Inhibitory action of Lipoxins on Superoxide production in neutrophils

Inhibitory action of Lipoxins on Superoxide production in neutrophils

Deregulated neutrophilic inflammation and chronic infection lead to progressive destruction of the airways in cystic fibrosis (CF). In normal tissues, the lipoxins are endogenous anti-inflammatory lipid mediators that are important regulators of neutrophilic inflammation [1]. In CF, the generation of lipoxins is impaired [2], [3].

In response to infection or tissue injury, arachidonic acid produces proinflammatory Leukotriene B4 that leads to neutrophil recruitment and acute inflammation [4], [5], [6].

Arachidonic acid also produces antiinflammatory lipoxins. Lipoxins mediate switch to chronic inflammation and promote resolution [6], [7], [8]. In CF, inflammatory response remains persistently neutrophilic (acute inflammation) that leads to tissue injury and further infection. This may be attributed to a documented defect in the generation of lipoxins [1], [2], [3].

Lipoxins are bioactive eicosanoids derived from arachidonic acid. In contrast to proinflammatory leukotrienes and prostaglandins, lipoxins (Lipoxin A4, 15-epi-LXA4 and its stable synthetic analog 15-epi-p-fluoro-phenoxy-LXA4) display potent antiinflammatory actions, including attenuation of neutrophil respiratory burst and transendothelial migration [1], [9].

Leukotriene B4 and Lipoxins (Lipoxin A4, 15-epi-LXA4 and 15-epi-p-fluoro-phenoxy-LXA4) interact with highly specific and distinct G protein-coupled membrane receptors [10], [11], [12], to evoke opposing leukocyte responses, including Lipoxin A4 inhibition of Leukotriene B4-initiated respiratory burst, chemotaxis, adhesion, and transmigration [13].

Leukotriene B4 binds to the Leukotriene B4 receptor (LTBR1) which activates both Phospholipase C beta 2 (PLC-beta2) and Phosphatidylinositol 3-kinase (PI3K reg class IB (p101) and PI3K cat class IB (p110-gamma)) signaling via G-protein alpha-i family, G-protein alpha-15 and G-protein beta/gamma subunits [4], [11], [14], [15], [16], [17], [18].

PLC-beta2 catalyzes the hydrolysis of phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) to inositol 1,4,5-trisphosphate (IP3) and diacylglycerol (DAG). IP3 stimulates Ca(2+) release from endoplasmic reticulum. Ca(2+) and DAG, in turn, activate Protein kinase C alpha (PKC-alpha). Phosphatidylinositol 3-kinase phosphorylates the membrane lipid PtdIns(4,5)P2 to phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) [14], [16], [19], [20], [21]. PtdIns(3,4,5)P3 recruits and activates diverse cytosolic effectors, including Phospholipase D1 (PLD1) [22], 3-phosphoinositide dependent protein kinase-1 (PDPK1) [23], [24], Protein kinase C zeta (PKC-zeta) [25] and Phosphatidylinositol 3,4,5-trisphosphate-dependent RAC exchanger 1 (PREX1) [26], [27]. PREX1 is the main guanine nucleotide exchange factor for the Ras-related C3 botulinum toxin substrate 2 (RAC2) in neutrophils [28], [29], [30].

Interleukin-8 (IL-8) is probably involved in the release of reactive oxygen species (ROS) by neutrophils. IL-8-induced activation of the respiratory burst is exclusively mediated by Interleukin 8 receptor alpha (IL8RA), and does not involve PLC-beta and calcium signaling [31], [32], [33].

Lipoxin A4, 15-epi-LXA4 and 15-epi-p-fluoro-phenoxy-LXA4 interact with the Formyl peptide receptor-like 1 (FPRL1) [1], [7], [8], [12] that transduces counter-regulatory signals in part via intracellular polyisoprenyl phosphate remodeling. Presqualene diphosphate is a polyisoprenyl phosphate in human neutrophils that is rapidly converted to Presqualene monophosphate upon cell activation. Phosphatidic acid phosphatase type 2 domain containing 2 (PPAPDC2) is a presqualene diphosphate phosphatase that converts Presqualene diphosphate to Presqualene monophosphate [34]. In human, neutrophils leukotriene-induced LTBR1 signaling initiates a rapid decrease in Presqualene diphosphate levels, probably through PPADC2 activation, to promote proinflammatory cell response, whereas lipoxin-induced FPRL1 signaling dramatically blocks Presqualene diphosphate turnover to Presqualene monophosphate, probably through PPADC2 inhibition, to prevent neutrophil activation [6], [35].

Presqualene diphosphate, but not Presqualene monophosphate, directly inhibits PI3K cat class IB (p110-gamma) and Phospholipase D1 (PLD1), preventing subsequent NADPH oxidase assembly and superoxide anion generation [6], [35], [36], [37], [38], [39].

Downstream of Phosphatidylinositol 3-kinase signaling PDPK1 can phosphorylate and activate PKC-zeta and PKC-alpha [40], [41], [42], [43], [44].

PLD1 hydrolyzes membrane Phosphatidylcholines to generate Phosphatidic acid that is a powerful activator of PKC-zeta, which is, together with PKC-alpha, involved in phosphorylation of NADPH oxidase complex subunits [45], [46], [47], [48], [49].

The NADPH oxidase is a multicomponent enzyme in which cytosolic regulatory components (Neutrophil cytosolic factors 1, 2 and 4 (p47-phox, p67-phox and p40-phox)) must assembly with membrane-ancored Cytochrome b-558 that is composed of two transmembrane catalytic subunits, alpha (p22-phox) and beta (gp91-phox). The NADPH oxidase catalyzes the NADPH-dependent one electron reduction of O(2) to form superoxide anion (O(2)(-), from which other reactive oxygen species, including hydrogen peroxide, hydroxyl radical, and hypochlorous acid, are derived [30].

The neutrophil NADPH oxidase assembly is directly regulated by PKC-zeta, PKC-alpha [48], [49], [50], RAC2 [30], [51] and its effector, p21/Cdc42/Rac1-activated kinase 1 (PAK1) [52], [53], [54].

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