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Inhibitory action of Lipoxins on neutrophil
Deregulated neutrophilic inflammation and chronic infection lead to progressive
destruction of the airways in cystic fibrosis (CF). In normal tissues, lipoxins are
endogenous anti-inflammatory lipid mediators in regulation of neutrophilic inflammation
. In CF, production of lipoxins is impaired , .
One striking feature of CF airways is the progressive accumulation of neutrophils.
This "acute inflammation" never converts to a more "chronic" pattern. There is certainly
an excess of chemoattractants such as Interleukin-8 (IL-8)
and Leukotriene B4 recovered in bronchoalveolar lavage
fluid. When present in excess, neutrophils and their products actually impair the host's
ability to clear bacterial infection .
Colonized by bacteria, the CF lung contains a range of potent neutrophil
chemoattractants, including the host-derived inflammatory mediators IL-8
and Leukotriene B4. N-formyl-Met-Leu-Phe
peptide (fMLP), produced by bacteria, usually stimulates neutrophils to migrate by a
mechanism that is mediated by alpha-M/beta-2 integrin (MAC-1), whereas IL-8
and Leukotriene B4 stimulate neutrophils to
migrate using an alternative, MAC-1-independent pathway, that is mediated by
alpha-L/beta-2 integrin (LFA-1) , , , , , . Over
70% of migrating neutrophils from CF patients appeared to favor this, LFA-1-dependent,
migratory route , .
The circulating neutrophils from normal tissues express two receptors for
IL-8, Interleukin 8 receptor alpha
(IL8RA) and Interleukin 8 receptor beta
(IL8RB). In contrast, neutrophils from patients with acute
and chronic pulmonary inflammation have decreased expression of
IL8RB, and only IL8RA is the
functionally dominant receptor on these neutrophils , .
In response to infection or tissue injury, arachidonic acid produces proinflammatory
Leukotriene B4 that also induces neutrophil recruitment and
acute inflammation , , .
In normal airways, arachidonic acid also produces antiinflammatory lipoxins. Lipoxins
mediate switch to chronic inflammation and promote resolution , , . In CF the inflammatory response remains persistently
neutrophilic that leads to tissue injury and further infection. This may be attributed to
a documented defect in the generation of lipoxins , , .
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 adhesion to endothelial
cells , .
IL-8, Leukotriene B4 and
Lipoxins (Lipoxin A4 and
15-epi-LXA4) interact with highly specific and distinct G
protein-coupled membrane receptors , , to evoke opposing
leukocyte responses, including Lipoxin-induced inhibition of chemoattractant-initiated
migration of neutrophils , , .
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 , , , , , , .
IL-8 binding to IL8RA
also stimulates PI3K cat class
IB (p110-gamma) that phosphorylates the membrane lipid
phosphatidylinositol 4,5-bisphosphate (PtdIns(4,5)P2) to
phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3)
PtdIns(3,4,5)P3 recruits and activates diverse cytosolic
effectors, including Phospholipase D1 (PLD1) , 3-phosphoinositide dependent protein kinase-1
(PDPK1) , v-Akt murine thymoma viral oncogene
homologs (AKT) , , Protein
kinase C zeta (PKC-zeta)  and
Phosphatidylinositol 3,4,5-trisphosphate-dependent RAC exchanger 1
(PREX1) , .
PREX1 is the main guanine nucleotide exchange factors for
the Ras-related C3 botulinum toxin substrates 1 and 2 (Rac1
and Rac2) in neutrophils , , , . Rac1 and
Rac2 stimulate the kinase activity of p21-activated kinase 1
(PAK1) that is important for
regulating neutrophil chemotactic responsiveness , .
PDPK1, in turn, phosphorylates and activates
AKT, PKC-zeta and
PAK1 , .
Lipoxin A4 and 15-epi-LXA4
interact with the Formyl peptide receptor-like 1
(FPRL1) , , 
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
. 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 , .
Presqualene diphosphate, but not
Presqualene monophosphate, directly inhibits
PLD1 and PI3K cat class IB
(p110-gamma) , , , , , .
PLD1 hydrolyzes membrane
Phosphatidylcholines to generate Phosphatidic
acid that is a powerful activator of PKC-zeta
, , .
PKC-zeta has been shown to control lymphocyte
alpha-L/beta-2 integrin rapid lateral mobility induced by
chemokines , .
Phosphatidic acid also activates Type I
phosphatidylinositol-4-phosphate 5-kinases (PIP5KI) that
catalyze the synthesis of PtdIns(4,5)P2 , , which, in turn, mediates Talin activation
of alpha-L/beta-2 integrin required for neutrophil
transendothelial migration , , , . This migration is mediated via binding of neutrophil
alpha-L/beta-2 integrin to endothelial Ligand intercellular
adhesion molecule-1 (ICAM-1) , , , .
Cell motility also requires polarized rearrangements of the actin/myosin cytoskeleton.
PAK1 regulates directional cell motility through its effects
on regulatory light chains of Myosin II (MRLC) .
Downstream of Rac1, PAK1 activates
LIMK1, which, in turn, regulates the actin cytoskeletal
reorganization through the phosphorylation and inactivation of the actin-depolymerizing
factor Cofilin , . Actin-organizing complex
(Arp2/3) nucleates new Actin
filaments from the sides of preexisting filaments. This interaction requires
phosphorylation of Arp2/3 complex by
PAK1, which promotes Actin
PDPK1 and AKT also
phosphorylate PAK1 that can regulate cell migration , , .
Leukotriene B4 can also induce neutrophil migration by
Reactive oxygen species (ROS)/ Extracellular signal-regulated kinases 1 and 2
(ERK1/2)-linked cascade .
Leukotriene B4 signaling activates the NADPH oxidase that
catalyzes the production of Superoxide anion (O(2)(-)), from
which other ROS, including Hydrogen peroxide, are derived
, , . ERK1/2
activated by Hydrogen peroxide ,  can modulate actin/myosin cytoskeleton remodeling via
regulation of Myosin II phosphorylation.
ERK1/2 can phosphorylate and inactivate the Myosin light
chain phosphatase (MLCP) , which attenuates
Myosin light chains (MELC) and
Myosin regulatory light chains (MRLC) phosphorylation . In addition, ERK1/2 can phosphorylate and
activate Myosin light chain kinase (MYLK1) .
Myosin II function is regulated by phosphorylation of the
MRLC by Myosin light chain kinases
(MLCK) that promotes myosin ATPase activity and
polymerization of actin cables. This results in generating contractile force necessary
for cell motility .
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