PPAR Activation Induces M1 Macrophage Polarization via cPLA₂-COX-2 Inhibition, Activating ROS Production againstLeishmania 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 PPARγ, 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-1β, 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.

An M1-like Macrophage Polarization in Decidual Tissue during Spontaneous Preterm Labor That Is Attenuated by Rosiglitazone Treatment

“…Locally, treatment with RSG reduced the mRNA and protein expression of NFκB, TNF, and IL10 by myometrial and decidual macrophages from mice injected with LPS. The suppressive role of PPARγ activation in macrophages has been previously demonstrated in the NFκB pathway (60, 61, 144), and in the expression/secretion of TNF (111, 144-146) and IL10 (147, 148). Taken together, these data demonstrate that RSG prevents LPS-induced preterm birth by attenuating the systemic immune response in the mother and suppressing the local pro-inflammatory response mediated, at least in part, by decidual and myometrial macrophages.…”

Macrophage development and polarization in chronic inflammation

“…The nuclear receptors PPAR␥ and PPAR␦ [45][46][47][48][49], for instance, control genes associated with M2 macrophage activation while induction of p50 nuclear factor kappa B (NF-B) homodimers is essential for M2 polarization in vitro and in vivo [50]. In addition, c-Jun N-terminal kinase (JNK) activation is required for M1 polarization of macrophages during obesity-induced inflammation and insulin resistance (IR) [51].…”

PPAR-α activation reduced LPS-induced inflammation in alveolar epithelial cells

“…Interestingly, we were not able to detect an impact of WY-14643 on PGE 2 levels. It has been shown in various cell type and models that PPAR-α activation inhibits COX-2 expression [42][43][44] being essential for biosynthesis of PGE 2 . As we could not observe changes in PGE 2 concentration after PPAR-α activation upon LPS challenge, we sought to investigate the expression profile of COX-2 as a key regulator of PGE 2 synthesis in AEC.…”