ReviewOld and new generation lipid mediators in acute inflammation and resolution
Introduction
Inflammation is a protective response initiated after injury through physical damage or infection by microorganisms. While both systemic and local responses can be activated, inflammation is an essential biological process with the conserved objective to (1) eliminate the aberrant factors, (2) promote tissue repair/wound healing, and (3) establish memory, which enables the host to mount a faster and more specific response upon a future encounter. The acute inflammatory response is a complex yet highly coordinated sequence of events involving a large number of molecular, cellular and physiological changes. It begins with the production of soluble mediators by resident cells in the injured/infected tissue (i.e. tissue macrophages, dendritic cells, lymphocytes, endothelial cells, fibroblasts and mast cells) that promote the exudation of proteins and influx of granulocytes from the blood. Upon arrival these leukocytes, typically neutrophils, primarily function to phagocytose and eliminate foreign microorganisms via distinct intracellular killing mechanisms, an event accompanied by active anti-inflammatory and pro-resolution processes that block excessive/continuous neutrophil recruitment and oedema formation. In a typical acute inflammatory response, effective clearance of microbial infections and/or damaged tissue is followed by resolution. This involves the elimination of neutrophils via programmed cell death (apoptosis) [1], [2], the non-phlogistic phagocytosis (efferocytosis) of these apoptotic cells by monocyte-derived macrophages that have been recruited to the inflamed site following neutrophil influx [3], [4], [5] and in turn, the clearance of these macrophages by either in situ apoptosis [6] or egression via the lymphatic system [7], [8].
If this sequential set of responses is followed then acute inflammation will resolve, causing complete restoration of the inflamed tissue to its prior physiological functioning and reinstatement of homeostasis. However, if defects arise during any part of this highly conserved pathway, inflammation will persist and become chronic, lasting for longer periods (days, months or years), leading to excess tissue damage. This is characteristic of the pathogenesis of various prevalent diseases in modern Western civilisation such as rheumatoid arthritis and periodontal disease [9]; cardiovascular diseases such as myocardial infarction [10], and atherosclerosis [11]; various neuropathological disorders such as stroke, Alzheimer’s disease or Parkinson’s disease [12] and cancer [13], [14].
Although it is well-appreciated that pro-inflammatory mediators generated in the inflamed tissue drive acute inflammation, there is also systemic and local production of endogenous mediators that counter-balance these pro-inflammatory events, evolved to avoid development of pathologies such as those highlighted above. Lipid mediators derived from polyunsaturated fatty acids (PUFA), such as arachidonic acid (AA), and the omega-3 PUFA eicosapentaenoic (EPA) and docosahexaenoic acid (DHA), are synthesised during normal cell haemostasis or, more often, after cell activation and in conditions of stress, functioning as activators of counter-regulatory, anti-inflammatory and pro-resolution mechanisms. Interestingly, these immuno-modulatory effects are also found in a family of lipids, prostanoids, which are well-appreciated to be involved in driving some of the cardinal signs of inflammation (heat, redness, swelling, pain and loss of function). As the role of lipids in inflammation is diverse, this review aims to provide an update of AA/DHA/EPA-derived signaling molecules that not only drive acute inflammation but also counter-regulate its severity and bring about its timely resolution.
Section snippets
AA-derived lipid mediators (eicosanoids)
AA, a 20-carbon fatty acid is the main eicosanoid precursor and is a basic constituent of all cells. While it is not freely available AA is released from membrane phospholipid stores through the activity of several phospholipase enzymes (predominantly PLA2), which are activated by various cellular agonists including receptor-mediated agonists (i.e. formyl peptide [fMLP], interleukin-8 [IL-8], and platelet activating factor [PAF]), microorganisms, phagocytic particles or even non-specific
Cyclooxygenase
COX is a bifunctional enzyme that carries out a complex free radical reaction by acting successively as a bis-dioxygenase and peroxidase. It begins by catalysing the bisoxygenation and cyclisation of AA to form the hydroperoxy arachidonate metabolite PGG2 [19]. After which the peroxidase element of the enzyme reduces the carbon 15 position hydroperoxide to its corresponding alcohol to form PGH2 [20], [21]. There are two main isoforms involved in the conversion of AA, COX-1 and COX-2. While
