Molecular mechanisms involving sigma receptor-mediated induction of MCP-1: Implication for increased monocyte transmigration

Honghong Yao, Yanjing Yang, Kee Jun Kim, Crystal Bethel-Brown, Nan Gong, Keiko Funa, Howard Eliot Gendelman, Tsung Ping Su, John Q. Wang, Shilpa J Buch

Research output: Contribution to journalArticle

94 Citations (Scopus)

Abstract

Cocaine abuse hastens the neurodegeneration often associated with advanced HIV-1 infection. The mechanisms, in part, revolve around the neuroinflammatory processes mediated by the chemokine monocyte chemotactic protein-1 (MCP-1/CCL2). Understanding factors that modulate MCP-1 and, in turn, facilitate monocyte extravasation in the brain is thus of paramount importance. We now demonstrate that cocaine induces MCP-1 in rodent microglia through translocation of the sigma receptor to the lipid raft microdomains of the plasma membrane. Sequential activation of Src, mitogen-activated protein kinases (MAPKs), and phosphatidylinositol-3′ kinase (PI3K)/Akt and nuclear factor κB (NF-κB) pathways resulted in increased MCP-1 expression. Furthermore, conditioned media from cocaine-exposed microglia increased monocyte transmigration, and thus was blocked by antagonists for CCR2 or sigma receptor. These findings were corroborated by demonstrating increased monocyte transmigration in mice exposed to cocaine, which was attenuated by pretreatment of mice with the sigma receptor antagonist. Interestingly, cocaine-mediated transmigratory effects were not observed in CCR2 knockout mice. We conclude that cocaine-mediated induction of MCP-1 accelerates monocyte extravasation across the endothelium. Understanding the regulation of MCP-1expression and functional changes by cocaine/sigma receptor system may provide insights into the development of potential therapeutic targets for HIV-1-associated neurocognitive disorders.

Original languageEnglish (US)
Pages (from-to)4951-4962
Number of pages12
JournalBlood
Volume115
Issue number23
DOIs
StatePublished - Jun 10 2010

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sigma Receptors
Cocaine
Monocytes
Microglia
HIV-1
CCR2 Receptors
Phosphatidylinositol 3-Kinase
Cocaine-Related Disorders
Chemokine CCL2
Conditioned Culture Medium
Mitogen-Activated Protein Kinases
Chemokines
Knockout Mice
HIV Infections
Endothelium
Rodentia
Cell membranes
Cell Membrane
Lipids
Brain

ASJC Scopus subject areas

  • Biochemistry
  • Immunology
  • Hematology
  • Cell Biology

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Molecular mechanisms involving sigma receptor-mediated induction of MCP-1 : Implication for increased monocyte transmigration. / Yao, Honghong; Yang, Yanjing; Kim, Kee Jun; Bethel-Brown, Crystal; Gong, Nan; Funa, Keiko; Gendelman, Howard Eliot; Su, Tsung Ping; Wang, John Q.; Buch, Shilpa J.

In: Blood, Vol. 115, No. 23, 10.06.2010, p. 4951-4962.

Research output: Contribution to journalArticle

Yao, Honghong ; Yang, Yanjing ; Kim, Kee Jun ; Bethel-Brown, Crystal ; Gong, Nan ; Funa, Keiko ; Gendelman, Howard Eliot ; Su, Tsung Ping ; Wang, John Q. ; Buch, Shilpa J. / Molecular mechanisms involving sigma receptor-mediated induction of MCP-1 : Implication for increased monocyte transmigration. In: Blood. 2010 ; Vol. 115, No. 23. pp. 4951-4962.
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