title: Macrophage migration arrest due to a winning balance of Rac2/Sp1 repression over β-catenin-induced PLD expression.
abstract: Monocytes and neutrophils infiltrate into tissues during inflammation and stay for extended periods of time until the initial insult is resolved or sometimes remain even longer in the case of chronic inflammation. The mechanism as to why phagocytes become immobilized after the initial cell migration event is not understood completely. Here, we show that overexpression or hyperactivation of Rac2 decreases sustained chemotactic responses of macrophages to MCP-1/CCL2. The resulting leukocyte arrest is not caused by a diminished availability of the cytokine receptor CCR2 that remains intact during MCP-1 stimulation. We show a novel mechanism that links the Rac2-dependent arrest of chemotaxis to decreased expression of PLD2 through the transcription regulator Sp1. Prolonged Rac2 activity leads to nuclear overactivation of Sp1, which acts as a repressor for PLD2. Also, another signaling component plays a regulatory role: β-catenin. Although early times of stimulation (≈ 20 min) with MCP-1/CCL2 resulted in activation of β-catenin with a positive effect on PLD2, after ≈ 3 h of stimulation, the levels of β-catenin were reduced and not able to prevent the negative effect of Rac2 on PLD2 activity. This is a novel molecular mechanism underlying immobilization of monocyte/macrophage migration that is important for the physiological maintenance of leukocytes at the site of inflammation. If this immobilization is prolonged enough, it could lead to chronic inflammation.
authors.affiliation: 1.Dept. of Biochemistry and Molecular Biology, 3640 Colonel Glenn Highway, Dayton, OH 45435, USA. julian.cambronero@wright.edu.
authors.forename: Francis J
authors.initials: FJ
authors.lastname: Speranza
authors.forename: Madhu
authors.initials: M
authors.lastname: Mahankali
authors.forename: Julian
authors.initials: J
authors.lastname: Gomez-Cambronero
mesh_terms: D000818:Animals; D002465:Cell Movement; D002478:Cells, Cultured; D002633:Chemotaxis; D008264:Macrophages / Q000166:cytology / Q000502:physiology*; D051379:Mice; D010739:Phospholipase D / Q000235:genetics* / Q000502:physiology; D016329:Sp1 Transcription Factor / Q000502:physiology*; D051176:beta Catenin / Q000502:physiology*; D020744:rac GTP-Binding Proteins / Q000502:physiology*; D000097766:RAC2 GTP-Binding Protein
chemical_list: D010739:Phospholipase D; D016329:Sp1 Transcription Factor; D051176:beta Catenin; D020744:rac GTP-Binding Proteins; D000097766:RAC2 GTP-Binding Protein; C495267:CTNNB1 protein, mouse
keywords: cell migration; chemotaxis; gene expression regulation; granulocyte; monocyte signaling cascade
references.citation: Biochem Biophys Res Commun. 2006 Aug 18;347(1):109-16
references.pmid: 16815294
references.citation: Science. 2009 Apr 17;324(5925):384-7
references.pmid: 19325080
references.citation: J Cell Sci. 2005 Nov 1;118(Pt 21):4917-9
references.pmid: 16254237
references.citation: J Biol Chem. 2010 Mar 19;285(12):8782-92
references.pmid: 20097750
references.citation: PLoS One. 2012;7(4):e33830
references.pmid: 22511927
references.citation: Blood. 2003 Oct 1;102(7):2660-9
references.pmid: 12829592
references.citation: PLoS One. 2007 Mar 21;2(3):e312
references.pmid: 17375198
references.citation: PLoS One. 2012;7(10):e48208
references.pmid: 23110215
references.citation: Carcinogenesis. 2009 Feb;30(2):356-65
references.pmid: 19126647
references.citation: J Biol Chem. 2005 Jul 29;280(30):28061-71
references.pmid: 15878880
references.citation: PLoS One. 2009 Nov 16;4(11):e7841
references.pmid: 19924227
references.citation: J Leukoc Biol. 2012 Sep;92(3):461-7
references.pmid: 22750546
references.citation: J Biol Chem. 2002 May 17;277(20):17901-5
references.pmid: 11834740
references.citation: Innate Immun. 2013 Jun;19(3):278-89
references.pmid: 23060458
references.citation: J Immunol. 2001 Dec 15;167(12):6786-93
references.pmid: 11739494
references.citation: J Leukoc Biol. 2010 Aug;88(2):383-92
references.pmid: 20483925
references.citation: FEBS Lett. 2003 Jun 5;544(1-3):38-44
references.pmid: 12782287
references.citation: Mol Cell Biol. 2002 Nov;22(21):7645-57
references.pmid: 12370311
references.citation: Cell Signal. 2011 Aug;23(8):1320-6
references.pmid: 21440060
references.citation: Mol Cell Endocrinol. 2002 Sep 30;195(1-2):27-38
references.pmid: 12354670
references.citation: Nature. 1991 Jan 10;349(6305):175-8
references.pmid: 1898772
references.citation: J Biol Chem. 1995 Oct 27;270(43):25549-56
references.pmid: 7592725
references.citation: J Biol Chem. 2006 Apr 14;281(15):9971-6
references.pmid: 16476742
references.citation: PLoS One. 2010 Aug 12;5(8):e12109
references.pmid: 20711340
references.citation: Nat Genet. 2007 Feb;39(2):189-98
references.pmid: 17237784
references.citation: Blood. 2006 Nov 15;108(10):3564-72
references.pmid: 16873675
references.citation: PLoS One. 2009 Sep 15;4(9):e7035
references.pmid: 19753117
references.citation: Mol Cell Biol. 2011 Jun;31(11):2227-40
references.pmid: 21444720
references.citation: Curr Biol. 2001 Oct 30;11(21):1645-55
references.pmid: 11696321
references.citation: J Cell Biol. 2003 Jan 6;160(1):17-23
references.pmid: 12515821
references.citation: Nat Immunol. 2005 Dec;6(12):1182-90
references.pmid: 16369557
references.citation: Science. 2003 Dec 5;302(5651):1704-9
references.pmid: 14657486
references.citation: Nagoya J Med Sci. 2009 Sep;71(3-4):127-36
references.pmid: 19994725
references.citation: J Cell Biochem. 2011 Aug;112(8):2089-96
references.pmid: 21465530
references.citation: Mol Cell Biol. 2011 Nov;31(22):4524-37
references.pmid: 21930784
references.citation: Mol Immunol. 2007 May;44(12):3211-21
references.pmid: 17346796
references.citation: J Leukoc Biol. 2008 Sep;84(3):760-8
references.pmid: 18550788
references.citation: Cancer Res. 2010 May 15;70(10):4233-42
references.pmid: 20442281
references.citation: Cell Signal. 2011 Aug;23(8):1291-8
references.pmid: 21419846
references.citation: J Biol Chem. 2011 May 6;286(18):16308-20
references.pmid: 21378159
references.citation: Genomics. 1991 Sep;11(1):168-73
references.pmid: 1662663
references.citation: Nat Immunol. 2005 Aug;6(8):827-35
references.pmid: 15995708
references.citation: Neoplasia. 2011 Dec;13(12):1101-12
references.pmid: 22247700
references.citation: J Biol Chem. 2007 Apr 13;282(15):11221-9
references.pmid: 17287208