Prostanoids in inflammation
Prostanoids were first identified in the mid 1930s as potent bioactive compounds in human semen [36]. Now it is widely appreciated that prostanoids are generated in most tissues and cells, modulating biological processes such as smooth muscle tone [37], [38], [39], vascular permeability [40], [41], hyperalgesia [42], fever [43], [44], [45], and platelet aggregation [46]. Indeed, the clinical importance of prostanoids is emphasised by the fact that their biosynthesis is the target of
Lipoxygenase
AA is also metabolised by LOX enzymes, found as 5-, 12-, or 15-LOX in leukocytes, platelets and endothelial cells, respectively. Leukocyte 5-LOX, for example, is responsible for the generation of the slow-reacting substances of anaphylaxis (LTC4, LTD4 and LTE4: potent mediators of the allergic response) [139] and LTB4, a powerful polymorphonuclear (PMN) leukocyte (i.e. neutrophils and eosinophils) chemoattractant [140], [141]. As 5-LOX has received the most attention in inflammation research
Leukotrienes and the inflammatory response
Generated primarily by inflammatory cells such as PMNs, macrophages and mast cells at sites of infection/inflammation, LTs play a central role in inflammatory response by acting predominantly as pro-inflammatory lipid mediators. Physiologically, each of the 5-LOX-derived compounds has a distinct role in driving different phases of inflammation. For example, LTB4 attracts and activates neutrophils, monocytes, and lymphocytes, a hallmark of tissue inflammation [151], [160], [161], whereas LTD4 is
5-Oxo-6,8,11,14-eicosatetraenoic acid
Another product whose synthesis is initiated by 5-LOX activity is 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE), which has potent biological activities that have only recently been appreciated, including eosinophil activation and chemoattraction (Fig. 2). It is formed by the oxidation of 5S-HETE by 5-hydroxyeicosanoid dehydrogenase (5-HEDH), a microsomal enzyme widely distributed in both inflammatory and structural cells including leukocytes and platelets [199]. 5-HEDH however, cannot
Role of 5-oxo-ETE in inflammation
5-oxo-ETE is produced by eosinophils, neutrophils, basophils and monocytes and as with other inflammatory lipids, acts in an autocrine manner. Although its most potent bio-action is as a chemoattractant for eosinophils [204], 5-oxo-ETE also induces calcium mobilisation, actin polymerisation, CD11b expression, and l-selectin shedding [205]. Furthermore 5-oxo-ETE induces degranulation and superoxide production in leukocytes primed with cytokines such as granulocyte macrophage-colony stimulating
Lipoxins – biosynthesis and receptors
Lipoxins (LXs) are a series of trihydroxytetraene-containing bioactive eicosanoids first isolated from human leukocytes [17]. In contrast to LTs and 5-oxo-ETEs however, which are generated by intracellular biosynthesis, LXs are generated through cell–cell interactions by a process known as transcellular biosynthesis. LXs are distinct from other lipid mediators such as PGs and LTs that are biosynthesised in the initial steps of the acute inflammatory response. Another discrete property of LXs is
Lipoxins in inflammation
Lipoxins (including aspirin-dependent 15-epi-LXs) are anti-inflammatory at nanomolar concentrations regulating both granulocyte (neutrophil and eosinophil) and monocyte entry to sites of inflammation. Yet, while they inhibit the transmigration of neutrophils and eosinophils down a chemokine gradient into inflamed sites [246], [247], [248], [249], they promote non-inflammatory infiltration of monocytes required for resolution and wound healing [250], without inducing neutrophil degranulation or
Omega-3 polyunsaturated fatty acid pathway
Omega-3 polyunsaturated fatty acids (ω3-PUFA) have long been known to be important in maintaining organ function and health and even in reducing the incidence of infection and inflammation [114], [115], [276], [277], [278], [279]. One such clinical trial (GISSI–Prevenzione) assessing the benefits of aspirin with and without ω-3 PUFA supplementation in patients recovering from myocardial infarctions revealed a significant decrease in mortality in the group taking the supplement [280]. More
Resolvins and protectins
Rvs can be generated from either EPA or DHA and are therefore categorised as either members of the E-series (from EPA) or D-series (from DHA). Rvs of both series were first isolated in vivo from murine dorsal air pouches treated with aspirin and EPA or DHA. Transcellular formation of E-series Rvs can occur with the conversion of EPA to 18R-hydroxyeicosapentanoic acid (18R-HEPE) by endothelial cells expressing COX-2 treated with aspirin. As with 15R-HETE in 15-epi-LX formation, 18R-HEPE can be
