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

Won-Tak Choi,Ziwei Huang,Marcus Kaul,Santosh Kumar,I.M Krishna Kumar,Stuart A Lipton,Jing An,Chang-Zhi Dong,Jun Wang

doi:10.1074/jbc.m611599200

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-1alpha 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-1alpha 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.

Highlights

Children and a quarter of adults infected with human immunodeficiency virus type 1 (HIV-1) eventually develop some form of dementia [2, 3], there is no specific treatment for HIV-associated dementia (HAD)
Whether or not neuronal damage and apoptosis occur via indirect or direct pathways or both, chemokine receptors are involved in the development of HAD, which suggests that therapeutic interventions at the level of chemokine receptors may reverse or attenuate the symptoms associated with HAD
We used rodent cerebrocortical cultures (RCCs) that contained the type and proportion of cells found in human brain, i.e. neurons, astrocytes, and macrophages/microglia, and expressed CXCR4, CCR5, and other chemokine receptor homologues (14, 26 –28) that are capable of mediating HIV-1 infection via gp120 binding similar to their human homologues [29, 30]

Summary

Introduction

Children and a quarter of adults infected with HIV-1 eventually develop some form of dementia [2, 3], there is no specific treatment for HAD. We examined the potential neuroprotective or neurotoxic effects of CXCR4- and CCR5-selective SMM-chemokines and their mechanism(s) of action in preventing or inducing neuronal apoptosis, which would provide new insights into the distinct signaling pathways of HAD-associated neuronal apoptosis activated by different chemokine receptor ligands that were either agonists or antagonists.

Results

Conclusion