The Src Kinase Lyn is Required for CCR5 Signaling in Response to MIP-1beta and R5 HIV-1 Gp120 in Human Macrophages

Overview

Journal Blood

Publisher Elsevier

Specialty Hematology

Date 2006 Apr 20

PMID 16621960

Citations 31

Authors

Brian Tomkowicz

Chuhee Lee

Vipa Ravyn

Ricky Cheung

Andrzej Ptasznik

Ronald G Collman

Affiliations

Soon will be listed here.

Abstract

CCR5 is a receptor for several beta chemokines and the entry coreceptor used by macrophage-tropic (R5) strains of HIV-1. In addition to supporting viral entry, CCR5 ligation by the HIV-1 envelope glycoprotein 120 (gp120) can activate intracellular signals in macrophages and trigger inflammatory mediator release. Using a combination of in vitro kinase assay, Western blotting for phospho-specific proteins, pharmacologic inhibition, CCR5 knockout (CCR5Delta32) cells, and kinase-specific blocking peptide, we show for the first time that signaling through CCR5 in primary human macrophages is linked to the Src kinase Lyn. Stimulation of human monocyte-derived macrophages with either HIV-1 gp120 or MIP-1beta results in the CCR5-mediated activation of Lyn and the concomitant Lyn-dependent activation of the mitogen-activated protein (MAP) kinase ERK-1/2. Furthermore, activation of the CCR5/Lyn/ERK-1/2 pathway is responsible for gp120-triggered production of TNF-alpha by macrophages, which is believed to contribute to HIV-1 pathogenesis. Thus, Lyn kinase may play an important role both in normal CCR5 function in macrophages and in AIDS pathogenesis in syndromes such as AIDS dementia where HIV-1 gp120 contributes to inappropriate macrophage activation, mediator production, and secondary injury.

Citing Articles

Co-receptor signaling in the pathogenesis of neuroHIV.

Nickoloff-Bybel E, Festa L, Meucci O, Gaskill P Retrovirology. 2021; 18(1):24.

PMID: 34429135 PMC: 8385912. DOI: 10.1186/s12977-021-00569-x.

Modeling of CCR5 Recognition by HIV-1 gp120: How the Viral Protein Exploits the Conformational Plasticity of the Coreceptor.

Jacquemard C, Koensgen F, Colin P, Lagane B, Kellenberger E Viruses. 2021; 13(7).

PMID: 34372601 PMC: 8310383. DOI: 10.3390/v13071395.

Mechanisms underlying of antiretroviral drugs in different cellular reservoirs with a focus on macrophages.

Aquaro S, Borrajo A, Pellegrino M, Svicher V Virulence. 2020; 11(1):400-413.

PMID: 32375558 PMC: 7219522. DOI: 10.1080/21505594.2020.1760443.

CCR5 is a required signaling receptor for macrophage expression of inflammatory genes in response to viral double-stranded RNA.

Shaheen Z, Christmann B, Stafford J, Moran J, Buller R, Corbett J Am J Physiol Regul Integr Comp Physiol. 2019; 316(5):R525-R534.

PMID: 30811246 PMC: 6589596. DOI: 10.1152/ajpregu.00019.2019.

Wu-Tou Decoction in Rheumatoid Arthritis: Integrating Network Pharmacology and Pharmacological Evaluation.

Guo Q, Zheng K, Fan D, Zhao Y, Li L, Bian Y Front Pharmacol. 2017; 8:230.

PMID: 28515692 PMC: 5414545. DOI: 10.3389/fphar.2017.00230.

References

Premack B, Schall T . Chemokine receptors: gateways to inflammation and infection. Nat Med. 1996; 2(11):1174-8. DOI: 10.1038/nm1196-1174. View

Cicala C, Arthos J, Selig S, Dennis Jr G, Hosack D, Ryk D . HIV envelope induces a cascade of cell signals in non-proliferating target cells that favor virus replication. Proc Natl Acad Sci U S A. 2002; 99(14):9380-5. PMC: 123149. DOI: 10.1073/pnas.142287999. View

Dikic I, Tokiwa G, Lev S, Courtneidge S, Schlessinger J . A role for Pyk2 and Src in linking G-protein-coupled receptors with MAP kinase activation. Nature. 1996; 383(6600):547-50. DOI: 10.1038/383547a0. View

Fantuzzi L, Purificato C, Donato K, Belardelli F, Gessani S . Human immunodeficiency virus type 1 gp120 induces abnormal maturation and functional alterations of dendritic cells: a novel mechanism for AIDS pathogenesis. J Virol. 2004; 78(18):9763-72. PMC: 515003. DOI: 10.1128/JVI.78.18.9763-9772.2004. View

