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Methamphetamine Induces Trace Amine‐Associated Receptor 1 (TAAR1) Expression in Human T Lymphocytes: Role in Immunomodulation

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Methamphetamine Induces Trace Amine‐Associated Receptor 1 (TAAR1) Expression in Human T Lymphocytes: Role in Immunomodulation Article Methamphetamine induces trace amine- associated receptor 1 (TAAR1) expression in human T lymphocytes: role in immunomodulation Uma Sriram, Jonathan M. Cenna, Bijayesh Haldar, Nicole C. Fernandes, Roshanak Razmpour, Shongshan Fan, Servio H. Ramirez, and Raghava Potula1 Department of Pathology and Laboratory Medicine, Temple University School of Medicine, Philadelphia, Pennsylvania, USA RECEIVED AUGUST 13, 2014; REVISED JULY 27, 2015; ACCEPTED AUGUST 5, 2015. DOI: 10.1189/jlb.4A0814-395RR ABSTRACT Introduction The novel transmembrane G protein-coupled receptor, Among the various substances of abuse, METH is gaining trace amine-associated receptor 1 (TAAR1), represents increasing popularity among drug-abusing populations world- a potential, direct target for drugs of abuse and mono- wide for its addictive psychostimulant effects [1, 2]. Recreational aminergic compounds, including amphetamines. For the METH use is one of the fastest growing substance-abuse first time, our studies have illustrated that there is an problems in the United States [3, 4]. METH use is associated with induction of TAAR1 mRNA expression in resting high-risk sexual behavior and high rates of HIV acquisition [5]. T lymphocytes in response to methamphetamine. Meth- amphetamine treatment for 6 h significantly increased Animal and human studies have demonstrated that METH – TAAR1 mRNA expression (P , 0.001) and protein ex- suppresses innate and adaptive immunity [6 8]. More insights pression (P , 0.01) at 24 h. With the use of TAAR1 gene into the mechanism of action of METH have been revealed in silencing, we demonstrate that methamphetamine- the last decade with the discovery of the receptor(s) for METH induced cAMP, a classic response to methamphetamine that belong to specific families of GPCRs [9, 10]. Members of this stimulation, is regulated via TAAR1. We also show by large family of GPCRs are now referred to as TAARs, and TAAR1 TAAR1 knockdown that the down-regulation of IL-2 is the prototypical member [11, 12], which is activated by in T cells by methamphetamine, which we reported a broad range of monoamines and amphetamine-related earlier, is indeed regulated by TAAR1. Our results also psychostimulants, including METH [13, 14]. show the presence of TAAR1 in human lymph nodes from There is substantial evidence for TAAR1 mRNA expression in the HIV-1-infected patients, with or without a history of meth- rodent and primate brain [15–17]. TAAR1 mRNA and protein amphetamine abuse. TAAR1 expression on lymphocytes was largely in the paracortical lymphoid area of the lymph expression have also been shown in other peripheral tissues, such as nodes with enhanced expression in lymph nodes of HIV-1- liver, kidney, spleen, pancreas, heart, and gastrointestinal tract, in infected methamphetamine abusers rather than infected- rodent and primate models [9], as well as in leukocyte subpopu- only subjects. In vitro analysis of HIV-1 infection of human lations of mice and humans [18]. TAAR1 mRNA has been shown to PBMCs revealed increased TAAR1 expression in the be up-regulated in human PBMCs following in vitro stimulation presence of methamphetamine. In summary, the ability of with PHA [18]. Miller et al. [15] have pharmacologically methamphetamine to activate trace TAAR1 in vitro and to characterized rhesus monkey TAAR1 in HEK293 cells by use of regulate important T cell functions, such as cAMP activa- a highly sensitive CRE-Luc (cAMP response element - luciferase) tion and IL-2 production; the expression of TAAR1 in assay. Activation of TAAR1 has been shown to induce cAMP, which T lymphocytes in peripheral lymphoid organs, such as involves phosphorylation-dependent, downstream effects of PKA lymph nodes; and our in vitro HIV-1 infection model in PBMCs suggests that TAAR1 may play an important role in and PKC pathways [9, 16]. methamphetamine -mediated immune-modulatory re- METH abuse has seriously impacted management of HIV-1 – sponses. J. Leukoc. Biol. 99: 213–223; 2016. infection globally [8, 19 21], as evidenced by studies of various cohorts in the United States [4, 22, 23] and around the world [24, 25]. METH abuse has been shown to be associated with high b b Abbreviations: -PEA = -phenylethylamine, ADA = adenosine deaminase, viral loads, especially in the CNS [26, 27], development of GPCR = G protein-coupled receptor, HEK = human embryonic kidney, METH = – methamphetamine, MFI = median fluorescence intensity, PKA/C = protein kinase antiretroviral resistance, and rapid progression to AIDS [28 31]. A/C, pPKA RIIa = phospho-PKA regulatory subunit IIa, qRT-PCR = quantitative RT- PCR, siRNA = small interfering RNA, TAAR1 = trace amine-associated receptor 1 1. Correspondence: Dept. of Pathology and Laboratory Medicine, Temple The online version of this paper, found at www.jleukbio.org, includes