Inhibitory action of Lipoxin A4 on PDGF, EGF and LTD4 signaling

Inhibitory action of Lipoxin A4 on PDGF, EGF and LTD4 signaling

Control of inflammation is crucial to prevent damage to the host during infection. Lipoxins, which are metabolites of trihydroxytetraene-containing arachidonic acid, are crucial modulators of proinflammatory response. In the absence of Lipoxin A4 biosynthetic pathways, uncontrolled inflammation during infection is lethal, even in the case of pathogen clearance [1], [2], [3], [4].

Lipoxin A4 exerts its action via an interaction with its cognate G protein-coupled receptor (GPCR), Formyl peptide receptor-like 1 (FPRL1) [5], [6], [7], [8].

Lipoxins display potent antiinflammatory action, including attenuation of neutrophil migration and reactive oxygen species (ROS) production that mediates the switch to chronic inflammation and promotes resolution [5], [6], [8], [9], [10].

FPRL1 interaction with Lipoxin A4 and aspirin-triggered lipoxins on neutrophils regulates the polyisoprenyl phosphate signaling pathway. FPRL1 activation by lipoxins reverses Leukotriene B4-initiated polyisoprenyl phosphate remodeling, leading to accumulation of Presqualene diphosphate, a potent negative intracellular signal in neutrophils that inhibits phospholipase D 1 (PLD1) and superoxide anion generation [7], [10], [11], [12].

In monocytes and macrophages (but not neutrophils), Lipoxin A4, can induce Ras homolog gene family, member A (RhoA)-dependent cytoskeleton reorganization, via FPRL1 / G-protein alpha-i family / Adenylate cyclase pathway and inhibition of Cyclic AMP (cAMP). Lipoxin-induced migration of monocytes and macrophages may contribute to the resolution of inflammation [6], [13].

Lipoxin A4 also acts as a partial agonist to mediate the bioactions in several tissues and cell types other than leukocytes, via interactions with two GPCRs, Cysteinyl Leukotriene Receptor 1 and 2 (CysLT1 and CysLT2) [7], [14]. Lipoxin A4 blocks Leukotriene D4 (LTD4) actions and also competes for specific LTD4 binding on mesangial cells [15] and human umbilical vein endothelial cells [16]. Lipoxin A4 and LTD4 bind and compete with essentially equal affinity at CysLT1 and CysLT2 [17], [5], [14], [18], [19], providing a molecular basis for Lipoxin serving as a local damper of both vascular CysLT1 / CysLT2 signals as well as Lipoxin/ FPRL1-regulated neutrophil trafficking [7].

In human renal mesangial cells, Lipoxin A4 has been shown to inhibit Platelet-derived growth factor beta (PDGF-B) and LTD4-stimulated cell proliferation. LTD4 transactivates Platelet-derived growth factor receptor beta (PDGF-R-beta) via CysLT2 / G-protein alpha-q/11 / c-Src signaling. Lipoxin A4 inhibits LTD4-induced phosphorylation of PDGF-R-beta by c-Src and also inhibits PDGF-B activation of PDGF-R-beta and proliferative responses to PDGF-B [20].

Lipoxin A4 / FPRL1 signaling is also coupled with reactivation of Protein tyrosine phosphatase SHP-2, that specifically dephosphorylates the recruitment sites of the Phosphoinositide-3-kinase, regulatory subunit 1 (alpha) (PI3K reg class IA (p85)) on the platelet-derived growth factor receptor beta (PDGF-R-beta) and Epidermal growth factor receptor (EGFR) [21]. Platelet-derived growth factor beta (PDGF-B)-activated PDGF-R-beta and Epidermal growth factor (EGF)-activated EGFR undergo autophosphorylation at multiple tyrosine residues followed by association with numerous signal transduction proteins that include Phospholipase C gamma 1 (PLC-gamma 1), PI3K reg class IA (p85) and SHP-2. H2O2 can oxidatively inactivate SHP-2, within the microenvironment of PDGF-R-beta. Activation of the lipid raft-bound FPRL1 induces recruitment to and activation/reactivation of SHP-2 through direct stimulation of SHP-2 and/or indirectly by attenuating H2O2 production. Although Peroxiredoxin 2 (PRDX2) allows oxidatively inactivated SHP-2 to be reactivated by removing endogenous H2O2 [22], [23], [24], Lipoxin A4 attenuation of H2O2 production and hence activation of SHP-2 has been shown to be independent of PRDX2 [21].

