Frontline Science: Buprenorphine decreases CCL2-mediated migration of CD14+CD16+ monocytes

Abstract

HIV infection of the CNS causes neuroinflammation and damage that contributes to the development of HIV-associated neurocognitive disorders (HAND) in greater than 50% of HIV-infected individuals, despite antiretroviral therapy (ART). Opioid abuse is a major risk factor for HIV infection. It has been shown that opioids can contribute to increased HIV CNS pathogenesis, in part, by modulating the function of immune cells. HIV enters the CNS within two weeks after peripheral infection by transmigration of infected monocytes across the blood brain barrier (BBB). CD14 CD16 monocytes are a mature subpopulation that is increased in number in the peripheral blood of HIV-infected people. Mature monocytes can be productively infected with HIV, and they transmigrate preferentially across the BBB in response to CCL2, a chemokine elevated in the CNS and CSF of HIV-infected people even with ART. Buprenorphine, an opioid derivate, is an opioid replacement therapy for heroin addiction. It is a partial agonist of μ-opioid receptor and full antagonist of κ-opioid receptor. The effects of buprenorphine on CCL2-mediated CD14 CD16 monocytes transmigration across the BBB, a critical mechanism that promotes neuroinflammation and HAND, have not been characterized. We showed for the first time that buprenorphine decreases several steps of CCL2-mediated human mature monocyte transmigration. We propose that buprenorphine treatment in the context of HIV infection could serve a dual purpose, to treat opioid addiction and also to reduce neuroinflammation. Additionally, buprenorphine may be used as a treatment for HAND not only in the context of opioid abuse.

Treatment with buprenorphine prior to EcoHIV infection of mice prevents the development of neurocognitive impairment

“…CCL2 is the most potent monocyte chemoattractant, and remains elevated in the CNS of HIV‐infected people despite ART 34 . Previously we demonstrated in in vitro studies using primary human monocytes that buprenorphine decreases multiple steps of CCL2‐mediated monocyte migration across the BBB 35,36 . Ly6C hi monocytes in mice express surface CCR2, and CCL2, its ligand, is important for their migration into the brain 37 .…”

Targeting FROUNT with disulfiram suppresses macrophage accumulation and its tumor-promoting properties

“…DSF potently inhibits FROUNT by directly binding to the FROUNT and interfering with FROUNT-chemokine-receptor interactions. This is the first report of FROUNT inhibitor directly binding to FROUNT, and its therapeutic effect is demonstrated by using an animal disease model, although there has been a recent report on an inhibitor of FROUNT-chemokine-receptor interactions assessed using cultured cells 41 . The direct tumoricidal activity of DSF has been known for some time, which was mediated via an ALDH-dependent mechanism in the context of cancer stem cells 42 or, via the NF-κB pathway 32,33 .…”

Peripheral inflammation and blood–brain barrier disruption: effects and mechanisms

“…Monocytes may migrate across the BBB depending on the upregulation of cytokines (IL‐1) and junction molecules (ALCAM, JAM‐A, PECAM‐1, and CD99) 148,149 . As a result, HIV‐infected monocytes with upregulation of ALCAM, JAM‐A, and CCR2 on their surface are more likely to cross the endothelium monolayer than noninfected monocytes in response to CCL2, a chemokine, which is elevated in the CNS and CSF of HIV‐infected people 150,151 . The bone marrow‐derived monocytes (BMDMs) can affect the BBB integrity and control immune infiltration by releasing related cytokines during stroke, whereby exacerbating BBB injury 127 .…”