Desensitization of Chemokine Receptor CCR5 in Dendritic Cells at the Early Stage of Differentiation by Activation of Formyl Peptide Receptors

Le, Yingying; Wetzel, Michele A.; Shen, Weiping; Gong, Wanghua; Rogers, Thomas J.; Henderson, Earl E.; Wang, Ji Ming

doi:10.1006/clim.2001.5021

Cited by 40 publications

(25 citation statements)

References 34 publications

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“…Reduction of CCR5 and CXCR4 membrane expression might notably be related to a heterologous desensitization of these receptors. This process has been described in another model (56) that provided evidence that activation of the formyl peptide receptors of DCs by the bacterial chemotactic peptide fMLF resulted in a dramatic decrease in CCR5 and CXCR4 membrane expression through a protein kinase C-dependent pathway. As expected, fMLF was also able to reduce HIV-1 multiplication in DCs.…”

Section: Discussionmentioning

confidence: 73%

Advanced Glycation End Products Inhibit Both Infection and TransmissionIn Transof HIV-1 from Monocyte-Derived Dendritic Cells to Autologous T Cells

Nasreddine

Borde

Gozlan

et al. 2011

The Journal of Immunology

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Highly active antiretroviral therapy is associated with carbohydrate metabolic alterations that may lead to diabetes. One consequence of hyperglycemia is the formation of advanced glycation end products (AGEs) that are involved in diabetes complications. We investigated the impact of AGEs on the infection of monocyte-derived dendritic cells (MDDCs) by HIV-1 and the ability of MDDCs to transmit the virus to T cells. We showed that AGEs could inhibit infection of MDDCs with primary R5-tropic HIV-1Ba-L by up to 85 ± 9.2% and with primary X4-tropic HIV-1VN44 by up to 60 ± 8.5%. This inhibitory effect of AGEs was not prevented by a neutralizing anti-receptor for advanced glycation end products (anti-RAGE) Ab, demonstrating a RAGE-independent mechanism. Moreover, AGEs inhibited by 70–80% the transmission in trans of the virus to CD4 T cells. Despite the inhibitory effect of AGEs on both MDDC infection and virus transmission in trans, no inhibition of virus attachment to cell membrane was observed, confirming that attachment and transmission of the virus involve independent mechanisms. The inhibitory effect of AGEs on infection was associated with a RAGE-independent downregulation of CD4 at the cell membrane and by a RAGE-dependent repression of the CXCR4 and CCR5 HIV-1 receptors. AGEs induce the secretion of proinflammatory cytokines IL-6, TNF-α, and IL-12, but not RANTES or MIP-1α, and did not lead to MDDC maturation as demonstrated by the lack of expression of the CD83 molecule. Taken together, our results suggest that AGEs can play an inhibiting role in HIV-1 infection in patients who accumulate circulating AGEs, including patients treated with protease inhibitors that developed diabetes.

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Section: Discussionmentioning

confidence: 73%

Advanced Glycation End Products Inhibit Both Infection and TransmissionIn Transof HIV-1 from Monocyte-Derived Dendritic Cells to Autologous T Cells

Nasreddine

Borde

Gozlan

et al. 2011

The Journal of Immunology

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“…Previous reports have suggested that PKC family members are involved in the cross-desensitization of CCR5 following activation of the high affinity formyl peptide receptor (FPR) in monocyte-derived immature dendritic cells (30). In these studies, W peptide, a potent agonist of FPR, induced phosphorylation of CCR5 in a PKC-dependent (staurosporine-inhibitable) manner (31).…”

Section: Discussionmentioning

confidence: 99%

Protein Kinase Cζ Mediates μ-Opioid Receptor-induced Cross-desensitization of Chemokine Receptor CCR5

