Animals; D002478:Cells, Cultured; D051546:Cyclooxygenase 2 / Q000235:genetics / Q000378:metabolism*; D052246:Cyclooxygenase 2 Inhibitors / Q000494:pharmacology; D015232:Dinoprostone / Q000378:metabolism; D054513:Group IV Phospholipases A2 / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D019746:Intramolecular Oxidoreductases / Q000378:metabolism; D007894:Leishmania mexicana / Q000187:drug effects / Q000378:metabolism* / Q000472:pathogenicity; D016774:Leishmaniasis, Diffuse Cutaneous / Q000235:genetics / Q000378:metabolism* / Q000469:parasitology; D008264:Macrophages / Q000378:metabolism; D051379:Mice; D047495:PPAR gamma / Q000819:agonists / Q000235:genetics / Q000378:metabolism*; D000071876:Prostaglandin-E Synthases; D017382:Reactive Oxygen Species / Q000378:metabolism
chemical_list: D052246:Cyclooxygenase 2 Inhibitors; D047495:PPAR gamma; D017382:Reactive Oxygen Species; D051546:Cyclooxygenase 2; C496540:PTGS2 protein, human; C472331:PLA2G4C protein, human; D054513:Group IV Phospholipases A2; D019746:Intramolecular Oxidoreductases; D000071876:Prostaglandin-E Synthases; D015232:Dinoprostone
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