Immune response - CCR5 signaling in macrophages and T lymphocytes

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CCR5 signaling in macrophages and T lymphocytes

Chemokine (C-C motif) receptor 5 (CCR5) is a functional receptor for various inflammatory CC-chemokines, including Chemokine (C-C motif) ligands 3, 4 and 5 (MIP-1-alpha, MIP-1-beta and CCL5). CCR5 is expressed on memory T cells, macrophages, dendritic cells, and migroglia and has been shown to modulate chemotaxis, proliferation, and immune functions [1], [2], [3], [4].

CCR5 belongs to family of G-protein coupled receptors and mediates its action via activation of G-protein alpha-i family and G-protein alpha-q [5]. CCR5 stimulation of G-protein alpha-i family leads to inhibition of Adenylate cyclase 1 (Adenylate cyclase type I) activity and decreasing cellular levels of Cyclic AMP cytosol production [6]. Additionally, CCR5 stimulates -G-protein alpha-i family -coupled G-protein beta/gamma activity leading to Phosphoinositide-3-kinase, regulatory subunit 5 (PI3K reg class IB (p101)) and subsequently to Phosphoinositide-3-kinase, catalytic, gamma polypeptide (PI3K cat class IB (p110-gamma)) activation [7]. PI3K cat class IB (p110-gamma) enhances PtdIns(3,4,5)P3 production leading to activation of Ras-related C3 botulinum toxin substrate 1 (Rac1) (most likely via T-cell lymphoma invasion and metastasis 1 (Tiam1) stimulation). Rac1 activates p21 protein (Cdc42/Rac)-activated kinase 2 (PAK2) and promotes lamellipodia formation that stimulates macrophage migration during chemotaxis [7], [8], [9]. PI3K cat class IB (p110-gamma) also activates v-akt murine thymoma viral oncogene homolog (AKT(PKB)) leading to macrophage survival [10]. CCR5 via G-protein alpha-i family induces Mitogen-activated protein kinase kinases 1, 2 (MEK1(MAP2K1), MEK2(MAP2K2))/ Mitogen activated protein kinases 1/3 (ERK1/2) pathway activation leading to enhanced survival and cell proliferation [8], [10], [11].

CCR5 stimulation of G-protein alpha-q and G-protein beta/gamma leads to Phospholipase C, beta 1 (PLC-beta1) activation and enhanced production of 1,2-Diacyglycerol and IP3 cytosol. IP3 cytosol promotes Ca('2+) release from endoplasmic reticulum. Ca('2+) depletion in endoplasmic reticulum leads to rapid translocation of calcium adapter Stromal interaction molecule 1 (STIM1) to plasma membrane and activation of ORAI calcium release-activated calcium modulator 1 (CRACM1) [12], [13], [14]. CRACM1 induces Ca('2+) influx into the cell [15]. Elevated Ca('2+) cytosol and 1,2-Diacyglycerol levels activate Protein kinase C, alpha (PKC-alpha), which phosphorylates PTK2B protein tyrosine kinase 2 beta (Pyk2(FAK2)) [16]. Pyk2(FAK2) activates Paxillin stimulating chemotaxis [17], [18]. Pyk2(FAK2) also activates Mitogen-activated protein kinase 8 -10 (JNK(MAPK8-10)) and Mitogen-activated protein kinase 14 (p38 MAPK) most likely via Mitogen-activated protein kinase kinase kinase 4 (MEKK4(MAP3K4))/ Mitogen-activated protein kinase kinases 3, 4 (MEK3(MAP2K3), MEK4(MAP2K4)) [5], [11], [12]. JNK(MAPK8-10) and p38 MAPK phosphorylates Jun oncogene (c-Jun) and Activating transcription factor 2 (ATF-2) respectively, stimulating cytokine production and T cell proliferation [3], [5], [12], [18]. p38 MAPK also phosphorylates Mitogen-activated protein kinase-activated protein kinase 2 (MAPKAPK2) [19].

CCR5 via increase in Ca('2+) cytosol activates Calmodulin 2 (Calmodulin) and protein Phosphatase 3 (formerly 2B), catalytic subunits (Calcineurin A (catalytic)) leading to Nuclear factor of activated T-cells, cytoplasmic, calcineurin-dependent 1 (NF-AT2(NFATC1)) nuclear translocation and activation of Interleukin 2 (IL-2) transcription. CCR5 -induced IL-2 signaling stimulates T cell proliferation [20].

