Prostaglandins, Leukotrienes and Essential Fatty Acids
Anti-inflammatory circuitry: Lipoxin, aspirin-triggered lipoxins and their receptor ALX☆
Introduction
Acute inflammation in healthy individuals is normally a localized protective response to microbial invasion, trauma/injury or chemical stimuli. Excessive and prolonged inflammatory responses can lead to diverse disorders that are now widely recognized to underlie the pathogenesis of some of the most prevalent diseases, such as rheumatic diseases, diabetes, Alzheimer's disease, reperfusion injury as well as atherosclerosis [1]. The accumulation and activation of leukocytes are central in most of the inflammatory disorders. Results from many experimental systems and animal models now point out that the resolution of acute inflammation is an active rather than passive response. Resolution is a well-orchestrated series of temporal events initiated by novel host mechanisms and endogenous mediators that actively participate in dampening host responses to orchestrate resolution (reviewed in Refs. [1], [2]). These novel molecules and “stop signaling” pathways were recently referred to as checkpoint controllers of inflammation (reviewed in [2]).
Studies from our laboratory focus on the identification and structural elucidation of endogenous autacoids and their receptors involved in anti-inflammation, and have led to the recognition of specific cellular and biochemical circuits that activate resolution (reviewed in Ref. [1]). In this context, lipoxins (LX) and aspirin-triggered LX (ATL) are generated endogenously and evoke actions of interest in a range of physiologic and pathophysiologic processes. These two series have emerged as founding members of the first class of lipid/chemical mediators that are “switched on” in the resolution phase of an inflammatory response and can function as “braking signals” in inflammation (Fig. 1) [3]. These unique compounds possess a trihydroxytetraene structure and are both structurally and functionally distinct from the many other groups of lipid-derived bioactive mediators.
It is of interest that aspirin (ASA), the widely used non-steroidal anti-inflammatory drug with many beneficial properties [4] in addition to its well-appreciated ability to inhibit prostaglandins (PG) [5], acetylates cyclooxygenase (COX)-2 and triggers the formation of 15-epimeric LX, termed aspirin-triggered LX (ATL) [6]. More recently, we found that aspirin acetylated COX-2 also produces an array of novel local autacoids from omega-3 polyunsaturated fatty acid (PUFA) [7], [8]. Some of these new compounds display potent anti-inflammatory and pro-resolving actions and thus were termed resolvins (Fig. 1). These previously unappreciated pathways and compounds represent new opportunities to explore therapeutic approaches for the design of “resolution-targeted” therapeutics that may reduce unwanted side effects and control with a high degree of precision inflammatory responses.
LXA4 and 15-epi-LXA4 (a member of the ATL series) elicit the multicellular responses via a specific G protein-coupled receptor (GPCR), termed ALX that is identified in human, mouse and rat tissues. ALX also has the ability to interact with a wide panel of small peptides that give different signaling responses in vitro than LXA4, ATL or their analogs, suggesting that ALX is capable of serving as a multirecognition receptor in immune responses. In this chapter, the receptor ALX is reviewed with a focus on its roles in inflammation and resolution with respect to pharmacology, molecular biology, ligand specificity and signal transduction in several cell types and animal models investigated thus far.
Section snippets
Transcellular biosynthesis of lipoxins
Two major transcellular routes of LX biosynthesis in human cell types have been established (Fig. 2). LX generated by these two pathways carry their carbon-15 (C-15) hydroxyl group mainly in the 15S-configuration, which is inserted by lipoxygenase (LO)-based mechanisms. (I) The first pathway involves platelet–leukocyte interactions and/or platelet–leukocyte microaggregates that promote LX formation by transcellular conversion of the leukocyte 5-LO epoxide product LTA4. When platelets are
Enzymatic inactivation of LXs and ATL
As other autacoids, lipoxins are rapidly generated in response to stimuli, act locally and then are rapidly inactivated by metabolic enzymes. The major route of LX inactivation is through dehydrogenation by monocytes that convert LXA4 to 15-oxo-LXA4, followed by specific reduction of the double bond adjacent to the ketone [10]. 15-hydroxyprosglandin dehydrogenase (15-PGDH) catalyzes the oxidation of LXA4 to 15-oxo-LXA4 (Fig. 3). This compound is biologically inactive and is further converted to
Generation of LXA4 and ATL in animal models and in human diseases
LXA4 is produced in vivo during the course of inflammation such as in an experimental immune complex glomerulonephritis model [14] and in pleural exudate upon allergen challenge in rats [15]. Also, endogenous LXA4 was produced in ischemic lungs and elevated by reperfusion in a hind limb ischemia reperfusion model [16]. A recent report demonstrated that LXA4 is generated during microbial infection reported in a Toxoplasma gondii-exposed murine model [17], [18]. In addition, LXA4 is formed in rat
Molecular cloning of ALX: human, mouse and rat
The specific LXA4 binding sites were first characterized on human PMN that are likely to mediate many of its selective actions on these cells. Intact PMN demonstrate specific and reversible [11,12-3H]-LXA4 binding and these LXA4 binding sites are inducible in promyelocytic lineage (HL-60) cells exposed to differentiating agents (e.g. retinoic acid, DMSO and PMA) and confer LXA4-stimulated phospholipase activation. One of the orphan G protein coupled receptors (GPCR) cloned earlier from myeloid
Novel anti-inflammatory and pro-resolving signals
Recent results from this laboratory indicated that, with PMN, ALX interaction with LX and ATL analogs regulates a newly described polyisoprenyl phosphate (PIPP) signaling pathway [43] (Table 3). ALX activation reverses leukotriene B4-initiated polyisoprenyl phosphate remodeling, leading to accumulation of presqualene diphosphate (PSDP), a potent negative intracellular signal in PMN that inhibits recombinant PLD and superoxide anion generation. Along these lines, LXA4 reduces peroxynitrite
Conclusion
LXs are the trihydroxy-tetraene-containing eicosanoids generated primarily by cell–cell interactions via transcellular biosynthesis. Aspirin impinges on this homeostatic system and evokes the endogenous biosynthesis of ATL (the C-15 epimers of LXs) mimicking the bioactions of native LX in several biological systems and can thus modulate in part the beneficial actions of ASA in humans. Both the LX and ATL systems serve as local endogenous anti-inflammatory mediators switching the cellular
Acknowledgment
The authors thank Mary H. Small for expert assistance in manuscript preparation.
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Sources of support: The authors gratefully acknowledge support from the National Institutes of Health, grant numbers GM38765, P50-DE016191 and R01-074448.