TNF-α promotes LPA1- and LPA3-mediated recruitment of leukocytes in vivo through CXCR2 ligand chemokines

Lysophosphatidic acid (LPA) is a bioactive lysophospholipid present in low concentrations in serum and biological fluids but in high concentrations at sites of inflammation. LPA evokes a variety of cellular responses via binding to and activation of its specific G protein-coupled receptors (GPCR), namely LPA1-6. Even though LPA is a chemoattractant for inflammatory cells in vitro, such a role for LPA in vivo remains largely unexplored. In the present study, we used the murine air pouch model to study LPA-mediated leukocyte recruitment in vivo using selective LPA receptor agonist/antagonist and LPA3-deficient mice. We report that 1) LPA injection into the air pouch induced leukocyte recruitment and that both LPA1 and LPA3 were involved in this process; 2) LPA stimulated the release of the pro-inflammatory chemokines keratinocyte-derived chemokine (KC) and interferon-inducible protein-10 (IP-10) in the air pouch; 3) tumor necrosis factor-α (TNF-α) injected into the air pouch prior to LPA strongly potentiated LPA-mediated secretion of cytokines/chemokines, including KC, IL-6, and IP-10, which preceded the enhanced leukocyte influx; and 4) blocking CXCR2 significantly reduced leukocyte infiltration. We suggest that LPA, via LPA1 and LPA3 receptors, may play a significant role in inducing and/or sustaining the massive infiltration of leukocytes during inflammation. Lysophosphatidic acid (LPA) is a bioactive lysophospholipid present in low concentrations in serum and biological fluids but in high concentrations at sites of inflammation. LPA evokes a variety of cellular responses via binding to and activation of its specific G protein-coupled receptors (GPCR), namely LPA1-6. Even though LPA is a chemoattractant for inflammatory cells in vitro, such a role for LPA in vivo remains largely unexplored. In the present study, we used the murine air pouch model to study LPA-mediated leukocyte recruitment in vivo using selective LPA receptor agonist/antagonist and LPA3-deficient mice. We report that 1) LPA injection into the air pouch induced leukocyte recruitment and that both LPA1 and LPA3 were involved in this process; 2) LPA stimulated the release of the pro-inflammatory chemokines keratinocyte-derived chemokine (KC) and interferon-inducible protein-10 (IP-10) in the air pouch; 3) tumor necrosis factor-α (TNF-α) injected into the air pouch prior to LPA strongly potentiated LPA-mediated secretion of cytokines/chemokines, including KC, IL-6, and IP-10, which preceded the enhanced leukocyte influx; and 4) blocking CXCR2 significantly reduced leukocyte infiltration. We suggest that LPA, via LPA1 and LPA3 receptors, may play a significant role in inducing and/or sustaining the massive infiltration of leukocytes during inflammation. Lysophosphatidic acid (LPA) is a simple lipid with a single fatty acyl chain, a glycerol backbone, and a free phosphate group (1Tokumura A. A family of phospholipid autacoids: occurrence, metabolism and bioactions.Prog. Lipid Res. 1995; 34: 151-184Crossref PubMed Scopus (166) Google Scholar). Despite the simplicity of its structure, LPA has been implicated in various physiological (cell growth, differentiation, migration, and survival) and pathological (angiogenesis, cancer, and autoimmunity) situations. LPA is present in micromolar concentrations in serum and biological fluids and in higher concentrations at sites of inflammation and tumor (2Ishii I. Fukushima N. Ye X. Chun J. Lysophospholipid receptors: signaling and biology.Annu. Rev. Biochem. 2004; 73: 321-354Crossref PubMed Scopus (647) Google Scholar). LPA evokes a variety of cellular responses via binding to and activation of its specific G protein-coupled receptors (GPCR) (3Moolenaar W.H. Lysophosphatidic acid signalling.Curr. Opin. Cell Biol. 1995; 7: 203-210Crossref PubMed Scopus (222) Google Scholar). So far, five and possibly six GPCRs have been identified as specific LPA receptors, namely, LPA1-6 (4Choi J.W. Herr D.R. Noguchi K. Yung Y.C. Lee C.W. Mutoh T. Lin M.E. Teo S.T. Park K.E. Mosley A.N. et al.LPA receptors: subtypes and biological actions.Annu. Rev. Pharmacol. Toxicol. 2010; 50: 157-186Crossref PubMed Scopus (649) Google Scholar). Two additional GPCRs, GPR87 (5Tabata K. Baba K. Shiraishi A. Ito M. Fujita N. The orphan GPCR GPR87 was deorphanized and shown to be a lysophosphatidic acid receptor.Biochem. Biophys. Res. Commun. 2007; 363: 861-866Crossref PubMed Scopus (187) Google Scholar) and P2Y10 (6Murakami M. Shiraishi A. Tabata K. Fujita N. Identification of the orphan GPCR, P2Y(10) receptor as the sphingosine-1-phosphate and lysophosphatidic acid receptor.Biochem. Biophys. Res. Commun. 