Apoptotic and Antiapoptotic Effects of CXCR4: Is It a Matter of Intrinsic Efficacy? Implications for HIV Neuropathogenesis

Abstract

CXCR4, the specific receptor for the chemokine SDF-1α that also binds CXCR4-using HIV gp120s, affects survival of different cell types, including neurons. However, current data show that the outcome of CXCR4 activation on neuronal survival may vary depending on the ligand and/or the cellular conditions. In this study, we have systematically compared the effects of SDF-1α and gp120 IIIB (with or without CD4) on several intracellular pathways involved in cell survival, including MAP kinases and Akt-dependent pathways. Our data show that gp120 IIIB and SDF-1α are both potent activators of MAP kinases in neuronal and non-neuronal cells, though the kinetic of these responses is slightly different. Furthermore, unlike SDF-1α, and independently of CD4, gp120 IIIB is unable to stimulate Akt and some of its antiapoptotic targets (NF-κB and MDM2)-despite its ability to activate other signaling pathways in the same conditions. Finally, the viral protein is more efficient in recruiting some effectors (e.g., JNK) than others in comparison with SDF-1α (EC 50 = 0.1 vs. 0.6 nM). We conclude that the intrinsic efficacy of the two ligands is significantly different and is pathway dependent. These findings have important implications for our understanding of CXCR4-mediated responses in the CNS, as well as the role of this coreceptor in HIV neuropathogenesis.

Modulation of neuronal CXCR4 by the μ-opioid agonist DAMGO

“…In line with these studies, acute stimulation of neurons (in the absence of glia) with DAMGO, a selective μ-opioid peptide, or with CXCL12, the natural CXCR4 ligand, induced phosphorylation of both ERK1/2 and Akt ( Figures 1F and 2). As previously reported, time-course and dose-response experiments indicated that peak responses occurred around 5 min after treatment with DAMGO (1 to 10 μM; Figure 2) and 15 min with CXCL12 (20 nM; Khan et al, 2004, Meucci et al, 1998.…”

“…One such effect is the activation of the antiapoptotic kinase Akt that is required for the neuroprotective action of chemokines (Meucci et al, 2000;Khan et al, 2004). The ability of μ-opioid peptides to compromise stimulation of mitogen-activated protein (MAP) kinases by CXCL12, though, suggests that proteins regulating crucial steps of CXCR4 signaling, such as those involved in receptor desensitization and recycling, might be affected by opioids.…”

“…Of note, CXCL12 plays a crucial role in the proliferation and migration of neural progenitor cells (Klein et al, 2001;Stumm et al, 2003;Belmadani et al, 2005), whereas opiates-including morphine-are known to inhibit neurogenesis in vivo and in vitro (Eisch et al, 2000;Hauser et al, 2000). Furthermore, the activation of MOR by drugs of abuse may exacerbate neurotoxicity of viral proteins, such as the HIV-1 gp120 that acts as a partial CXCR4 agonist (Khan et al, 2004). Under the experimental conditions reported here, DAMGO increases gp120 neurotoxicity in vitro (Patel et al, unpublished data); morphine exerts similar effects in human fetal brain cultures (Hu et al, 2005).…”

“…The natural CXCR4 ligand is SDF-1 (recently renamed CXCL12), one of the best-characterized chemokines in the central nervous system (CNS) that regulates neural migration, differentiation, and survival . In vitro, CXCL12 promotes survival of different types of neurons (Meucci et al, 1998;Chalasani et al, 2003;Khan et al, 2004), but can also induce neurotoxicity (Kaul and Lipton, 1999)-likely depending on cleavage by proteases and/or other unknown factors . The crucial role of this chemokine/receptor pair in the central nervous system (CNS) in vivo was demonstrated by studies on animals lacking CXCL12 or CXCR4, showing serious deficits in hippocampus/ cerebellum development (Zou et al, 1998;Lu et al, 2002).…”

Differential involvement of p38 and JNK MAP kinases in HIV-1 Tat and gp120-induced apoptosis and neurite degeneration in striatal neurons

“…Recent studies suggest that the neurotoxicity caused by both viral proteins may be regulated by MAPKs. Gp120-induced increases in JNK phosphorylation, as well as intracellular Ca 2+ levels and ERK phosphorylation, in rat hippocampal neurons (Khan et al, 2004); however, the role of JNK in survival was not assessed. In another study, alterations in JNK through manipulation of its upstream kinase mixed-lineage kinase-3 (MLK3) prevented gp120-CXCR4 triggered death in cultured rat hippocampal neurons (Bodner et al, 2002).…”