Activated CCR5 could act also via G-protein-independent manner. Ligand binding to CCR5 stimulates its association with Janus kinases 1, 2 and 3 (JAK1, JAK2, JAK3) leading to Signal transducers and activators of transcription 1 and 3 (STAT1 and STAT3) activation [19], [21], [22]. STAT1 and STAT3 enhance transcription of v-fos FBJ murine osteosarcoma viral oncogene homolog (c-Fos) promoting cytokine production and T cell proliferation during immune response [8]. In addition, JAK3 in response to CCR5 activation phosphorylates Lymphocyte-specific protein tyrosine kinase (Lck) [19].

References:

  1. Gosling J, Monteclaro FS, Atchison RE, Arai H, Tsou CL, Goldsmith MA, Charo IF
    Molecular uncoupling of C-C chemokine receptor 5-induced chemotaxis and signal transduction from HIV-1 coreceptor activity. Proceedings of the National Academy of Sciences of the United States of America 1997 May 13;94(10):5061-6
  2. Zhou Y, Kurihara T, Ryseck RP, Yang Y, Ryan C, Loy J, Warr G, Bravo R
    Impaired macrophage function and enhanced T cell-dependent immune response in mice lacking CCR5, the mouse homologue of the major HIV-1 coreceptor. Journal of immunology (Baltimore, Md. : 1950) 1998 Apr 15;160(8):4018-25
  3. Aliberti J, Reis e Sousa C, Schito M, Hieny S, Wells T, Huffnagle GB, Sher A
    CCR5 provides a signal for microbial induced production of IL-12 by CD8 alpha+ dendritic cells. Nature immunology 2000 Jul;1(1):83-7
  4. Blanpain C, Doranz BJ, Bondue A, Govaerts C, De Leener A, Vassart G, Doms RW, Proudfoot A, Parmentier M
    The core domain of chemokines binds CCR5 extracellular domains while their amino terminus interacts with the transmembrane helix bundle. The Journal of biological chemistry 2003 Feb 14;278(7):5179-87
  5. Oppermann M
    Chemokine receptor CCR5: insights into structure, function, and regulation. Cellular signalling 2004 Nov;16(11):1201-10
  6. Zhao J, Ma L, Wu YL, Wang P, Hu W, Pei G
    Chemokine receptor CCR5 functionally couples to inhibitory G proteins and undergoes desensitization. Journal of cellular biochemistry 1998 Oct 1;71(1):36-45
  7. Weiss-Haljiti C, Pasquali C, Ji H, Gillieron C, Chabert C, Curchod ML, Hirsch E, Ridley AJ, Hooft van Huijsduijnen R, Camps M, Rommel C
    Involvement of phosphoinositide 3-kinase gamma, Rac, and PAK signaling in chemokine-induced macrophage migration. The Journal of biological chemistry 2004 Oct 8;279(41):43273-84
  8. Wong MM, Fish EN
    Chemokines: attractive mediators of the immune response. Seminars in immunology 2003 Feb;15(1):5-14
  9. Di Marzio P, Dai WW, Franchin G, Chan AY, Symons M, Sherry B
    Role of Rho family GTPases in CCR1- and CCR5-induced actin reorganization in macrophages. Biochemical and biophysical research communications 2005 Jun 17;331(4):909-16
  10. Tyner JW, Uchida O, Kajiwara N, Kim EY, Patel AC, O'Sullivan MP, Walter MJ, Schwendener RA, Cook DN, Danoff TM, Holtzman MJ
    CCL5-CCR5 interaction provides antiapoptotic signals for macrophage survival during viral infection. Nature medicine 2005 Nov;11(11):1180-7
