7phox and p67phox) elements of NADPH oxidase [115]. Interestingly, elevated ROS production led for the generation of oxidized low-density lipoproteins (oxLDL), which additional stimulated PPAR activation. Activated PPAR downregulated NO production by way of transrepression of iNOS [115]. That is an instance of PPAR differently regulating numerous innate immunity effector molecules, in this case, ROS and RNS. An unexpectedly exciting transcriptional CYP2 Inhibitor manufacturer regulation occurs inside the promoter of one more gene crucial for the generation of reactive species in the course of respiratory burst, namely, myeloperoxidase (MPO). The human promoter of this gene consists of primate-specific Alu elements which might be repetitive DNA mobile fragments spread throughout the human genome in about 1 million copies [116]. The Alu fragment inside the MPO gene promoter includes four hexamer sequences identical to or closely resembling canonical PPAR response components (PPREs): AGGTCA, with 2 or four bp spacing in between them [117]. The third and fourth hexamers serve as PPREs and accommodate PPAR/RXR or PPAR/RXR heterodimers, which enables transcriptional regulation by PPAR ligands. Surprisingly, MPO expression is regulated by PPAR agonist GW9578 and PPAR agonist MCC-555 in opposite directions in human macrophages, depending on the differentiation pathway; MPO is substantially downregulated in macrophages derived from MG-CSF-treated monocytes and upregulated in M-CSF differentiated cells [117]. The difference could possibly be attributed towards the differential utilization of nuclear co-repressors, including NCoR or silencing mediator of retinoid and thyroid receptors (SMRT), in macrophages differentiated with GM- vs. M-DAMP [117]. Notably, such a mode of regulation is completely human-specific, for the reason that mice do not possess Alu components in their genome. 6. PPAR as an Immunomodulator in the course of Infections Truly immunomodulatory action will not lie within the unilateral inhibition or activation of all inflammatory processes, but in selective influence around the chosen elements of innateInt. J. Mol. Sci. 2021, 22,12 Bcl-2 Inhibitor Storage & Stability ofimmunity. Such an immunomodulatory action of PPAR has been observed in parasitic or microbial infections. A single instance of such an activity relates towards the induction of M2 polarization in macrophages of patients infected with Trypanosoma cruzi, a parasitic euglenoid, that is responsible for Chagas disease development. The experiment carried out around the infected mice showed that PPAR agonist Wy-14643 elevated the expression of M2 macrophage markers, arginase-1, mannose receptor (CD206), Ym1, and TGF, and decreased the production of proinflammatory molecules characteristic of the M1 phenotype, such as iNOS, NO, IL-1, IL-6 and TNF [118]. On the other hand, this phenotypic switch was accompanied by a PPAR (but not PPAR)-dependent raise in phagocytic capacity and efficiency of parasite phagocytosis [118]. These benefits indicate that PPAR activation may have therapeutic significance, since its immunomodulatory action, on the one hand, strengthens macrophage effector capacity, but, alternatively, helps to alleviate extreme chronic inflammation connected with Chagas disease, which is destructive to a variety of organs. Similar immunomodulatory activity of PPAR in the context of phagocytosis was described in major peritoneal macrophage and microglia cultures treated with many PPAR agonists: endogenous cannabinomimetic (see below), PEA, fenofibrate, or palmitic acid [119]. These compounds, especially PEA, drastically
