Buprenorphine Decreases the CCL2-Mediated Chemotactic Response of Monocytes

Abstract

Despite successful cART, approximately 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 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.

Opioids and Opioid Maintenance Therapies: Their Impact on Monocyte-Mediated HIV Neuropathogenesis

“…We studied the effects of buprenorphine on the CCL2 mediated human monocyte migratory phenotype that facilitates their migration [116]. Human peripheral monocytes have a round morphology, but when treated with CCL2, they extend a leading edge, characterized by the colocalization of the actin and tubulin cytoskeleton [66].…”

“…Human peripheral monocytes have a round morphology, but when treated with CCL2, they extend a leading edge, characterized by the colocalization of the actin and tubulin cytoskeleton [66]. When monocytes were treated with CCL2 in the presence of buprenorphine, the percentage of monocytes extending protrusions decreased, to similar numbers as base line [116]. CCL2 mediated chemotaxis was also decreased when monocytes were pretreated with both buprenorphine and CCL2 by a mechanism regulated, in part, by delayed CCR2 receptor recycling to the surface [116].…”

“…When monocytes were treated with CCL2 in the presence of buprenorphine, the percentage of monocytes extending protrusions decreased, to similar numbers as base line [116]. CCL2 mediated chemotaxis was also decreased when monocytes were pretreated with both buprenorphine and CCL2 by a mechanism regulated, in part, by delayed CCR2 receptor recycling to the surface [116]. Additionally, we studied the effect of buprenorphine treatment on CCL2 mediated phosphorylation of p38, a MAP kinase associated with cell migration [117].…”

“…We found that buprenorphine inhibited CCL2 mediated p38 phosphorylation. This decrease involved the activation of MOR, because pretreatment of monocytes with CTAP, a MOR antagonist, reversed the effects [116]. Interestingly, when monocytes were treated with nor-BNI a KOR antagonist, CCL2 mediated p38 phosphorylation was decreased in the 60% of the experiments with primary human monocytes.…”

“…Interestingly, when monocytes were treated with nor-BNI a KOR antagonist, CCL2 mediated p38 phosphorylation was decreased in the 60% of the experiments with primary human monocytes. As all of the studies were performed with primary cells from different people, this may reflect intrinsic variability in surface KOR expression from person to person [116]. Thus, KOR antagonist activity may also play a role in the effects of buprenorphine.…”