  11. Popik W, Pitha PM
    Early activation of mitogen-activated protein kinase kinase, extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, and c-Jun N-terminal kinase in response to binding of simian immunodeficiency virus to Jurkat T cells expressing CCR5 receptor. Virology 1998 Dec 5;252(1):210-7
  12. Del Corno M, Liu QH, Schols D, de Clercq E, Gessani S, Freedman BD, Collman RG
    HIV-1 gp120 and chemokine activation of Pyk2 and mitogen-activated protein kinases in primary macrophages mediated by calcium-dependent, pertussis toxin-insensitive chemokine receptor signaling. Blood 2001 Nov 15;98(10):2909-16
  13. Liou J, Kim ML, Heo WD, Jones JT, Myers JW, Ferrell JE Jr, Meyer T
    STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx. Current biology : CB 2005 Jul 12;15(13):1235-41
  14. Zhang SL, Yu Y, Roos J, Kozak JA, Deerinck TJ, Ellisman MH, Stauderman KA, Cahalan MD
    STIM1 is a Ca2+ sensor that activates CRAC channels and migrates from the Ca2+ store to the plasma membrane. Nature 2005 Oct 6;437(7060):902-5
  15. Liu QH, Williams DA, McManus C, Baribaud F, Doms RW, Schols D, De Clercq E, Kotlikoff MI, Collman RG, Freedman BD
    HIV-1 gp120 and chemokines activate ion channels in primary macrophages through CCR5 and CXCR4 stimulation. Proceedings of the National Academy of Sciences of the United States of America 2000 Apr 25;97(9):4832-7
  16. Harmon B, Ratner L
    Induction of the Galpha(q) signaling cascade by the human immunodeficiency virus envelope is required for virus entry. Journal of virology 2008 Sep;82(18):9191-205
  17. Weissman D, Rabin RL, Arthos J, Rubbert A, Dybul M, Swofford R, Venkatesan S, Farber JM, Fauci AS
    Macrophage-tropic HIV and SIV envelope proteins induce a signal through the CCR5 chemokine receptor. Nature 1997 Oct 30;389(6654):981-5
  18. Ganju RK, Dutt P, Wu L, Newman W, Avraham H, Avraham S, Groopman JE
    Beta-chemokine receptor CCR5 signals via the novel tyrosine kinase RAFTK. Blood 1998 Feb 1;91(3):791-7
  19. Wong M, Uddin S, Majchrzak B, Huynh T, Proudfoot AE, Platanias LC, Fish EN
    Rantes activates Jak2 and Jak3 to regulate engagement of multiple signaling pathways in T cells. The Journal of biological chemistry 2001 Apr 6;276(14):11427-31
  20. Camargo JF, Quinones MP, Mummidi S, Srinivas S, Gaitan AA, Begum K, Jimenez F, VanCompernolle S, Unutmaz D, Ahuja SS, Ahuja SK
    CCR5 expression levels influence NFAT translocation, IL-2 production, and subsequent signaling events during T lymphocyte activation. Journal of immunology (Baltimore, Md. : 1950) 2009 Jan 1;182(1):171-82
  21. Wong M, Fish EN
    RANTES and MIP-1alpha activate stats in T cells. The Journal of biological chemistry 1998 Jan 2;273(1):309-14
  22. Mueller A, Strange PG
    CCL3, acting via the chemokine receptor CCR5, leads to independent activation of Janus kinase 2 (JAK2) and Gi proteins. FEBS letters 2004 Jul 16;570(1-3):126-32

