Eicosanoid storm in infection and inflammation

Abstract

Controlled immune responses to infection and injury involve complex molecular signalling networks with coordinated and often opposing actions. Eicosanoids and related bioactive lipid mediators derived from polyunsaturated fatty acids constitute a major bioactive lipid network that is among the most complex and challenging pathways to map in a physiological context. Eicosanoid signalling, similar to cytokine signalling and inflammasome formation, has primarily been viewed as a pro-inflammatory component of the innate immune response; however, recent advances in lipidomics have helped to elucidate unique eicosanoids and related docosanoids with anti-inflammatory and pro-resolution functions. This has advanced our overall understanding of the inflammatory response and its therapeutic implications. The induction of a pro-inflammatory and anti-inflammatory eicosanoid storm through the activation of inflammatory receptors by infectious agents is reviewed here.

Figure 1. Eicosanoid biosynthesis and receptor signaling

Lipidomic view of phospholipase A₂ (PLA₂), cyclooxygenase-1 and -2 (COX1/2), 5-lipoxygenase (5-LOX), 8-, 12-, and 15-lipoxygenases (8/12/15-LOX) and cytochrome P450 epoxyhydrolase (CYP) pathways of eicosanoid biosynthesis derived from arachidonic acid. Downstream enzymes are shown as yellow ovals followed by eicosanoid species and their receptors as green boxes. The peroxisome-proliferator activating receptors (PPARs), indicated as orange boxes, that are potentially activated by the eicosanoids are also shown.. The CYP ω-hydroxylase pathway and lipid species derived from other fatty acids are not shown. Abbreviations: COX, cyclooxygenase; CYP, cytochrome P450; EET, epoxyeicosatrienoic acid; GGT, gamma-glutamyl transferase; HETE, hydroxyeicosatetraenoic acid; HX, hepoxilin; LOX, lipoxygenase; LT, leukotriene; LTAH, LTA₄ hydrolase; LTCS, LTC₄ synthase; LX, lipoxin; MBD, membrane bound dipeptidase; PLA2, phospholipase A2; PPAR, peroxisome proliferator-activated receptor; TRPA1, transient receptor potential ankyrin 1; TRPV1, transient receptor potential vanilloid 1; and TX, thromboxane.

Figure 2. Enzyme functional coupling, transcellular biosynthesis, and eicosanoid class switching

(a) Functional coupling of cPLA₂ with metabolons comprised of COX-1 or COX-2 and different prostaglandin or thromboxane synthases; 5-LOX coupled to LTAH or LTCS; PGES represents microsomal PGES-1 and PGDS represents hematopoietic PGDS, while other isoforms are not shown; coupling schemes are not completely insulated thus products may derive from alternate routes depending on cell type and degree of cell activation. Functions of these products collectively describe the cardinal signs of inflammation. (b) Transcellular biosynthesis of lipoxins from arachidonic acid (AA) involving a cell expressing COX-2 acetylated by aspirin and/or 15-LOX that is upregulated by IL-4, both of which produce the same intermediate 15-HETE, which diffuses or is transported to an adjacent cell where it becomes incorporated in and subsequently released from membrane phospholipids by cPLA₂ (not shown). This 15-HETE is converted by 5-LOX (with its functionally coupled FLAP) to LXA₄/15-epi-LXA₄, thereby initiating eicosanoid class switching. Coordinate macrophage-neutrophil lipoxin biosynthesis and related SPM production (as depicted) provides putative mechanisms to enhance efferocytosis and redirection of neutrophils to the vasculature. (c) Eicosanoid class-switching involves receptor mediated reprogramming of biosynthetic enzyme expression or activation. A neutrophil is depicted being activated by PGE₂ binding of a cyclic adenosine monophosphate (cAMP) increasing EP receptor that increases 15-LOX expression, which shunts arachidonic acid (AA) synthesis from LTB₄ production by 5-LOX/LTAH to LXA₄ by 15-LOX/5-LOX.

Figure 3. Inflammasome formation and caspase activation parallels lipoxin formation for a complete inflammatory response

TLR4-mediated priming of macrophages by LPS induces pro-IL-1β production via activation of NF-κB. Subsequent purinergic P2X₇ receptor engagement by ATP initiates the process of caspase-1 activation through inflammasome initiation, which converts pro-IL-1β to IL-1β, but a parallel pathway in macrophages exists to initiate the resolution of inflammation. TLR4-mediated priming also activates cPLA₂ and induces COX2 production via NF-κB; this results in the release of arachidonic acid and conversion to 15-HETE, which becomes esterified into phospholipids. Subsequent purinergic P2X₇ receptor engagement activates cPLA₂ and 5-LOX in Ca²⁺-dependent processes, leading to the release of 15-HETE from membrane phospholipids and conversion of the 15-HETE to lipoxin. The first step in this process is enhanced by aspirin which causes complete eicosanoid class switching from pro-inflammatory prostaglandins to anti-inflammatory lipoxins.

Figure 4. Therapeutics targeting eicosanoid pathways

Enzymes in the cyclooxygenase pathway generate prostaglandins, thromboxanes, and lipoxins; lipoxygenase pathway enzymes generate leukotrienes, HETEs, and hepoxilins; and cytochrome P450 epoxyhydrolase pathway enzymes generate epoxides and dihydroxy polyunsaturated fatty acids (PUFA). All of the pathways have pharmacological intervention points including enzyme inhibitors and receptor antagonists (red hexagon), product enhancers (green circle) and mimetics (red box). NSAIDs and ω3 PUFAs inhibit COX formation of each product derived from AA (red hexagon), with the exception of one NSAID, aspirin, which enhances COX-2 formation of 15(R)-HETE (green circle) that can be converted to lipoxins by 5-LOX. COX-1-specific NSAIDS and ω3 PUFAs shift the vascular balance to higher PGI₂, whereas COX-2 specific NSAIDs shift the vascular balance to higher TxA₂ (gray), which are in opposite directions due to coupling of platelet COX-1 with TXAS and endothelial COX-2 with PGIS; analogs of prostaglandins are used clinically to mimic endogenous bioactivity (red box). Montelukast and zafirlukast specifically inhibit activation of cysLT1 (red hexagon). Zileuton inhibits 5-LOX conversion of arachidonic acid (red hexagon), but NSAIDs and ω3 PUFAs can increase conversion (green circle) via shunting of AA from inhibited COX-1 and COX-2. Inhibitors of sEH reduce inactivation of EETs as well as hepoxilins (red hexagon). Lipoxin, resolvin, and protectin mimetics (orange box) are being developed for treatment of ocular, periodontal, and cardiovascular diseases.