Cocaine Mediated Neuroinflammation: Role of Dysregulated Autophagy in Pericytes

Abstract

Cocaine, a known psychostimulant, results in oxidative stress and inflammation. Recent studies from our group have shown that cocaine induces inflammation in glial cells. Our current study was aimed at investigating whether cocaine exposure could also induce inflammation in non-glial cells such as the pericytes with a focus on the endoplasmic reticulum (ER) stress/autophagy axis. Our in vitro findings demonstrated that exposure of pericytes to cocaine resulted in upregulation of the pro-inflammatory cytokines (TNF-α, IL-1β, and IL-6) in both the intracellular as well as extracellular compartments, thus underpinning pericytes as yet another source of neuroinflammation. Cocaine exposure of pericytes resulted in increased formation of autophagosomes as demonstrated by a time-dependent increase of autophagy markers, with a concomitant defect in the fusion of the autophagosome with the lysosomes. Pharmacological blocking of the sigma 1 receptor underscored its role in cocaine-mediated activation of pericytes. Furthermore, it was also demonstrated that cocaine-mediated dysregulation of autophagy involved upstream activation of the ER stress pathways, with a subsequent downstream production of pro-inflammatory cytokines in pericytes. These findings were also validated in an in vivo model wherein pericytes in the isolated brain microvessels of cocaine injected mice (7 days) exhibited increased expression of both the autophagy marker-LC3 as well as the pro-inflammatory cytokine, IL-6. This is the first report describing the role of pericytes in cocaine-mediated neuroinflammation. Interventions aimed at blocking either the sigma-1 receptor or the upstream ER stress mediators could likely be envisioned as promising therapeutic targets for abrogating cocaine-mediated inflammation in pericytes.

Effects of Drugs of Abuse on the Blood-Brain Barrier: A Brief Overview

“…In addition, cocaine activates the Src-PDGFR-β-NF-κB pathway, which enhances CXCL10 [chemokine (C-X-C motif) ligand-1] secretion. This causes increased neuroinflammation in human brain vascular pericytes (Table 1), which further leads to neurovascular unit disruption and immune cell transmigration across the BBB (Niu et al, 2019;Sil et al, 2019).…”

Blood–brain barrier pericytes as a target for HIV-1 infection

“…Part of this effect may be mediated by increased production of IL-6 (Nakagawa et al , 2012), which can induce proinflammatory responses and decrease integrity of the neurovascular unit (Blecharz-Lang et al , 2018). An increase in pericyte-produced proinflammatory cytokines, along with dysregulation of autophagy, was also observed in response to cocaine exposure (Sil et al , 2018). Loss of pericyte coverage on the brain endothelium can also lead to a reduction of connexin expression, leading to compromised cell-cell communication.…”

Human Immunodeficiency Virus (HIV) Infection and Use of Illicit Substances Promote Secretion of Semen Exosomes that Enhance Monocyte Adhesion and Induce Actin Reorganization and Chemotactic Migration

“…Although cART has dramatically reduced HIV/AIDS-related pathologies and mortality [1], use of illicit substances (mostly psychostimulants) is a major barrier to combating the HIV pandemic [2,3,4,5]. Psychostimulants such as cocaine have been linked to exacerbated HIV disease progression and HIV-associated disorders [6,7,8,9,10,11,12,13]. In addition to its ability to promote risky behavior [14], cocaine impairs antiviral mechanisms [8,15], thus increasing the risk of HIV acquisition.…”