Bi-directional heterologous desensitization between the major HIV-1 co-receptor CXCR4 and the κ-opioid receptor

Finley, Matthew J.; Chen, Xiaohong; Bardi, Giuseppe; Davey, Penny; Geller, Ellen B.; Zhang, Lily; Adler, Martin W.; Rogers, Thomas J.

doi:10.1016/j.jneuroim.2008.04.021

Cited by 61 publications

(57 citation statements)

References 65 publications

(54 reference statements)

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“…2E-G). Other studies also reported cross-desensitization of the CXCL12/CXCR4-mediated chemotaxis of T lymphocytes by the chemokine receptor CCR5 (11), the k-opioid receptor (25), and the TCR complex (26). Consistent with our data, the results of these investigations showed a partial ] i was measured in FURA 2-AM-loaded Th1 cells by spectrophotometry.…”

Section: Discussionsupporting

confidence: 92%

“…The observed reduction in CXCR4 surface expression upon CXCL9 stimulation may also be the result of a modulation in transporting CXCR4 from intercellular vesicles to plasma membrane and was not necessarily a result of receptor desensitization and internalization. Nevertheless, the observed magnitude of CXCR4 downregulation is similar to comparable investigations reporting CXCR4 cross-desensitization by stimulation with ligands for CCR5, the k-opioid, or the TCR (25,26,34). To test whether CXCL12-dependent activation of prominent signaling molecules is modulated by CXCL9, we measured phosphorylation of Akt (Ser473), which was shown to be affected by a heterologous desensitization of CXCR4 upon CCR5 receptor stimulation (10,11).…”

Section: Discussionsupporting

confidence: 75%

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CXCL9 Causes Heterologous Desensitization of CXCL12-Mediated Memory T Lymphocyte Activation

Giegold

Ogrissek

Richter

et al. 2013

The Journal of Immunology

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The chemokine receptors CXCR3 and CXCR4 are primarily involved in memory Th1 cell–driven autoimmune diseases. Although recent studies in chronic inflammatory disease showed therapeutic success using combined blockade, details of CXCR3 and CXCR4 synergism are not understood. In this investigation, we intended to unravel the interaction of these chemokine receptors in static and dynamic cell-migration assays at both the cellular and molecular levels. Effects of combined stimulation by murine CXCL9 and CXCL12, ligands of CXCR3 and CXCR4, respectively, were analyzed using a murine central memory Th1 cell clone. Costimulation with CXCL9 desensitized the chemotaxis of Th1 cells toward CXCL12 by up to 54%. This effect was found in murine EL-4 cells, as well as in primary human T cells. Furthermore, under dynamic flow conditions CXCL12-induced crawling and endothelial transmigration of Th1 cells was desensitized by CXCL9. Subsequent experiments uncovered several molecular mechanisms underlying the heterologous cross-regulation of CXCR4 signaling by the CXCR3 ligand. CXCR4 surface expression was reduced, whereas CXCL12-induced Akt phosphorylation and intracellular Ca2+ signals were modulated. Moreover, blockade of Rac by NSC23766 revealed differential effects on CXCL12 and CXCL9 chemotaxis and abolished the desensitizing effect of CXCL9. The desensitization of CXCR4 via CXCR3 in memory Th1 cells suggests that their in vivo homeostasis, widely regulated by CXCL12, seemed to be significantly altered by CXCR3 ligands. Our data provide a more detailed understanding for the continuing extravasation and recruitment of Th1 lymphocytes into sites of persistent inflammation.

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Section: Discussionsupporting

confidence: 92%

Section: Discussionsupporting

confidence: 75%

CXCL9 Causes Heterologous Desensitization of CXCL12-Mediated Memory T Lymphocyte Activation

Giegold

Ogrissek

Richter

et al. 2013

The Journal of Immunology

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“…Several studies have shown that opiates, including morphine (the major metabolite of heroin, which easily reaches the brain), alter CXCR4 function in immune and neural cells (24)(25)(26). Recently, our group has shown that morphine (and selective μ-opioid receptor [MOR] agonists, such as DAMGO) specifically impairs CXCL12/CXCR4 signaling in neurons, both in vitro and in vivo, by increasing protein levels of ferritin heavy chain (FHC), a recently described CXCR4 regulator (25,(27)(28)(29).…”

Section: Introductionmentioning

confidence: 99%

Neuronal ferritin heavy chain and drug abuse affect HIV-associated cognitive dysfunction