Song

Rahim

Davey

et al. 2011

Journal of Biological Chemistry

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We have previously shown that the -opioid receptor (MOR) is capable of mediating cross-desensitization of several chemokine receptors including CCR5, but the biochemical mechanism of this process has not been fully elucidated. We have carried out a series of functional and biochemical studies and found that the mechanism of MOR-induced cross-desensitization of CCR5 involves the activation of PKC. Inhibition of PKC by its pseudosubstrate inhibitor, or its siRNA, or dominant negative mutants suppresses the cross-desensitization of CCR5. Our results further indicate that the activation of PKC is mediated through a pathway involving phosphoinositol-dependent kinase-1 (PDK1). In addition, activation of MOR elevates the phosphorylation level and kinase activity of PKC. The phosphorylation of PKC can be suppressed by a dominant negative mutant of PDK1. We observed that following MOR activation, the interaction between PKC and PDK1 is immediately increased based on the analysis of fluorescent resonance energy transfer in cells with the expression of PKC-YFP and PDK1-CFP. In addition, cells expressing PKC kinase motif mutants (Lys-281, Thr-410, Thr-560) fail to exhibit full MOR-induced desensitization of CCR5 activity. Taken together, we propose that upon DAMGO treatment, MOR activates PKC through a PDK1-dependent signaling pathway to induce CCR5 phosphorylation and desensitization. Because CCR5 is a highly proinflammatory receptor, and a critical coreceptor for HIV-1, these results may provide a novel approach for the development of specific therapeutic agents to treat patients with certain inflammatory diseases or AIDS.There are three structurally related opioid receptors, designated , , and ␦, and it is well established that activation of one or more of these receptors modulates the function of immune cells (1-5). For example, morphine suppresses chemotactic responses and chemokine expression in human and murine cells (6 -9). Similarly, Tyr-D-Ala-Gly-N-Me-PheGly-ol (DAMGO), 3 a highly selective ligand for the -opioid receptor (MOR), suppresses chemokine receptor function in vitro (7, 10 -12). Recent work from our laboratories, and others, suggest that heterologous desensitization is the primary mechanism for the inhibitory activity of opioids for chemokine receptor function. Studies reported by Grimm et al. (13,14) show that activation of and ␦ opioid receptors (MOR and DOR) induced cross-desensitization of the chemokine receptors CCR1, CCR2, CXCR1, and CXCR2, but not FPR (the high affinity receptor for fMLF), resulting in a failure of monocytes and neutrophils to manifest chemotactic responses to chemokines such as CCL2, CCL3, and CCL5 in a dose-dependent manner. Further studies have shown that activation of MOR in HEK293 cells stably expressing both MOR and CCR1, failed to migrate in response to CCL3, a CCR1 ligand (15). More recently, using both primary cells as well as stably transfected cell lines, we have shown that MOR activation induces heterologous desensitization of CCR5 but not CXCR4 (16), a finding which i...

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“…However, the function of FPR is more complex, as signaling events mediated by these receptors via their interaction with a wide variety of ligands are associated with different diseases, including amyloidosis, Alzheimer's, and prion diseases. Furthermore, activation of FPR modulates the expression and function of certain G␣ i -protein-coupled receptors, such as the HIV-1 coreceptors CXCR4 and CCR5 and consequently reduces HIV-1 infection, in iDC, through heterologous receptor desensitization (24). The latter process correlates with the degree of phosphorylation of serine residues present in the relevant receptor components.…”

Section: Discussionmentioning

confidence: 99%

“…Activation of FPR has been shown to modulate the expression and function of certain G␣ i -protein-coupled receptors such as the HIV-1 coreceptors CXCR4 and CCR5 by heterologous receptor desensitization, which is correlated with enhanced phosphorylation of serine residues present in the relevant receptor components (24). The functional effects of A-SAA were therefore analyzed on in vitro-generated myeloid iDC that, like their monocyte precursor cells, express FPR at their surface (results not shown) and that are susceptible to infection with HIV-1 via CCR5.…”

Section: A-saa Inhibits In Vitro Hiv-1 Infection In Idcmentioning

confidence: 99%

IL-22 Participates in an Innate Anti-HIV-1 Host-Resistance Network through Acute-Phase Protein Induction

Missé¹,

Yssel

Trabattoni

et al. 2007

The Journal of Immunology

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Certain individuals are resistant to HIV-1 infection, despite repeated exposure to the virus. Although protection against HIV-1 infection in a small proportion of Caucasian individuals is associated with mutant alleles of the CCR5 HIV-1 coreceptor, the molecular mechanism underlying resistance in repeatedly HIV-1-exposed, uninfected individuals (EU) is unclear. In this study, we performed complementary transcriptome and proteome analyses on peripheral blood T cells, and plasma or serum from EU, their HIV-1-infected sexual partners, and healthy controls, all expressing wild-type CCR5. We report that activated T cells from EU overproduce several proteins involved in the innate immunity response, principally those including high levels of peroxiredoxin II, a NK-enhancing factor possessing strong anti-HIV activity, and IL-22, a cytokine involved in the production of acute-phase proteins such as the acute-phase serum amyloid A (A-SAA). Cell supernatants and serum levels of these proteins were up-regulated in EU. Moreover, a specific biomarker for EU detected in plasma was identified as an 8.6-kDa A-SAA cleavage product. Incubation of in vitro-generated myeloid immature dendritic cells with A-SAA resulted in CCR5 phosphorylation, down-regulation of CCR5 expression, and strongly decreased susceptibility of these cells to in vitro infection with a primary HIV-1 isolate. Taken together, these results suggest new correlates of EU protection and identify a cascade involving IL-22 and the acute phase protein pathway that is associated with innate host resistance to HIV infection.

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Desensitization of Chemokine Receptor CCR5 in Dendritic Cells at the Early Stage of Differentiation by Activation of Formyl Peptide Receptors

Cited by 40 publications

References 34 publications

Advanced Glycation End Products Inhibit Both Infection and TransmissionIn Transof HIV-1 from Monocyte-Derived Dendritic Cells to Autologous T Cells

Advanced Glycation End Products Inhibit Both Infection and TransmissionIn Transof HIV-1 from Monocyte-Derived Dendritic Cells to Autologous T Cells

Protein Kinase Cζ Mediates μ-Opioid Receptor-induced Cross-desensitization of Chemokine Receptor CCR5

IL-22 Participates in an Innate Anti-HIV-1 Host-Resistance Network through Acute-Phase Protein Induction

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