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PMID: 10393974 Published · ppublish English Journal Article Research Support, U.S. Gov't, P.H.S.

Chemokines and activated macrophages in HIV gp120-induced neuronal apoptosis.

Proceedings of the National Academy of Sciences of the United States of America ·Vol. 96 ·No. 14 ·1999-07-06 ·Pages 8212-6

Kaul M, Lipton SA

Abstract

HIV-1 glycoprotein gp120 induces injury and apoptosis in rodent and human neurons in vitro and in vivo and is therefore thought to contribute to HIV-associated dementia. In addition to CD4, different gp120 isolates bind to the alpha- or beta-chemokine receptors CXCR4 and CCR5, respectively. These and other chemokine receptors are on brain macrophages/microglia, astrocytes, and neurons. Thus, apoptosis could occur via direct interaction of gp120 with neurons, indirectly via stimulation of glia to release neurotoxic factors, or via both pathways. Here we show in rat cerebrocortical cultures that recapitulate the type and proportion of cells normally found in brain, i.e., neurons, astrocytes, and macrophages/microglia, that the beta-chemokines RANTES (regulated on activation, normal T cell expressed and secreted) and macrophage inflammatory protein (MIP-1beta) protect neurons from gp120SF2-induced apoptosis. The gp120SF2 isolate prefers binding to CXCR4 receptors, similar to the physiological alpha-chemokine ligands, stromal cell-derived factor (SDF)-1alpha/beta. SDF-1alpha/beta failed to prevent gp120SF2 neurotoxicity, and in fact also induced neuronal apoptosis. We could completely abrogate gp120SF2-induced neuronal apoptosis with the tripeptide TKP, which inhibits activation of macrophages/microglia. In contrast, TKP or depletion of macrophages/microglia did not prevent SDF-1 neurotoxicity. Inhibition of p38 mitogen-activated protein kinase ameliorated both gp120SF2- and SDF-1-induced neuronal apoptosis. Taken together, these results suggest that gp120SF2 and SDF-1 differ in the cell type on which they stimulate CXCR4 to induce neuronal apoptosis, but both ligands use the p38 mitogen-activated protein kinase pathway for death signaling. Moreover, gp120SF2-induced neuronal apoptosis depends predominantly on an indirect pathway via activation of chemokine receptors on macrophages/microglia, whereas SDF-1 may act directly on neurons or astrocytes.

MeSH Terms
AIDS Dementia Complex/physiopathology Animals Apoptosis Cells, Cultured Cerebral Cortex/cytology Chemokine CCL4 Chemokine CCL5/pharmacology Chemokine CXCL12 Chemokines/pharmacology,physiology Cytokines/pharmacology Embryo, Mammalian HIV Envelope Protein gp120/metabolism,pharmacology HIV-1/physiology Humans Immunoglobulin Fragments/pharmacology Macrophage Activation Macrophage Inflammatory Proteins/pharmacology Macrophages/cytology,drug effects,physiology Neuroglia/cytology,drug effects,physiology Neurons/cytology,drug effects,physiology Oligopeptides/pharmacology Rats Rats, Sprague-Dawley Recombinant Proteins/pharmacology T-Lymphocytes/physiology
Chemicals
Chemokine CCL4 Chemokine CCL5 Chemokine CXCL12 Chemokines Cytokines HIV Envelope Protein gp120 Immunoglobulin Fragments Macrophage Inflammatory Proteins Oligopeptides Recombinant Proteins threonyl-lysyl-proline
Authors & Affiliations
2 authors, click to expand affiliations / ORCID
Kaul M
CNS Research Institute, Brigham and Women's Hospital, and Program in Neuroscience, Harvard Medical School, Boston, MA 02115, USA.
Lipton S A
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Article Info
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abbr.
Proc Natl Acad Sci U S A
ISSN
0027-8424
DOI
10.1073/pnas.96.14.8212
Published
1999-07-06
Pages
8212-6
Language
English
Region
United States
NLM ID
7505876
PMCID
PMC22214
Subset
IM
Grants
NICHD NIH HHS · P01 HD029587 · United States
NEI NIH HHS · R01 EY009024 · United States
NICHD NIH HHS · P01 HD29587 · United States
NEI NIH HHS · R01 EY09024 · United States
External Links
PubMed source DOI: 10.1073/pnas.96.14.8212 PMC Full Text View journal details
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