Resolvins and protectins in inflammation
One of the most potent anti-inflammatory properties of RvE1 is its ability to inhibit neutrophil and dendritic cell accumulation at sites of inflammation by blocking trans-endothelial migration as well as enhancing their clearance from mucosal epithelial cells [114], [289], [291]. Other bio-actions of RvE1 include inhibition of neutrophil ROI in response to TNF-α and bacterial peptide, fMLP [292], abrogation of LTB4-BLT1 signalling via NF-κB and thus the production of pro-inflammatory cytokines
Maresins in inflammation
Maresins (MaR) were identified in 2008 after 17S-D-series Rvs, PDs as well as 14S-hydroxydocosahexaenoic acid (14S-HDHA) were isolated from the resolution phase of mouse peritonitis were added to stimulated resident peritoneal macrophages [285]. These macrophages then converted these intermediates to novel dihydroxy-containing products, which possesses potent anti-inflammatory and pro-resolving properties. Although the exact biosynthetic pathway is yet to be elucidated a hypothetic scheme was
Cytochrome P450
In the last decade, interest into a third less well-characterised pathway of AA metabolism, cytochrome P450 (CYP) pathway has been rekindled. CYP are families of membrane-bound, haeme-containing enzymes found in the liver, brain, kidneys, lung, heart and the CV system, thought initially to be involved in catalysing NADPH-dependent oxidation of drugs, chemical and carcinogens [312], [313]. It is now well-appreciated that CYPs also catalyse the conversion of fatty acids including AA into products
Cytochrome P450-derived products and inflammation
EETs catalysed by CYPs 2C8, 2C9 and 2J2 block the adhesion of PMNs to the vascular wall by suppressing the expression of cell-adhesion molecules, including intracellular adhesion molecule-1 (ICAM-1), vascular cell-adhesion molecule-1 (VCAM-1) and E-selectin on the surface of endothelial cells in response to cytokines (TNF-α and IL-1α), and LPS [319], [324]. Mechanistically, this is associated with inhibiting the activation of the transcription factor NF-κB via the inhibitor of κB kinase (IKK)
Concluding remarks
Resulting from the beneficial usage of NSAIDs in the treatment of chronic inflammatory diseases, AA metabolites were once considered pro-inflammatory. While NSAIDs have provided great benefit in terms of anti-inflammation and pain relief, they have recently revealed beneficial properties of some LOX and COX products. Thus, our understanding of eicosanoids in physiology and pathology has come a long way since the earliest observations of Kurzrok and Lieb [332]. Thus, PGs may drive oedema but
References (332)
- et al.
Interactions between Alzheimer’s disease and cerebral ischemia – focus on inflammation
Brain Res Brain Res Rev
(2005) - et al.
Inflammation as a tumor promoter in cancer induction
Semin Cancer Biol
(2004) - et al.
Trihydroxytetraenes: a novel series of compounds formed from arachidonic acid in human leukocytes
Biochem Biophys Res Commun
(1984) - et al.
Cytochrome P-450 arachidonate oxygenase
Methods Enzymol
(1990) - et al.
Immunochemical evidence for the involvement of prostaglandin H synthase in hydroperoxide-dependent oxidations by ram seminal vesicle microsomes
J Biol Chem
(1983) - et al.
Isolation and properties of intermediates in prostaglandin biosynthesis
Biochim Biophys Acta
(1973) - et al.
Purification of PGH-PGD isomerase from rat brain
Methods Enzymol
(1982) - et al.
Immunochemical and kinetic evidence for two different prostaglandin H-prostaglandin E isomerases in sheep vesicular gland microsomes
J Biol Chem
(1987) - et al.
Enzymatic conversion of prostaglandin H2 to prostaglandin F2 alpha by aldehyde reductase from human liver: comparison to the prostaglandin F synthetase from bovine lung
J Biol Chem
(1989) - et al.
Purification of prostacyclin synthase from bovine aorta by immunoaffinity chromatography. Evidence that the enzyme is a hemoprotein
J Biol Chem
(1983)
COX-1 and COX-2 contribute differentially to the LPS-induced release of PGE2 and TxA2 in liver macrophages
Prostaglandins Other Lipid Mediat
Arachidonic acid is preferentially metabolized by cyclooxygenase-2 to prostacyclin and prostaglandin E2
J Biol Chem
Prostaglandin D2 is a potent chemoattractant for human eosinophils that acts via a novel DP receptor
Blood
Pharmacology and signaling of prostaglandin receptors: multiple roles in inflammation and immune modulation
Pharmacol Ther
Inflammatory effects of prostacyclin (PGI2) and 6-oxo-PGF1alpha in the rat paw
Prostaglandins
Prostaglandin I2 as a potentiator of acute inflammation in rats
Prostaglandins
Neural and humoral pathways of communication from the immune system to the brain: parallel or convergent?