Pitcher¹,

Abt²,

Myers³

et al. 2014

J. Clin. Invest.

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Interaction of the chemokine CXCL12 with its receptor CXCR4 promotes neuronal function and survival during embryonic development and throughout adulthood. Previous studies indicated that μ-opioid agonists specifically elevate neuronal levels of the protein ferritin heavy chain (FHC), which negatively regulates CXCR4 signaling and affects the neuroprotective function of the CXCL12/CXCR4 axis. Here, we determined that CXCL12/CXCR4 activity increased dendritic spine density, and also examined FHC expression and CXCR4 status in opiate abusers and patients with HIV-associated neurocognitive disorders (HAND), which is typically exacerbated by illicit drug use. Drug abusers and HIV patients with HAND had increased levels of FHC, which correlated with reduced CXCR4 activation, within cortical neurons. We confirmed these findings in a nonhuman primate model of SIV infection with morphine administration. Transfection of a CXCR4-expressing human cell line with an iron-deficient FHC mutant confirmed that increased FHC expression deregulated CXCR4 signaling and that this function of FHC was independent of iron binding. Furthermore, examination of morphine-treated rodents and isolated neurons expressing FHC shRNA revealed that FHC contributed to morphine-induced dendritic spine loss. Together, these data implicate FHC-dependent deregulation of CXCL12/CXCR4 as a contributing factor to cognitive dysfunction in neuroAIDS.

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“…Both CB2 and CXCR4 are G i/o -coupled receptors. Potential mechanisms by which activation of CB2 receptors might inhibit the signaling of CXCR4 are suggested by the interactions of opiates with CXCR4 and include CXCR4 internalization, the formation of inactive heterodimers, and expression of proteins that inhibit chemokine receptor function (Finley et al, 2008;Pello et al, 2008;Sengupta et al, 2009).…”

mentioning

confidence: 99%

Activation of Cannabinoid Type 2 Receptors Inhibits HIV-1 Envelope Glycoprotein gp120-Induced Synapse Loss

Kim

Shin

Thayer³

2011

Mol Pharmacol

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HIV-1 infection of the central nervous system is associated with dendritic and synaptic damage that correlates with cognitive decline in patients with HIV-1-associated dementia (HAD). HAD is due in part to the release of viral proteins from infected cells. Because cannabinoids modulate neurotoxic and inflammatory processes, we investigated their effects on changes in synaptic connections induced by the HIV-1 envelope glycoprotein gp120. Morphology and synapses between cultured hippocampal neurons were visualized by confocal imaging of neurons expressing DsRed2 and postsynaptic density protein 95 fused to green fluorescent protein (PSD95-GFP). Twenty-four-hour treatment with gp120 IIIB decreased the number of PSD95-GFP puncta by 37 Ϯ 4%. The decrease was concentration-dependent (EC 50 ϭ 153 Ϯ 50 pM). Synapse loss preceded cell death as defined by retention of DsRed2 fluorescence gp120 activated CXCR4 on microglia to evoke interleukin-1␤ (IL-1␤) release. Pharmacological studies determined that sequential activation of CXCR4, the IL-1␤ receptor, and the N-methyl-D-aspartate receptor was required. Expression of alternative reading frame polypeptide, which inhibits the ubiquitin ligase murine double minute 2, protected synapses, implicating the ubiquitin-proteasome pathway. Cannabimimetic drugs are of particular relevance to HAD because of their clinical and illicit use in patients with AIDS. The cannabinoid receptor full agonist-benzoxazinyl]-(1-naphthalenyl) methanone mesylate salt] (Win55,212-2) inhibited gp120-induced IL-1␤ production and synapse in a manner reversed by a cannabinoid type 2 receptor antagonist. In contrast, Win55,212-2 did not inhibit synapse loss elicited by exposure to the HIV-1 protein Tat. These results indicate that cannabinoids prevent the impairment of network function produced by gp120 and, thus, might have therapeutic potential in HAD.

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Bi-directional heterologous desensitization between the major HIV-1 co-receptor CXCR4 and the κ-opioid receptor

Cited by 61 publications

References 65 publications

CXCL9 Causes Heterologous Desensitization of CXCL12-Mediated Memory T Lymphocyte Activation

CXCL9 Causes Heterologous Desensitization of CXCL12-Mediated Memory T Lymphocyte Activation

Neuronal ferritin heavy chain and drug abuse affect HIV-associated cognitive dysfunction

Activation of Cannabinoid Type 2 Receptors Inhibits HIV-1 Envelope Glycoprotein gp120-Induced Synapse Loss

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