Methamphetamine Inhibits Antigen Processing, Presentation, and Phagocytosis

Abstract

Methamphetamine (Meth) is abused by over 35 million people worldwide. Chronic Meth abuse may be particularly devastating in individuals who engage in unprotected sex with multiple partners because it is associated with a 2-fold higher risk for obtaining HIV and associated secondary infections. We report the first specific evidence that Meth at pharmacological concentrations exerts a direct immunosuppressive effect on dendritic cells and macrophages. As a weak base, Meth collapses the pH gradient across acidic organelles, including lysosomes and associated autophagic organelles. This in turn inhibits receptor-mediated phagocytosis of antibody-coated particles, MHC class II antigen processing by the endosomal–lysosomal pathway, and antigen presentation to splenic T cells by dendritic cells. More importantly Meth facilitates intracellular replication and inhibits intracellular killing of Candida albicans and Cryptococcus neoformans, two major AIDS-related pathogens. Meth exerts previously unreported direct immunosuppressive effects that contribute to increased risk of infection and exacerbate AIDS pathology.

TLR9 Contributes to the Recognition of EBV by Primary Monocytes and Plasmacytoid Dendritic Cells

“…In addition, pretreatment of pDCs with CQ strongly inhibits the effects of EBV on the expression levels of CD40 and CD86, suggesting a dependence of endosome acidification in this process. CQ does not seem to impact only on TLR9 activity, but also on essential functions, such as Ag processing, MHC class II presentation, and expression of CD40 as reported (43,44). Our results are thus in perfect agreement with those observations.…”

Amphetamines promote mitochondrial dysfunction and DNA damage in pulmonary hypertension

“…In separate experiments using 24-hour serum withdrawal as a stimulus, we determined that AMPH (Supplemental Figure 1A; supplemental material available online with this article; doi:10.1172/jci.insight.90427DS1) and METH (Supplemental Figure 1B) promote caspase-3/7 activation in a dose-dependent manner using concentrations relevant to the clinical setting (24,25). We then identified an AMPH-mediated reduction in Akt phosphorylation (Supplemental Figure 1C) that we attributed to high protein phosphatase (PP1 and PP2) activities, since it was reversed by PP1 and PP2 inhibition with okadaic acid but not by restoring PI (3,4,5)P3 levels with the phosphatase and tensin homolog (PTEN) inhibitor (VO-OHpic; Supplemental Figure 1D).…”

Human Immunodeficiency Virus (HIV) Infection of Human Macrophages Is Increased by Dopamine

“…26 -30 The use of both cocaine and methamphetamine generates extracellular CNS dopamine levels far higher than those found in the brains of non-drug-abusers. 26,[31][32][33][34][35][36] Dopamine acts through dopamine receptors, which are members of the G-protein coupled seven transmembrane domain family of receptors. Dopamine receptors (DRs) are divided into two subtypes designated D1-like DRs, comprised of dopamine receptor 1 (D1R) and D5R, and D2-like DRs, comprised of D2R, D3R, and D4R.…”

“…These concentrations of DA were chosen to approximate the large amount of DA that can be produced in a brain exposed to psychostimulants such as cocaine or methamphetamine. 26,[31][32][33][34][35][36] Inoculation with HIV in the presence of 5 mol/L DA induced a significant increase in HIV replication, but at lower levels of replication than did inoculation in the presence of 20 and 80 mol/L DA, which both induced similar, significant increases in HIV replication (data for 20 mol/L DA in Figure 1, data for 5 mol/L and 80 mol/L not shown). Thus, 20 mol/L DA was chosen as the concentration to be used in further experiments.…”