Auton Neurosci
Excitatory amino acid receptor activation in the raphe pallidus area mediates prostaglandin-evoked thermogenesis
Neuroscience
Raphe pallidus neurons mediate prostaglandin E2-evoked increases in brown adipose tissue thermogenesis
Neuroscience
Prostaglandin on cutaneous vasculature
J Invest Dermatol
Major roles of prostanoid receptors IP and EP(3) in endotoxin-induced enhancement of pain perception
Biochem Pharmacol
Role of dose potency in the prediction of risk of myocardial infarction associated with nonsteroidal anti-inflammatory drugs in the general population
J Am Coll Cardiol
Protein kinase A inhibits leukotriene synthesis by phosphorylation of 5-lipoxygenase on serine 523
J Biol Chem
PGE2 and the immune response. A central role for prostaglandin E2 in downregulating the inflammatory immune response
Mol Med Today
Regulation of interleukin 1 production by mouse peritoneal macrophages. Effects of arachidonic acid metabolites, cyclic nucleotides, and interferons
J Biol Chem
Prostaglandin E2 regulates macrophage-derived tumor necrosis factor gene expression
J Biol Chem
Macrophage recognition of cells undergoing programmed cell death (apoptosis)
Immunology
J Clin Invest
Cutting edge: lipoxins rapidly stimulate nonphlogistic phagocytosis of apoptotic neutrophils by monocyte-derived macrophages
J Immunol
Glucocorticoid-mediated regulation of granulocyte apoptosis and macrophage phagocytosis of apoptotic cells: implications for the resolution of inflammation
J Endocrinol
Resolvin E1 and protectin D1 activate inflammation-resolution programmes
Nature
Inducible cyclooxygenase-derived 15-deoxy(Delta)12-14PGJ2 brings about acute inflammatory resolution in rat pleurisy by inducing neutrophil and macrophage apoptosis
FASEB J
In vivo fate of the inflammatory macrophage during the resolution of inflammation: inflammatory macrophages do not die locally but emigrate to the draining lymph nodes
J Immunol
Adhesion molecule-dependent mechanisms regulate the rate of macrophage clearance during the resolution of peritoneal inflammation
J Exp Med
Resolution of inflammation: a new paradigm for the pathogenesis of periodontal diseases
J Dent Res
Myocardial ischemia, stunning, inflammation, and apoptosis during cardiac surgery: a review of evidence
Eur J Cardiothorac Surg
Inflammation and atherosclerosis
Circulation
NF-kappaB: linking inflammation and immunity to cancer development and progression
Nat Rev Immunol
The release of prostaglandins from lung and other tissues
Ann N Y Acad Sci
Leukotrienes and lipoxins: structures, biosynthesis, and biological effects
Science
Detection and isolation of an endoperoxide intermediate in prostaglandin biosynthesis
Proc Natl Acad Sci USA
Cyclooxygenase in biology and disease
FASEB J
Thromboxane synthase as a cytochrome P450 enzyme
Adv Prostaglandin Thromboxane Leukot Res
Segregated coupling of phospholipases A2, cyclooxygenases, and terminal prostanoid synthases in different phases of prostanoid biosynthesis in rat peritoneal macrophages
J Immunol
Identification of human prostaglandin E synthase: a microsomal, glutathione-dependent, inducible enzyme, constituting a potential novel drug target
Proc Natl Acad Sci USA
Differential regulation of prostaglandin E2 and thromboxane A2 production in human monocytes: implications for the use of cyclooxygenase inhibitors
J Immunol
Prostaglandin D2 selectively induces chemotaxis in T helper type 2 cells, eosinophils, and basophils via seven-transmembrane receptor CRTH2
J Exp Med
Prostaglandin D2 causes preferential induction of proinflammatory Th2 cytokine production through an action on chemoattractant receptor-like molecule expressed on Th2 cells
J Immunol
On the specific vaso-dilating and plain muscle stimulating substances from accesory genital glands in man and certain animals (prostaglandins and vesiglandins)
J Physiol
Prostaglandins, oxygen tension and smooth muscle tone
Br J Pharmacol
Cited by (266)
Cancer cell growth suppressibility of ω-3 fatty acid whose carboxy group converted to ester group
2023, Bioorganic and Medicinal Chemistry LettersPhospholipase signaling in inflammation and promiscuity of phospholipase active site ligands
2023, Phospholipases in Physiology and Pathology: Volumes 1-7Restoration of myelination in the central nervous system via specific dietary bioactive lipids: An opportunity to halt disease progression in multiple sclerosis
2023, Diet and Nutrition in Neurological DisordersIn vivo models of understanding inflammation (in vivo methods for inflammation)
2023, Recent Developments in Anti-Inflammatory TherapyInflammation resolution in environmental pulmonary health and morbidity
2022, Toxicology and Applied Pharmacology