In addition to inducing G-protein-coupled receptor FPRL1 signaling, lipoxins, can also activate a nuclear receptor Aryl hydrocarbon receptor (AHR) [25], which triggers expression of Suppressor of cytokine signaling 2 (SOCS2). Both receptors, FPRL1 and AHR, are involved in SOCS2 induction in dendritic cells [4]. SOCS2-deficient cells are hyper-responsive to microbial stimuli, as well as refractory to the inhibitory actions of Lipoxin A4. Upon infection with an intracellular pathogen, SOCS2-deficient mice had uncontrolled production of proinflammatory cytokines, decreased microbial proliferation, aberrant leukocyte infiltration and elevated mortality. SOCS2 is a crucial intracellular mediator of the anti-inflammatory actions of lipoxins [4], [26].

References:

1. Aliberti J, Hieny S, Reis e Sousa C, Serhan CN, Sher A
   Lipoxin-mediated inhibition of IL-12 production by DCs: a mechanism for regulation of microbial immunity. Nature immunology 2002 Jan;3(1):76-82
2. Aliberti J, Serhan C, Sher A
   Parasite-induced lipoxin A4 is an endogenous regulator of IL-12 production and immunopathology in Toxoplasma gondii infection. The Journal of experimental medicine 2002 Nov 4;196(9):1253-62
3. Bafica A, Scanga CA, Serhan C, Machado F, White S, Sher A, Aliberti J
   Host control of Mycobacterium tuberculosis is regulated by 5-lipoxygenase-dependent lipoxin production. The Journal of clinical investigation 2005 Jun;115(6):1601-6
4. Machado FS, Johndrow JE, Esper L, Dias A, Bafica A, Serhan CN, Aliberti J
   Anti-inflammatory actions of lipoxin A4 and aspirin-triggered lipoxin are SOCS-2 dependent. Nature medicine 2006 Mar;12(3):330-4
5. Karp CL, Flick LM, Yang R, Uddin J, Petasis NA
   Cystic fibrosis and lipoxins. Prostaglandins, leukotrienes, and essential fatty acids 2005 Sep-Oct;73(3-4):263-70
6. Chiang N, Arita M, Serhan CN
   Anti-inflammatory circuitry: lipoxin, aspirin-triggered lipoxins and their receptor ALX. Prostaglandins, leukotrienes, and essential fatty acids 2005 Sep-Oct;73(3-4):163-77
7. Chiang N, Serhan CN, Dahlen SE, Drazen JM, Hay DW, Rovati GE, Shimizu T, Yokomizo T, Brink C
   The lipoxin receptor ALX: potent ligand-specific and stereoselective actions in vivo. Pharmacological reviews 2006 Sep;58(3):463-87
8. Serhan CN
   Resolution phase of inflammation: novel endogenous anti-inflammatory and proresolving lipid mediators and pathways. Annual review of immunology 2007;25:101-37
9. Filep JG, Khreiss T, Jozsef L
   Lipoxins and aspirin-triggered lipoxins in neutrophil adhesion and signal transduction. Prostaglandins, leukotrienes, and essential fatty acids 2005 Sep-Oct;73(3-4):257-62
10. Bonnans C, Levy BD
    Lipid mediators as agonists for the resolution of acute lung inflammation and injury. American journal of respiratory cell and molecular biology 2007 Feb;36(2):201-5
11. Levy BD, Fokin VV, Clark JM, Wakelam MJ, Petasis NA, Serhan CN
    Polyisoprenyl phosphate (PIPP) signaling regulates phospholipase D activity: a 'stop' signaling switch for aspirin-triggered lipoxin A4. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 1999 May;13(8):903-11
12. Levy BD, Hickey L, Morris AJ, Larvie M, Keledjian R, Petasis NA, Bannenberg G, Serhan CN
    Novel polyisoprenyl phosphates block phospholipase D and human neutrophil activation in vitro and murine peritoneal inflammation in vivo. British journal of pharmacology 2005 Oct;146(3):344-51
