title: Buprenorphine decreases the CCL2-mediated chemotactic response of monocytes.
abstract: Despite successful combined antiretroviral therapy, ∼ 60% of HIV-infected people exhibit HIV-associated neurocognitive disorders (HAND). CCL2 is elevated in the CNS of infected people with HAND and mediates monocyte influx into the CNS, which is critical in neuroAIDS. Many HIV-infected opiate abusers have increased neuroinflammation that may augment HAND. Buprenorphine is used to treat opiate addiction. However, there are few studies that examine its impact on HIV neuropathogenesis. We show that buprenorphine reduces the chemotactic phenotype of monocytes. Buprenorphine decreases the formation of membrane projections in response to CCL2. It also decreases CCL2-induced chemotaxis and mediates a delay in reinsertion of the CCL2 receptor, CCR2, into the cell membrane after CCL2-mediated receptor internalization, suggesting a mechanism of action of buprenorphine. Signaling pathways in CCL2-induced migration include increased phosphorylation of p38 MAPK and of the junctional protein JAM-A. We show that buprenorphine decreases these phosphorylations in CCL2-treated monocytes. Using DAMGO, CTAP, and Nor-BNI, we demonstrate that the effect of buprenorphine on CCL2 signaling is opioid receptor mediated. To identify additional potential mechanisms by which buprenorphine inhibits CCL2-induced monocyte migration, we performed proteomic analyses to characterize additional proteins in monocytes whose phosphorylation after CCL2 treatment was inhibited by buprenorphine. Leukosialin and S100A9 were identified and had not been shown previously to be involved in monocyte migration. We propose that buprenorphine limits CCL2-mediated monocyte transmigration into the CNS, thereby reducing neuroinflammation characteristic of HAND. Our findings underscore the use of buprenorphine as a therapeutic for neuroinflammation as well as for addiction.
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461;
authors.forename: Loreto
authors.initials: L
authors.lastname: Carvallo
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461;
authors.forename: Lillie
authors.initials: L
authors.lastname: Lopez
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461;
authors.forename: Fa-Yun
authors.initials: FY
authors.lastname: Che
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461;
authors.forename: Jihyeon
authors.initials: J
authors.lastname: Lim
authors.affiliation: Public Health Research Institute, Newark, NJ 07103; Department of Microbiology and Molecular Genetics, Rutgers New Jersey Medical School, Rutgers The State University of New Jersey, Newark, NJ 07103;
authors.forename: Eliseo A
authors.initials: EA
authors.lastname: Eugenin
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461;
authors.forename: Dionna W
authors.initials: DW
authors.lastname: Williams
authors.affiliation: Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461;
authors.forename: Edward
authors.initials: E
authors.lastname: Nieves
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461;
authors.forename: Tina M
authors.initials: TM
authors.lastname: Calderon
authors.affiliation: Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, NY 10461; and.
authors.forename: Carlos
authors.initials: C
authors.lastname: Madrid-Aliste
authors.affiliation: Department of Systems and Computational Biology, Albert Einstein College of Medicine, Bronx, NY 10461; and.
authors.forename: Andras
authors.initials: A
authors.lastname: Fiser
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461;
authors.forename: Louis
authors.initials: L
authors.lastname: Weiss
authors.affiliation: Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Bronx, NY 10461;
authors.forename: Ruth Hogue
authors.initials: RH
authors.lastname: Angeletti
authors.affiliation: Department of Pathology, Albert Einstein College of Medicine, Bronx, NY 10461; Department of Microbiology and Immunology, Albert Einstein College of Medicine, Bronx, NY 10461 joan.berman@einstein.yu.edu.
authors.forename: Joan W
authors.initials: JW
authors.lastname: Berman
mesh_terms: D000701:Analgesics, Opioid / Q000494:pharmacology; D002047:Buprenorphine / Q000494:pharmacology; D015815:Cell Adhesion Molecules / Q000378:metabolism; D002462:Cell Membrane / Q000187:drug effects / Q000378:metabolism; D018932:Chemokine CCL2 / Q000378:metabolism*; D002634:Chemotaxis, Leukocyte / Q000187:drug effects / Q000276:immunology*; D006801:Humans; D009000:Monocytes / Q000187:drug effects / Q000276:immunology* / Q000378:metabolism*; D010641:Phenotype; D010748:Phosphopeptides / Q000378:metabolism; D010766:Phosphorylation; D020543:Proteome; D040901:Proteomics; D054390:Receptors, CCR2 / Q000378:metabolism; D011956:Receptors, Cell Surface / Q000378:metabolism; D011957:Receptors, Opioid / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D000701:Analgesics, Opioid; D015815:Cell Adhesion Molecules; D018932:Chemokine CCL2; C407243:F11R protein, human; D010748:Phosphopeptides; D020543:Proteome; D054390:Receptors, CCR2; D011956:Receptors, Cell Surface; D011957:Receptors, Opioid; D002047:Buprenorphine; D048051:p38 Mitogen-Activated Protein Kinases