Immune response - CCR5 signaling in macrophages and T lymphocytes

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].

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