University School of Medicine, 3500 N. Broad St., MERB 845A, supplemental information. Philadelphia, PA 19140, USA. E-mail: [email protected] 0741-5400/16/0099-213 © Society for Leukocyte Biology Volume 99, January 2016 Journal of Leukocyte Biology 213 METH-induced responses mediated through TAAR1 signaling 20 medium (Lonza, Walkersville, MD, USA), supplemented with 1% heat- have never been studied in the context of HIV-1 infection in inactivated normal human serum, 20 mg/ml gentamycin, and 2 mM m peripheral immune cells. glutamine. The concentration of METH used (100 M) was based on our previously published dose-response studies that produced a maximum We have shown that METH induces T cell dysfunction via biologic response without causing toxicity [7]. induction of oxidative stress and mitochondrial injury [7]. Mitochondrial dysfunction paralleled reduced IL-2 secretion and qRT-PCR T cell-proliferative responses after TCR-CD28 stimulation, in- 3 6 m m dicating impaired T cell function. In this study, we focused on Pan-isolated T cells (1 10 /ml) were stimulated with 100 M METH or 100 M b-PEA for 4, 6, and 8 h and harvested for RNA extraction by use of an RNA the mechanisms of METH action via TAAR1 in resting (non- Extraction Kit (Qiagen, Germantown, MD, USA). RNA was extracted, per the activated) human T cells from normal donors. Our studies show, manufacturer’s protocol, including DNase treatment. cDNA was made by use of for the first time, a significant induction of TAAR1 mRNA and 1 mg RNA template and proceeded to real-time PCR by use of TaqMan probes protein expression in resting T lymphocytes in response to for TAAR1 (Applied Biosystems, Life Technologies). Real-time PCR was run in METH. Similar to neuronal and non-neuronal cells, resting a StepOnePlus PCR thermocycler (Applied Biosystems, Life Technologies). DD T cells induced cAMP and cAMP-dependent PKA activation GAPDH was used as the housekeeping gene. The comparative threshold method was used to calculate the fold change in TAAR1 expression compared upon METH treatment. With the use of a gene-silencing with untreated control. technique, we confirm that the signaling is mediated via TAAR1. Previously, we have reported [7] that METH decreased IL-2 Confocal imaging production in T cells upon CD3/CD28 stimulation. In the b current study, we show that METH via TAAR1 signaling Total PBMCs were treated with METH, -PEA, or tyramine for 24 h and were harvested and plated on poly-D-lysine-coated coverslips and allowed to adhere modulates IL-2 production. These data suggest that METH has for 1 h at 37°C. Cells on coverslips were fixed with methanol/acetone (1:1) for an important immunomodulatory effect that is likely attributable 20 min at 220°C. Cells were then blocked with 3% BSA + 0.1% Triton X-100 to the activity of the receptor. Furthermore, increased TAAR1 in PBS for 15 min at room temperature. After blocking, cells were incubated expression was seen in T cells from PBMC upon METH with mouse anti-human CD3 (1:100; BioLegend) and rabbit anti-human treatment, followed by HIV-1 infection in an in vitro infection TAAR1 (10 mg/ml; MBL International; LS-A2041) primary antibodies for 1 h model. We also show increased TAAR1 expression in human at room temperature. Cells were then incubated with donkey anti-mouse Alexa Fluor 594 (1:400; Invitrogen, Life Technologies) and donkey anti-rabbit lymph nodes from HIV-1-infected patients with a history of Alexa Fluor 488 (1:400; Invitrogen, Life Technologies) secondary antibodies METH abuse compared with non-METH abusers. for 1 h at room temperature. Samples were washed and mounted on glass In summary, the current study clearly demonstrates the slides by use of ProLong Gold + DAPI reagent. Immunofluorescently labeled following: that 1) METH activates TAAR1 in vitro, 2) METH T lymphocytes were imaged at the Temple University Confocal Imaging regulates cAMP and IL-2 production in T cells, 3) HIV-infected Facility by use of a Leica SP5 confocal microscope. METH abusers express TAAR1 in T lymphocytes in peripheral lymphoid organs, such as lymph nodes, and 4) HIV-infected, Flow cytometry METH-exposed T cells in vitro express increased TAAR1. Taken Total PBMCs (1 3 106 /ml) were cultured in complete RPMI-1640 medium, together, the study suggests that TAAR1 may play an important supplemented with 10% heat-inactivated FBS, 2 mM L-glutamine, 100 U/ml m role in METH-mediated, immune-modulatory responses. penicillin, 100 g/ml streptomycin, and 20 mM HEPES (Life Technologies, Carlsbad, CA, USA) for 24 h, with or without 100 mM METH, tyramine, or b-PEA. Cells were harvested and stained with purified rabbit anti-human TAAR1 (1:100 dilution; MBL International), followed by allophycocyanin- MATERIALS AND METHODS tagged anti-rabbit secondary, along with FITC-tagged anti-human CD3, PE- tagged anti-human CD4, and eFlour 450-tagged anti-human CD8. Cells were Sample collection washed in FACS buffer, fixed in 1% paraformaldehyde/PBS, and read in a BD fl PBMCs were isolated from leukopheresis packs (Pall, Port Washington, NY, FACSCanto II ow cytometer (BD Biosciences, San Jose, CA, USA).
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