2008; 371: 707-712Crossref PubMed Scopus (124) Google Scholar), have been suggested to be activated by LPA. LPA has been shown to be a chemoattractant for human inflammatory cells in in vitro studies. Chettibi et al. showed that LPA was a powerful stimulator of human neutrophil polarization and motility (7Chettibi S. Lawrence A.J. Stevenson R.D. Young J.D. Effect of lysophosphatidic acid on motility, polarisation and metabolic burst of human neutrophils.FEMS Immunol. Med. Microbiol. 1994; 8: 271-281Crossref PubMed Scopus (40) Google Scholar). Similarly, Fischer et al. described chemoattractive effects of LPA toward human PMNs under agarose (8Fischer L.G. Bremer M. Coleman E.J. Conrad B. Krumm B. Gross A. Hollmann M.W. Mandell G. Durieux M.E. Local anesthetics attenuate lysophosphatidic acid-induced priming in human neutrophils.Anesth. Analg. 2001; 92: 1041-1047Crossref PubMed Scopus (66) Google Scholar). LPA also causes an increase in binding of monocytes and neutrophils to human aortic endothelial cells (9Rizza C. Leitinger N. Yue J. Fischer D.J. Wang D.A. Shih P.T. Lee H. Tigyi G. Berliner J.A. Lysophosphatidic acid as a regulator of endothelial/leukocyte interaction.Lab. Invest. 1999; 79: 1227-1235PubMed Google Scholar). Emerging evidence suggests a role for autotaxin (ATX)-LPA in facilitating lymphocyte migration into lymphoid and chronically inflamed nonlymphoid tissues (10Kanda H. Newton R. Klein R. Morita Y. Gunn M.D. Rosen S.D. Autotaxin, an ectoenzyme that produces lysophosphatidic acid, promotes the entry of lymphocytes into secondary lymphoid organs.Nat. Immunol. 2008; 9: 415-423Crossref PubMed Scopus (211) Google Scholar, 11Nakasaki T. Tanaka T. Okudaira S. Hirosawa M. Umemoto E. Otani K. Jin S. Bai Z. Hayasaka H. Fukui Y. et al.Involvement of the lysophosphatidic acid-generating enzyme autotaxin in lymphocyte-endothelial cell interactions.Am. J. Pathol. 2008; 173: 1566-1576Abstract Full Text Full Text PDF PubMed Scopus (93) Google Scholar). The study of Kanda et al. demonstrated that LPA, locally generated by ATX in high endothelial venules, facilitates lymphocyte transendothelial migration via stimulating chemokinesis rather than chemotaxis (10Kanda H. Newton R. Klein R. Morita Y. Gunn M.D. Rosen S.D. Autotaxin, an ectoenzyme that produces lysophosphatidic acid, promotes the entry of lymphocytes into secondary lymphoid organs.Nat. Immunol. 2008; 9: 415-423Crossref PubMed Scopus (211) Google Scholar). The role of LPA in the recruitment of leukocytes to inflammatory sites in vivo, however, remains elusive. Accumulating evidence suggests that LPA-induced cell migration may be mediated, in part, by chemokines. We recently reported that LPA induces the expression of a potent chemoattractant, interleukin (IL)-8 (12Zhao C. Fernandes M.J. Prestwich G.D. Turgeon M. Di Battista J. Clair T. Poubelle P.E. Bourgoin S.G. Regulation of lysophosphatidic acid receptor expression and function in human for Pharmacol. 2008; 73: PubMed Scopus Google Scholar). chemoattractant that play in the of inflammatory cells at the of inflammation. chemokines the and for neutrophil recruitment via binding to and activation of receptors CXCR2 in and Rev. 9: PubMed Scopus (66) Google Scholar, PubMed Google Scholar). In the and a of and keratinocyte-derived chemokine and inflammatory to be the chemokines at sites of inflammation and/or C. C. M.J. R. C. and of the murine chemokine Immunol. 1995; PubMed Google Scholar, B. S. S. A. in a model of the of and PubMed Scopus Google Scholar, S. J.D. of inflammatory and in J. Pathol. Google Scholar, The murine chemokines KC, and have and to in Biol. PubMed Scopus Google Scholar, R. J. M. of and is during J. Google Scholar). is that neutrophil migration in this is by and via binding to receptor CXCR2 C. M.J. R. C. The murine interleukin receptor and its and biological Biol. 1994; Full Text PDF PubMed Google Scholar, J. G. T. K. M.W. binding and by the Immunol. 1995; PubMed Google Scholar). LPA was shown to the expression of and the of in using LPA3-deficient X. K. B. A. H. T. G. H. et lysophosphatidic acid in and PubMed Scopus Google Scholar). LPA has been shown to the of and chemokines in with (12Zhao C. Fernandes M.J. Prestwich G.D. Turgeon M. Di Battista J. Clair T. Poubelle P.E. Bourgoin S.G. Regulation of lysophosphatidic acid receptor expression and function in human for Pharmacol. 2008; 73: PubMed Scopus Google Scholar, H. H. M. Tanaka N. K. T. T. K. H. et role of lysophosphatidic acid in by of with in Immunol. 