  1. Gosling J, Monteclaro FS, Atchison RE, Arai H, Tsou CL, Goldsmith MA, Charo IF
    Molecular uncoupling of C-C chemokine receptor 5-induced chemotaxis and signal transduction from HIV-1 coreceptor activity. Proceedings of the National Academy of Sciences of the United States of America 1997 May 13;94(10):5061-6
  2. Zhou Y, Kurihara T, Ryseck RP, Yang Y, Ryan C, Loy J, Warr G, Bravo R
    Impaired macrophage function and enhanced T cell-dependent immune response in mice lacking CCR5, the mouse homologue of the major HIV-1 coreceptor. Journal of immunology (Baltimore, Md. : 1950) 1998 Apr 15;160(8):4018-25
  3. Aliberti J, Reis e Sousa C, Schito M, Hieny S, Wells T, Huffnagle GB, Sher A
    CCR5 provides a signal for microbial induced production of IL-12 by CD8 alpha+ dendritic cells. Nature immunology 2000 Jul;1(1):83-7
  4. Blanpain C, Doranz BJ, Bondue A, Govaerts C, De Leener A, Vassart G, Doms RW, Proudfoot A, Parmentier M
    The core domain of chemokines binds CCR5 extracellular domains while their amino terminus interacts with the transmembrane helix bundle. The Journal of biological chemistry 2003 Feb 14;278(7):5179-87
  5. Oppermann M
    Chemokine receptor CCR5: insights into structure, function, and regulation. Cellular signalling 2004 Nov;16(11):1201-10
  6. Zhao J, Ma L, Wu YL, Wang P, Hu W, Pei G
    Chemokine receptor CCR5 functionally couples to inhibitory G proteins and undergoes desensitization. Journal of cellular biochemistry 1998 Oct 1;71(1):36-45
  7. Weiss-Haljiti C, Pasquali C, Ji H, Gillieron C, Chabert C, Curchod ML, Hirsch E, Ridley AJ, Hooft van Huijsduijnen R, Camps M, Rommel C
    Involvement of phosphoinositide 3-kinase gamma, Rac, and PAK signaling in chemokine-induced macrophage migration. The Journal of biological chemistry 2004 Oct 8;279(41):43273-84
  8. Wong MM, Fish EN
    Chemokines: attractive mediators of the immune response. Seminars in immunology 2003 Feb;15(1):5-14
  9. Di Marzio P, Dai WW, Franchin G, Chan AY, Symons M, Sherry B
    Role of Rho family GTPases in CCR1- and CCR5-induced actin reorganization in macrophages. Biochemical and biophysical research communications 2005 Jun 17;331(4):909-16
  10. Tyner JW, Uchida O, Kajiwara N, Kim EY, Patel AC, O'Sullivan MP, Walter MJ, Schwendener RA, Cook DN, Danoff TM, Holtzman MJ
    CCL5-CCR5 interaction provides antiapoptotic signals for macrophage survival during viral infection. Nature medicine 2005 Nov;11(11):1180-7
  11. Popik W, Pitha PM
    Early activation of mitogen-activated protein kinase kinase, extracellular signal-regulated kinase, p38 mitogen-activated protein kinase, and c-Jun N-terminal kinase in response to binding of simian immunodeficiency virus to Jurkat T cells expressing CCR5 receptor. Virology 1998 Dec 5;252(1):210-7
  12. Del Corno M, Liu QH, Schols D, de Clercq E, Gessani S, Freedman BD, Collman RG
    HIV-1 gp120 and chemokine activation of Pyk2 and mitogen-activated protein kinases in primary macrophages mediated by calcium-dependent, pertussis toxin-insensitive chemokine receptor signaling. Blood 2001 Nov 15;98(10):2909-16
  13. Liou J, Kim ML, Heo WD, Jones JT, Myers JW, Ferrell JE Jr, Meyer T
    STIM is a Ca2+ sensor essential for Ca2+-store-depletion-triggered Ca2+ influx. Current biology : CB 2005 Jul 12;15(13):1235-41
  14. Zhang SL, Yu Y, Roos J, Kozak JA, Deerinck TJ, Ellisman MH, Stauderman KA, Cahalan MD
    STIM1 is a Ca2+ sensor that activates CRAC channels and migrates from the Ca2+ store to the plasma membrane. Nature 2005 Oct 6;437(7060):902-5
  15. Liu QH, Williams DA, McManus C, Baribaud F, Doms RW, Schols D, De Clercq E, Kotlikoff MI, Collman RG, Freedman BD
    HIV-1 gp120 and chemokines activate ion channels in primary macrophages through CCR5 and CXCR4 stimulation. Proceedings of the National Academy of Sciences of the United States of America 2000 Apr 25;97(9):4832-7
  16. Harmon B, Ratner L
    Induction of the Galpha(q) signaling cascade by the human immunodeficiency virus envelope is required for virus entry. Journal of virology 2008 Sep;82(18):9191-205
  17. Weissman D, Rabin RL, Arthos J, Rubbert A, Dybul M, Swofford R, Venkatesan S, Farber JM, Fauci AS
    Macrophage-tropic HIV and SIV envelope proteins induce a signal through the CCR5 chemokine receptor. Nature 1997 Oct 30;389(6654):981-5
  18. Ganju RK, Dutt P, Wu L, Newman W, Avraham H, Avraham S, Groopman JE
    Beta-chemokine receptor CCR5 signals via the novel tyrosine kinase RAFTK. Blood 1998 Feb 1;91(3):791-7
  19. Wong M, Uddin S, Majchrzak B, Huynh T, Proudfoot AE, Platanias LC, Fish EN
    Rantes activates Jak2 and Jak3 to regulate engagement of multiple signaling pathways in T cells. The Journal of biological chemistry 2001 Apr 6;276(14):11427-31
  20. Camargo JF, Quinones MP, Mummidi S, Srinivas S, Gaitan AA, Begum K, Jimenez F, VanCompernolle S, Unutmaz D, Ahuja SS, Ahuja SK
    CCR5 expression levels influence NFAT translocation, IL-2 production, and subsequent signaling events during T lymphocyte activation. Journal of immunology (Baltimore, Md. : 1950) 2009 Jan 1;182(1):171-82
  21. Wong M, Fish EN
    RANTES and MIP-1alpha activate stats in T cells. The Journal of biological chemistry 1998 Jan 2;273(1):309-14
  22. Mueller A, Strange PG
    CCL3, acting via the chemokine receptor CCR5, leads to independent activation of Janus kinase 2 (JAK2) and Gi proteins. FEBS letters 2004 Jul 16;570(1-3):126-32

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