Misse D, Esteve P, Renneboog B, Vidal M, Cerutti M, St Pierre Y . HIV-1 glycoprotein 120 induces the MMP-9 cytopathogenic factor production that is abolished by inhibition of the p38 mitogen-activated protein kinase signaling pathway. Blood. 2001; 98(3):541-7. DOI: 10.1182/blood.v98.3.541. View

Popik W, Hesselgesser J, Pitha P . Binding of human immunodeficiency virus type 1 to CD4 and CXCR4 receptors differentially regulates expression of inflammatory genes and activates the MEK/ERK signaling pathway. J Virol. 1998; 72(8):6406-13. PMC: 109793. DOI: 10.1128/JVI.72.8.6406-6413.1998. View

Fahey 3rd T, Tracey K, Cousens L, Jones W, SHIRES G, Cerami A . Macrophage inflammatory protein 1 modulates macrophage function. J Immunol. 1992; 148(9):2764-9. View

Wong M, Uddin S, Majchrzak B, Huynh T, Proudfoot A, Platanias L . Rantes activates Jak2 and Jak3 to regulate engagement of multiple signaling pathways in T cells. J Biol Chem. 2001; 276(14):11427-31. DOI: 10.1074/jbc.M010750200. View

Atchison R, Gosling J, Monteclaro F, Franci C, Digilio L, Charo I . Multiple extracellular elements of CCR5 and HIV-1 entry: dissociation from response to chemokines. Science. 1996; 274(5294):1924-6. DOI: 10.1126/science.274.5294.1924. View

10.

Xu Y, Harder K, Huntington N, Hibbs M, Tarlinton D . Lyn tyrosine kinase: accentuating the positive and the negative. Immunity. 2005; 22(1):9-18. DOI: 10.1016/j.immuni.2004.12.004. View

11.

Kaul M, Garden G, Lipton S . Pathways to neuronal injury and apoptosis in HIV-associated dementia. Nature. 2001; 410(6831):988-94. DOI: 10.1038/35073667. View

12.

Luttrell D, Luttrell L . Not so strange bedfellows: G-protein-coupled receptors and Src family kinases. Oncogene. 2004; 23(48):7969-78. DOI: 10.1038/sj.onc.1208162. View

13.

Ma Y, Huang X . Novel regulation and function of Src tyrosine kinase. Cell Mol Life Sci. 2002; 59(3):456-62. PMC: 11337436. DOI: 10.1007/s00018-002-8438-2. View

14.

Lee C, Tomkowicz B, Freedman B, Collman R . HIV-1 gp120-induced TNF-{alpha} production by primary human macrophages is mediated by phosphatidylinositol-3 (PI-3) kinase and mitogen-activated protein (MAP) kinase pathways. J Leukoc Biol. 2005; 78(4):1016-23. DOI: 10.1189/jlb.0105056. View

15.

Fantuzzi L, Canini I, Belardelli F, Gessani S . HIV-1 gp120 stimulates the production of beta-chemokines in human peripheral blood monocytes through a CD4-independent mechanism. J Immunol. 2001; 166(9):5381-7. DOI: 10.4049/jimmunol.166.9.5381. View

16.

Rottman J, Ganley K, Williams K, Wu L, Mackay C, Ringler D . Cellular localization of the chemokine receptor CCR5. Correlation to cellular targets of HIV-1 infection. Am J Pathol. 1997; 151(5):1341-51. PMC: 1858074. View

17.

Yi Y, Shaheen F, Collman R . Preferential use of CXCR4 by R5X4 human immunodeficiency virus type 1 isolates for infection of primary lymphocytes. J Virol. 2005; 79(3):1480-6. PMC: 544090. DOI: 10.1128/JVI.79.3.1480-1486.2005. View

18.

Arthos J, Rubbert A, Rabin R, Cicala C, Machado E, Wildt K . CCR5 signal transduction in macrophages by human immunodeficiency virus and simian immunodeficiency virus envelopes. J Virol. 2000; 74(14):6418-24. PMC: 112149. DOI: 10.1128/jvi.74.14.6418-6424.2000. View

19.

Gauld S, Cambier J . Src-family kinases in B-cell development and signaling. Oncogene. 2004; 23(48):8001-6. DOI: 10.1038/sj.onc.1208075. View

20.

Wan Y, Kurosaki T, Huang X . Tyrosine kinases in activation of the MAP kinase cascade by G-protein-coupled receptors. Nature. 1996; 380(6574):541-4. DOI: 10.1038/380541a0. View