Actors and Factors in the Resolution of Intestinal Inflammation: Lipid Mediators As a New Approach to Therapy in Inflammatory Bowel Diseases

Abstract

In the last few decades, the pathogenesis of inflammatory bowel disease (IBD) in genetically predisposed subjects susceptible to specific environmental factors has been attributed to disturbance of both the immune and non-immune system and/or to the imbalanced interactions with microbes. However, increasing evidences support the idea that defects in pro-resolving pathways might strongly contribute to IBD onset. The resolution of inflammation is now recognized as a dynamic event coordinated by specialized pro-resolving lipid mediators (LMs), which dampen inflammation-sustaining events, such as angiogenesis, release of pro-inflammatory cytokines, clearance of apoptotic cells, and microorganisms. Among these pro-resolving molecules, those derived from essential polyunsaturated fatty acids (PUFAs) have been shown to induce favorable effects on a plethora of human inflammatory disorders, including IBD. Here, we offer a summary of mechanisms involving both cellular and molecular components of the immune response and underlying the anti-inflammatory and pro-resolving properties of PUFAs and their derivatives in the gut, focusing on both ω-3 and ω-6 LMs. These fatty acids may influence IBD progression by: reducing neutrophil transmigration across the intestinal vasculature and the epithelium, preventing the release of pro-inflammatory cytokines and the up-regulation of adhesion molecules, and finally by promoting the production of other pro-resolving molecules. We also discuss the numerous attempts in using pro-resolving PUFAs to ameliorate intestinal inflammation, both in patients with IBD and mouse models. Although their effects in reducing inflammation is incontestable, results from previous works describing the effects of PUFA administration to prevent or treat IBD are controversial. Therefore, more efforts are needed not only to identify and explain the physiological functions of PUFAs in the gut, but also to unveil novel biosynthetic pathways of these pro-resolving LMs that may be dysregulated in these gut-related disorders. We suppose that either PUFAs or new medications specifically promoting resolution-regulating mediators and pathways will be much better tolerated by patients with IBD, with the advantage of avoiding immune suppression.

Keywords: inflammatory bowel disease; mucosal inflammation; pathogenesis; polyunsatured fatty acids; pro-resolving lipid mediators; resolution of inflammation; tissue homeostasis.

Figure 1

Metabolic route of ω-6- and ω-3-derived lipid mediators. (A) Essential fatty acid linoleic acid, classified as ω-6 polyunsaturated fatty acid, can be converted into arachidonic acid (AA). In turn, AA is metabolized in hydroxy-eicosatetraenoic acids (HETEs) and epoxy-eicosatrienoic acids (EETs) via cytochrome P450 (CYP450). Via lipoxygenase (LOX) pathway, AA is converted to lipoxins (LXs) and leukotriens (LTs), whereas via cyclooxygenase it is metabolized in prostaglandins (PGs) and tromboxanes (TBXs). HETEs, EETs, PGs, TBXs, and LTs are all pro-inflammatory, while LXs are considered pro-resolving mediators. (B) Essential fatty acid α-linolenic acid is converted to eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). EPA and DHA may be substrate of CYP450, resulting into production of E-series resolvins (Rv) and epoxides, respectively. In addition, DHA is metabolized via LOX to D-series Rv, maresins, and protectins. All these EPA- and DHA-derived mediators are recognized to harbor pro-resolving properties.

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.