2008; PubMed Scopus Google Scholar), a inflammatory by leukocyte infiltration into the of PubMed Scopus Google Scholar). In the present study, we an in vivo model of the murine air pouch to the of LPA on leukocyte recruitment in The LPA receptor and the of LPA-induced leukocyte recruitment in vivo were using both a receptor and a We that both LPA1 and LPA3 the recruitment of leukocytes into the air pouch a that is on LPA-mediated chemokine and by the pro-inflammatory (LPA) was The specific receptor acid was Lipid The specific and LPA3 were and was CXCR2 was CXCR2 and were and A were The was LPA3 receptor were generated X. K. B. A. H. T. G. H. et lysophosphatidic acid in and PubMed Scopus Google Scholar). were to for LPA3 as described X. K. B. A. H. T. G. H. et lysophosphatidic acid in and PubMed Scopus Google Scholar, Fukushima N. J.A. Chun J. for the lysophosphatidic acid receptor in PubMed Scopus Google Scholar). were used as were by the at and to of and were on the of by injection of air on and as described D.A. The of the air pouch to study and Google Scholar). the injection of were with LPA LPA receptor agonist/antagonist in of the were injected into air In was injected into air prior to with LPA LPA receptor a of LPA receptor on LPA-induced leukocyte was injected prior to LPA injection into the air the role of CXCR2 and chemokines in LPA-induced leukocyte the CXCR2 and blocking KC, and CXCR2 were injected prior to LPA injection into the air specific were by using The air pouch were by with of and with of at cell were with and the leukocytes were to cells were at for using a The were air and with to of leukocyte the of air were with of The were at for at and were at for the air pouch was using and into with was using were as at and used in were as KC, The air of were injected with its prior to LPA of in to LPA, and were using the the The air pouch group were with A to the and at The was with by of in the a The air of were with for prior to LPA of the air pouch at LPA injection were for the of by to the were in were using a at The were with a that was generated using concentrations of and were in The air of were with for prior to LPA injection of of the air pouch were for the of by to the was in The were with a that was generated using concentrations of The of the is The air of were with for prior to LPA chemokines in the air pouch were using a to the The was used for the of IL-6, KC, and interferon-inducible protein-10 The of the is were with and as as studies. were using of the of was by the and and and at with at was by of and was using in the were using than were LPA is to leukocytes in vivo, of LPA in of the to was injected into air on mice. The of concentrations of LPA was on the of a in vitro study using human (12Zhao C. Fernandes M.J. Prestwich G.D. Turgeon M. Di Battista J. Clair T. Poubelle P.E. Bourgoin S.G. Regulation of lysophosphatidic acid receptor expression and function in human for Pharmacol. 2008; 73: PubMed Scopus Google Scholar). in the air pouch was of LPA in a of leukocytes in air leukocyte were in air and of LPA for LPA A of LPA was used for A with LPA that an increase in the of leukocytes to be the and of the leukocytes with that the of leukocytes at injection was neutrophils of the and a monocytes the of LPA in LPA-induced leukocyte a LPA3 and LPA receptor was in was and the of leukocytes to the air pouch in to LPA for for and for for LPA and for for and for for were used as the The of leukocytes into air in a A significant of leukocytes in the air of was the injection of LPA and however, was in by LPA was injected into air with the receptor LPA-induced leukocyte recruitment was in both and in to the air pouch of injection of this also significantly leukocyte recruitment into air by LPA in both and the role of the LPA3 receptor in LPA-mediated leukocyte the LPA3 receptor in of the that to was injected into air on The of concentrations of was on the a in vitro study using human (12Zhao C. Fernandes M.J. Prestwich G.D. Turgeon M. Di Battista J. Clair T. Poubelle P.E. Bourgoin S.G. Regulation of lysophosphatidic acid receptor expression and function in human for Pharmacol. 