Abstract
Both the initiation and the resolution of inflammatory responses are governed by the sequential activation, migration, and control/suppression of immune cells at the site of injury. Bioactive lipids play a major role in the fine-tuning of this dynamic process in a timely manner. During inflammation and its resolution, polymorphonuclear cells (PMNs) and macrophages switch from producing pro-inflammatory prostaglandins and leukotrienes to specialized pro-resolving lipid mediators (SPMs), namely, lipoxins, resolvins, protectins, and maresins, which are operative at the local level to limit further inflammation and tissue injury and restore homeostasis. Accumulating evidences expand now the role and actions of these lipid mediators from innate to adaptive immunity. In particular, SPMs have been shown to contribute to the control of chronic inflammation, and alterations in their production and/or function have been associated with the persistence of several pathological conditions, including autoimmunity, in human and experimental models. In this review, we focus on the impact of pro-resolving lipids on T cells through their ability to modulate T-cell responses. In particular, the effects of the different families of SPMs to restrain effector T-cell functions while promoting regulatory T cells will be reviewed, along with the underlying mechanisms. Furthermore, the emerging concept of SPMs as new biological markers for disease diagnostic and progression and as putative therapeutic tools to regulate the development and magnitude of inflammatory and autoimmune diseases is discussed.
Highlights
The natural resolution of inflammation is a tightly controlled dynamic process that engages several molecular and cellular mediators to prevent excessive and/or chronic immune responses and tissue damage that may compromise organ function
The biosynthesis of all specialized pro-resolving lipid mediators (SPMs) identified to date is initiated by the enzymatic addition of oxygen to four dietary polyunsaturated fatty acids (PUFAs), namely, w-6 arachidonic acid (AA), w-3 eicosapentaenoic acid (EPA), w-3 docosahexaenoic acid (DHA), and w-3 docosapentaenoic acid (DPA), by means of the stereoselective and concerted action of the very same enzymes used for eicosanoid production, namely, the lipoxygenase (LOX) isozymes, the cyclooxygenase-2 (COX2), and, to a minor extent, the cytochrome P450 [6]
SPMs display a wide range of anti-inflammatory actions, which are increasingly explored in adaptive immunity, notably through their ability to bind several G protein-coupled receptors (GPCRs) expressed by T cells, to regulate T-cell functions, and to trigger the resolution of inflammatory and immune-mediated diseases in animal models
Summary
The natural resolution of inflammation is a tightly controlled dynamic process that engages several molecular and cellular mediators to prevent excessive and/or chronic immune responses and tissue damage that may compromise organ function. Administration of EP antagonists impaired the development of experimental arthritis, psoriasis, and multiple sclerosis through the inhibition of Th1 and Th17 responses [29,30,31] These pro-inflammatory effects are in line with the capacity of PGE2 to dampen the differentiation of type 1 regulatory T cells (Tr1) [32] and Foxp3+ Tregs [33], some contradictory results were reported [34]. Overall, both LTs and PGs, being central in the perpetuation of inflammatory signals that are at the basis of the transition from acute to chronic inflammation, act as “cytokine amplifiers” by stimulating almost all Teff subsets (Figure 2)
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