13. Maderna P, Cottell DC, Berlasconi G, Petasis NA, Brady HR, Godson C
    Lipoxins induce actin reorganization in monocytes and macrophages but not in neutrophils: differential involvement of rho GTPases. The American journal of pathology 2002 Jun;160(6):2275-83
14. Norel X, Brink C
    The quest for new cysteinyl-leukotriene and lipoxin receptors: recent clues. Pharmacology & therapeutics 2004 Jul;103(1):81-94
15. Badr KF, DeBoer DK, Schwartzberg M, Serhan CN
    Lipoxin A4 antagonizes cellular and in vivo actions of leukotriene D4 in rat glomerular mesangial cells: evidence for competition at a common receptor. Proceedings of the National Academy of Sciences of the United States of America 1989 May;86(9):3438-42
16. Fiore S, Maddox JF, Perez HD, Serhan CN
    Identification of a human cDNA encoding a functional high affinity lipoxin A4 receptor. The Journal of experimental medicine 1994 Jul 1;180(1):253-60
17. Papayianni A, Serhan CN, Brady HR
    Lipoxin A4 and B4 inhibit leukotriene-stimulated interactions of human neutrophils and endothelial cells. Journal of immunology (Baltimore, Md. : 1950) 1996 Mar 15;156(6):2264-72
18. McMahon B, Stenson C, McPhillips F, Fanning A, Brady HR, Godson C
    Lipoxin A4 antagonizes the mitogenic effects of leukotriene D4 in human renal mesangial cells. Differential activation of MAP kinases through distinct receptors. The Journal of biological chemistry 2000 Sep 8;275(36):27566-75
19. Gronert K, Martinsson-Niskanen T, Ravasi S, Chiang N, Serhan CN
    Selectivity of recombinant human leukotriene D(4), leukotriene B(4), and lipoxin A(4) receptors with aspirin-triggered 15-epi-LXA(4) and regulation of vascular and inflammatory responses. The American journal of pathology 2001 Jan;158(1):3-9
20. McMahon B, Mitchell D, Shattock R, Martin F, Brady HR, Godson C
    Lipoxin, leukotriene, and PDGF receptors cross-talk to regulate mesangial cell proliferation. The FASEB journal : official publication of the Federation of American Societies for Experimental Biology 2002 Nov;16(13):1817-9
21. Mitchell D, O'Meara SJ, Gaffney A, Crean JK, Kinsella BT, Godson C
    The Lipoxin A4 receptor is coupled to SHP-2 activation: implications for regulation of receptor tyrosine kinases. The Journal of biological chemistry 2007 May 25;282(21):15606-18
22. Kang SW, Chae HZ, Seo MS, Kim K, Baines IC, Rhee SG
    Mammalian peroxiredoxin isoforms can reduce hydrogen peroxide generated in response to growth factors and tumor necrosis factor-alpha. The Journal of biological chemistry 1998 Mar 13;273(11):6297-302
23. Chae HZ, Kim HJ, Kang SW, Rhee SG
    Characterization of three isoforms of mammalian peroxiredoxin that reduce peroxides in the presence of thioredoxin. Diabetes research and clinical practice 1999 Sep;45(2-3):101-12
24. Choi MH, Lee IK, Kim GW, Kim BU, Han YH, Yu DY, Park HS, Kim KY, Lee JS, Choi C, Bae YS, Lee BI, Rhee SG, Kang SW
    Regulation of PDGF signalling and vascular remodelling by peroxiredoxin II. Nature 2005 May 19;435(7040):347-53
25. Schaldach CM, Riby J, Bjeldanes LF
    Lipoxin A4: a new class of ligand for the Ah receptor. Biochemistry 1999 Jun 8;38(23):7594-600
26. Rico-Bautista E, Flores-Morales A, Fernandez-Perez L
    Suppressor of cytokine signaling (SOCS) 2, a protein with multiple functions. Cytokine & growth factor reviews 2006 Dec;17(6):431-9