lial effector functions in a PPAR-dependent manner and improved the phagocytosis and killing of Porphyromonas gingivalis by microglia and chemotaxis to 2-AG [160]. In addition to the modulation of antimicrobial phagocytosis-based defense, PEA can modulate regenerative functions of macrophages, including efferocytosis (i.e., phagocytosis and clearance of apoptotic cells) [161]. PEA is developed IDO Inhibitor site endogenously by M2c-polarized but not M1-polarized macrophages [161]. Exogenous chronic administration of PEA restricted early plaque formation, protected from accumulation from the proinflammatory M1 macrophage within the plaque, and promoted efferocytosis by M2a- and M2c-polarized macrophages, which delayed the onset of arteriosclerosis [161]. These benefits show that endogenous PPAR ligand PEA is capable of modulating microglia and macrophage biological functions. 7.4. PPAR’s Function in Restoration of Neural Function soon after Injury or Infection Neuroprotective OEA activity was also demonstrated as an inhibition of so-called glial scar (i.e., zones enriched with reactive inflammatory astrocytes, microglia, fibroblasts, and accumulated extracellular matrix components) formation, after focal cerebral ischemia injury [162]. Glial scar is really a natural physiological reaction to injury, but it impedes neurite formation, axon regrowth, and recovery following brain stroke. OEA improved PPAR expression inside the cerebral cortex and downregulated glial scar markers (S100B, glial fibrillary acidic protein GFAP, metalloproteinases MMP-2, MMP-9, and neurocan) inside the ischemicInt. J. Mol. Sci. 2021, 22,16 ofregion by means of a PPAR-dependent mechanism [162]. Importantly, these biological processes translated into a superior recovery of motor function in mice DYRK4 Inhibitor Synonyms immediately after stroke [162]. OEA also decreases the inflammatory response of endothelial cells (such as IL-6, IL-8, ICAM-1, and VCAM expression) evoked by TNF, in a PPAR- and CB2-dependent manner [163]. The biological activities of OEA and PEA seem similar and often overlap, but are usually not generally identical, as shown in distinct experimental settings. An intriguing difference between OEA and PEA actions was observed inside a study that analyzed functional impairments of neurological functions in an animal model of neonatal anoxia/ischemia-induced brain injury [164]. PEA, but not OEA treatment was capable of limiting hippocampal astrogliosis markers (e.g., ionized calcium-binding adaptor protein Iba-1, GFAP) and restoring PPAR protein expression in anoxia/ischemia-affected brain regions [164]. These effects were related with improved cognitive skills along with a superior recovery of spatial and recognition memory, as in comparison with control animals subjected to anoxia/ischemia [164]. Nevertheless, OEA was proved powerful in ameliorating cognitive deficits and in supporting neurogenesis in ischemia-affected brain regions of rats subjected to middle cerebral artery occlusion [165]. An important immunomodulatory action of OEA and PEA requires TLR3 signaling during the innate response to viral infections. A current report by Flannery et al. [166] demonstrated that intracerebroventricular administration of a TLR3 ligand, viral mimetic polyinosinic olycytidynic acid (poly I:C), led for the induction of hypothalamic interferonand NF-B-regulated pathways of proinflammatory gene expression and hyperthermia. The therapy with each OEA and PEA attenuated TLR3-mediated hyperthermia, but only OEA (not PEA) was efficient in the downregulation of poly I:C-induced inf