Inhibitory action of Lipoxins and Resolvin E1 on neutrophil functions

Inhibitory action of Lipoxins and Resolvin E1 on neutrophil functions

Deregulated neutrophilic inflammation and chronic infection lead to progressive destruction of the airways in cystic fibrosis (CF). In normal tissues, the lipoxins and resolvins are endogenous anti-inflammatory lipid mediators that are important as regulators of neutrophilic inflammation [1], [2], [3]. In CF, production of lipoxins is impaired [4], [5].

In response to infection or tissue injury, arachidonic acid produces proinflammatory Leukotriene B4 that leads to neutrophil recruitment and acute inflammation [6], [7], [8].

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

Lipoxins mediate a transition from acute to chronic inflammation and promote resolution [2], [8], [10]. 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], [4], [5].

Resolvin E1 is also a potent anti-inflammatory and proresolving mediator derived from omega-3 eicosapentaenoic acid produced during the resolution phase of inflammation. Resolvin E1 possesses a unique structure and counter-regulatory actions that stop human neutrophil transendothelial migration [2], [3], [11].

Leukotriene B4 and Lipoxins (Lipoxin A4 and 15-epi-LXA4) interact with highly specific and distinct G protein-coupled membrane receptors [12], [13], [14] to evoke opposing leukocyte responses, including Lipoxin A4 inhibition of Leukotriene B4-initiated respiratory burst, chemotaxis, adhesion, and transmigration [15].

Leukotriene B4 binds to the Leukotriene B4 receptor (LTBR1) that via G-protein alpha-i family and G-protein beta/gamma subunits activates Phosphatidylinositol 3-kinase (PI3K reg class IB (p101) and PI3K cat class IB (p110-gamma)) signaling [6], [16].

Resolvin E1 selective binding to LTBR1 blocks its stimulation by Leukotriene B4 and inhibits receptor signaling. Resolvin E1/ LTBR1 interaction followed by attenuation of neutrophil superoxide production and transendothelial migration leads to the resolution of acute inflammation [11].

Lipoxin A4 and 15-epi-LXA4 interact with the Formyl peptide receptor-like 1 (FPRL1) [1], [2], [10], [14] 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 presqualene diphosphate phosphatase that converts Presqualene diphosphate to Presqualene monophosphate [17]. 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 [8], [18].

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 [8], [18], [19], [20], [21], [22].

Protein kinase C zeta (PKC-zeta) is activated downstream of Phosphatidylinositol 3-kinase signaling [23], [24], [25].

PLD1 hydrolyzes membrane Phosphatidylcholines to generate Phosphatidic acid, a powerful activator of PKC-zeta, which phosphorylates NADPH oxidase complex subunits [26], [27], [28], [29], [30].

Lipoxin A4 (or 15-epi-LXA4)/ (FPRL1) signaling leads to accumulation of Presqualene diphosphate, and, thereby, blocks assembly of NADPH oxidase [9], [18]. Decreased Superoxide anion (O(2)(-)) production is consistent with a shift in the O(2)(-) / Nitric Oxide ratio, resulting in decreased Peroxynitrite (ONOO(-)) formation. Reductions in ONOO(-) formation are associated with attenuation of nuclear accumulation of transcription factors Nuclear factor kappa-B (NF-kB) and AP-1 (c-Jun/c-Fos), which act in concert to induce Interleukin 8 (IL-8) gene transcription [31].

Lipoxin A4 and 15-epi-LXA4 signaling may protect NF-kappa-B inhibitor alpha (NFKBIA) from nitration by ONOO(-) [32], thereby preventing activation of NF-kB, or may attenuate Mitogen-activated protein kinase kinase kinase 14 (NIK(MAP3K14))/ I-kappa-B kinase-alpha (IKK-alpha)/ NF-kappa-B inhibitor (I-kB)/ NF-kB pathway [9], [33].

Leukotriene B4 also induces neutrophil migration by Reactive oxygen species-Extracellular signal-regulated kinases 1 and 2 (ERK1/2)-linked cascade [34]. Superoxide (O(2)(-)) production results in Hydrogen peroxide formation [35], [36], [37]. ERK1/2 activated by Hydrogen peroxide [34], [38] can modulate the actin/myosin cytoskeleton remodeling necessary for cell motility [39], [40], [41], [42], and, possibly, can participate in c-Jun/c-Fos activation.

IL-8 is one of the key pro-inflammatory chemokines in the airways of CF patients; therefore Lipoxin- and Resolvin-induced counter-regulation of IL-8 expression is the critical pathway for 'stop-signaling' to neutrophil accumulation and for resolving stage of acute inflammation [1], [2], [3], [10], [43], [44], [45], [46].

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