Figure 2.

Effects of pro-resolving polyunsaturated fatty acids (PUFAs) on immune and non-immune intestinal components. (A) Thanks to tight junctions, intestinal epithelial cells form a dynamic barrier protected by a thick mucus layer (inner and outer) which controls what can reach the lamina propria from the lumen. In order to counteract pathogen infections, epithelial cells are able to produce and release in the luminal mucus antibacterial and endotoxin-neutralizing molecules called bactericidal permeability-increasing protein (BPI). BPI is transcriptionally up-regulated by lipoxins (LXs) and resolvin (Rv) E1. In addition, it was observed that resolvin E1 (RvE1) significantly upregulates the expression of intestinal alkaline phosphatase. Moreover, LXs inhibit epithelial cells apoptosis. G protein-coupled receptor (GPR)120 activation by PUFAs [eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), and arachidonic acid] leads to accumulation of cytosolic Ca²⁺, activation of MAP kinase ERK1/2, inhibition of IL-1β-induced NF-κB activation, and TNFα-induced inflammation. Transcription of GPR120 is increased by bacteria belonging to the bacteroides, proteobacteria, and firmicutes phyla. (B) Neutrophils (polymorphonuclear) are the first immune cells recruited to the site of inflammation, but are also important players in the first stages of the resolution program. LXs reduce neutrophil recruitment to the inflamed tissue, transepithelial migration, and phagocytosis. Protectin D1 promotes neutrophil phagocytosis. Similar to LXs, RvE1 reduces neutrophil transepithelial migration and induces neutrophil phagocytosis. Moreover, both protectin D1 and RvD5 have been shown to reduce neutrophil–endothelial interaction. (C) Macrophages, important for the resolution of intestinal inflammation, express high level of GPR120. EPA- and DHA-dependent activation of GPR120 has been shown to repress Akt/JNK phosphorylation and NF-kB induction. LXs enhance non-phlogistic phagocytosis of apoptotic neutrophils by macrophages. Treatment with LXs may also polarize intestinal macrophages into a resolving phenotype, thus promoting resolution of inflammation. Maresins exert potent pro-resolution and anti-inflammatory activities, ultimately leading to reduced neutrophil migration and increase macrophage phagocytic activities. Maresins induces also the resolving phenotype of macrophages and inhibit reactive oxygen species production. (D) EPA and DHA (ω-3 PUFAs) inhibit T cell proliferation and reduce IL-2 production. (E) Pro-resolving lipid mediators (DHA, α-linolenic acid-derived) exert anti-inflammatory and anti-angiogenic effects on the gut endothelium. They reduce the production of IL-6, IL-8, GM-CSF PGE-2, and LTB-4 (pro-inflammatory signals), decrease the levels of adhesion molecules (intercellular adhesion molecule 1 and vascular cell adhesion protein 1), and vascular endothelial growth factor receptor 2, thus suppressing the angiogenic component of inflammation.