2008; 73: PubMed Scopus Google Scholar). A significant increase in leukocyte was at of and the of cells was at of for the the receptor on leukocyte recruitment to a using concentrations of a of leukocytes was in the air of and for In to leukocytes by LPA in LPA-induced leukocyte recruitment was leukocyte recruitment by was in The suggest that both LPA1 and LPA3 involved in LPA-mediated leukocyte recruitment in LPA-induced leukocyte recruitment is by of an inflammatory air on were injected with of prior to LPA into the air shown in significant on leukocyte with injection into the murine air pouch in a recruitment of leukocytes with at and to by I. in of and chemokines in neutrophil in vivo in to Immunol. PubMed Google Scholar). leukocytes in the air pouch have the C. Regulation of neutrophil via PubMed Scopus Google Scholar, C. D.A. of neutrophil 2001; PubMed Scopus Google Scholar) of with however, strongly enhanced LPA-induced leukocyte The of leukocytes in air by LPA by with air We the of on and leukocyte recruitment and In and leukocyte in air was reduced by and with mice. In air the LPA3 receptor LPA-induced leukocyte recruitment by showed that the expression of both LPA1 and LPA3 in the air pouch tissues was enhanced by LPA induces (12Zhao C. Fernandes M.J. Prestwich G.D. Turgeon M. Di Battista J. Clair T. Poubelle P.E. Bourgoin S.G. Regulation of lysophosphatidic acid receptor expression and function in human for Pharmacol. 2008; 73: PubMed Scopus Google Scholar), the were to chemokines in air play a role in the migration of leukocytes toward LPA in air described in this were with mice. we that neutrophils the leukocytes in of air injected with LPA and and that neutrophil migration in the is by and via binding to receptor CXCR2 C. M.J. R. C. The murine interleukin receptor and its and biological Biol. 1994; Full Text PDF PubMed Google Scholar, J. G. T. K. M.W. binding and by the Immunol. 1995; PubMed Google Scholar), the of chemokines in LPA-mediated leukocyte recruitment was shown in injection of the CXCR2 and a CXCR2 prior to LPA into the air pouch significantly LPA-mediated leukocyte recruitment in both and air In air at the LPA-induced infiltration of leukocytes by injection of the LPA-induced infiltration of leukocytes by Similarly, in air LPA-mediated leukocyte recruitment to in a the LPA-induced leukocyte recruitment by of by LPA-induced neutrophil recruitment In the blocking significant on LPA-induced leukocyte recruitment into the air pouch A in which a of and chemokine expression in air pouch be was of six was induced by LPA with including IL-6, KC, and and The expression of receptor on cells an receptor involved in inflammatory was also induced by LPA air were with LPA induced a and expression of inflammation In to IL-6, and also enhanced the expression of IP-10, and The of was to the expression of and chemokines. we an of the on LPA-induced leukocyte recruitment secretion in to LPA we on a for secretion of was in mice. The increase in secretion was at the using in to in air A significant increase of expression and secretion was in air The increase in secretion at and a at LPA injection for which expression of was also in air with air pouch which at injection the of secretion preceded that of neutrophil recruitment into the air was used to the secretion of induced by LPA and with in the air pouch The expression of KC, IL-6, and to a was in to LPA and in air The release of and in to LPA and was strongly enhanced the of and by the of to that of priming induced a release of which was to that induced by LPA and and higher than that of the group with for however, release and priming LPA, and significant of secretion with and secretion and in air with that in air the five was in to LPA in and air that the of this in the air pouch was the of the to to LPA and on significant increase in the of was in using the the The of this in LPA-induced leukocyte recruitment In the present study, we the role of LPA in leukocyte migration toward an in vivo inflammatory We that injection of LPA in the recruitment of a inflammatory leukocyte to murine air and that both LPA1 and LPA3 receptors were involved in this LPA-induced leukocyte in the air pouch was the release of the pro-inflammatory chemokine significantly concentrations of were in the of air which preceded LPA-induced leukocyte recruitment that was enhanced by this is the study to the by which LPA may leukocytes to an inflammatory in of evidence that LPA is an stimulator of leukocyte recruitment in Chettibi et al. reported that LPA stimulated neutrophil polarization and motility (7Chettibi S. 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LPA may the recruitment of inflammatory cells to the of by stimulating inflammatory secretion in the study to a of the involved in inflammation and that both LPA and CXCR2 receptors may be for The A. for and The to for The to for the of the of the for with autotaxin G protein-coupled receptor interleukin protein-10 keratinocyte-derived chemokine lysophosphatidic acid inflammatory tumor necrosis factor-α

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