Neuronal Apoptotic Signaling Pathways Probed and Intervened by Synthetically and Modularly Modified (SMM) Chemokines

Abstract

As the main coreceptors for human immunodeficiency virus type 1 (HIV-1) entry, CXCR4 and CCR5 play important roles in HIV-associated dementia (HAD). HIV-1 glycoprotein gp120 contributes to HAD by causing neuronal damage and death, either directly by triggering apoptotic pathways or indirectly by stimulating glial cells to release neurotoxins. Here, to understand the mechanism of CXCR4 or CCR5 signaling in neuronal apoptosis associated with HAD, we have applied synthetically and modularly modified (SMM)-chemokine analogs derived from natural stromal cell-derived factor-1␣ or viral macrophage inflammatory protein-II as chemical probes of the mechanism(s) whereby these SMM-chemokines prevent or promote neuronal apoptosis. We show that inherently neurotoxic natural ligands of CXCR4, such as stromal cell-derived factor-1␣ or viral macrophage inflammatory protein-II, can be modified to protect neurons from apoptosis induced by CXCR4-preferring gp120 IIIB , and that the inhibition of CCR5 by antagonist SMM-chemokines, unlike neuroprotective CCR5 natural ligands, leads to neurotoxicity by activating a p38 mitogen-activated protein kinase (MAPK)-dependent pathway. Furthermore, we discover distinct signaling pathways activated by different chemokine ligands that are either natural agonists or synthetic antagonists, thus demonstrating a chemical biology strategy of using chemically engineered inhibitors of chemokine receptors to study the signaling mechanism of neuronal apoptosis and survival.

CCR5 Knockout Prevents Neuronal Injury and Behavioral Impairment Induced in a Transgenic Mouse Model by a CXCR4-Using HIV-1 Glycoprotein 120

“…In any case, ample published evidence supports a crucial role for macrophages and microglia in HIV-1 and gp120-induced neurotoxicity (33,48,56–60). The implication of microglia in gp120-induced neuronal injury in vivo is also in line with our finding of increased numbers of this cell type in cerebral cortex and hippocampus of gp120 mice.…”

Mitogen-Activated Protein Kinase p38 in HIV Infection and Associated Brain Injury

“…Amyloid-β-induced activation of p38 MAPK resulted in upregulation of pro-inflammatory cytokines TNFα, inducible NO synthase (iNOS), and IL-1β, and subsequent neuronal death (Delgado et al 2008). Our and other groups have shown that inhibition of p38 MAPK activity in vitro with pharmacological inhibitor SB203580 or dominant negative p38αAF (TGY substituted with AGF) prevented neuronal apoptosis induced by HIV-1 gp120 or glutamate (Kaul and Lipton 1999; Singh et al 2005; Kaul et al 2007; Choi et al 2007; Chaparro-Huerta et al 2008; Fig. 1b).…”

“…However, we and others have found an essential role for p38 MAPK in the induction of neuronal injury and apoptotic death by HIV-1 gp120, Tat and the intact virus (Kaul and Lipton 1999; Kaul et al 2007; Choi et al 2007; Medders et al 2010; Singh et al 2005; Sui et al 2006; Eggert et al 2010; Fig. 1).…”

“…Interestingly, primary neuronal cell cultures and macrophages, perhaps gradually more than monocytic THP-1 cells, all display a substantial level of active p38 MAPK at baseline (Singh et al 2005; Kaul et al 2001; Semenova et al 2007; Choi et al 2007; Kaul et al 2007; Medders et al 2010; Eggert et al 2010). Given the diverse physiological functions in which p38 MAPK has been implicated, the observation of a clearly detectable baseline activity may not be surprising.…”

Chemotactic and mitogenic stimuli of neuronal apoptosis in patients with medically intractable temporal lobe epilepsy

“…CXCR4 signaling may be pro-apoptotic through activation of E2F1 [27] or anti-apoptotic through activation of Akt [42]. Although the role of SDF-1 signaling in epilepsy is unresolved, we speculate that it could be important therapeutically using synthetically modified CXCR4 and CCR5 ligands modulating neuronal survival rather than apoptosis [43]…”