Secondary Logo

Journal Logo

9-Tetrahydrocannabinol">Δ9-Tetrahydrocannabinol Suppresses Secretion of IFNα by Plasmacytoid Dendritic Cells From Healthy and HIV-Infected Individuals

Henriquez, Joseph E. MSc*,†,‡; Rizzo, Michael D. BS*,§,‡; Schulz, Matthias A. MS*; Crawford, Robert B. BS*,‡; Gulick, Peter DO*,‖; Kaminski, Norbert E. PhD*,†,‡

JAIDS Journal of Acquired Immune Deficiency Syndromes: August 15, 2017 - Volume 75 - Issue 5 - p 588–596
doi: 10.1097/QAI.0000000000001449
Translational Research
Free

Abstract: Plasmacytoid dendritic cells (pDCs) play a crucial role in host antiviral immune response through secretion of type I interferon. Interferon alpha (IFNα), a type I IFN, is critical for mounting the initial response to viral pathogens. A consequence of Human Immunodeficiency Virus-1 (HIV) infection is a decrease in both pDC number and function, but prolonged pDC activity has been linked with progression from HIV infection to the development of AIDS. Patients with HIV in the United States routinely use cannabinoid-based therapies to combat the side effects of HIV infection and antiretroviral therapy. However, cannabinoids, including 9-tetrahydrocannabinol">Δ9-tetrahydrocannabinol (THC), are well-characterized immunosuppressants. Here, we report that THC suppressed secretion of IFNα by pDC from both healthy and HIV+ donors through a mechanism involving impaired phosphorylation of interferon regulatory factor 7. These results suggest that THC can suppress pDC function during the early host antiviral response by dampening pDC activation.

*Michigan State University East Lansing, MI;

Department of Pharmacology and Toxicology East Lansing, MI;

Institute for Integrative Toxicology East Lansing, MI;

§Department of Cell and Molecular Biology East Lansing, MI; and

Department of Osteopathic Medicine East Lansing, MI.

Correspondence to: Norbert E. Kaminski, PhD, Michigan State University, Institute for Integrative Toxicology, 1129 Farm Lane, Rm 165G, Food Safety and Toxicology building, East Lansing, MI 48824 (e-mail: kamins11@msu.edu).

Supported by the National Institutes of Drug Abuse Grant DA07908 and the National Institutes of Environmental Health Sciences Training Grant T32 ES07255.

The authors have no conflicts of interest to disclose.

Received January 13, 2017

Accepted May 03, 2017

Back to Top | Article Outline

INTRODUCTION

Plasmacytoid dendritic cells (pDCs) compose a minor population (0.2%–0.5%) of circulating peripheral blood mononuclear cells (PBMCs) that play a crucial role in bridging the innate and adaptive antiviral immune response.1–4 On activation, pDC secrete 1000-fold more type I interferon (IFN) than any other population of PBMCs to stimulate other leukocytes including NK cells,5,6 B cells,4 and T cells.6,7

Somewhat paradoxically, pDC number and function is suppressed in association with certain types of viral infections including hepatitis C virus and HIV.8,9 In a rhesus macaque model of HIV infection, using simian immunodeficiency virus (SIV), the number of circulating pDC is reduced during the acute stage of SIV infection as pDC migrate to the gut.10 In both HIV and SIV infection, gut lymphoid tissue is a key site of viral replication and, therefore, a target for pDC recruitment. However, pDC may be susceptible to productive HIV infection because of their expression of CD4. Specifically, infection by HIV may perturb pDC function resulting in reduced secretion of interferon alpha (IFNα).11 This reduced capacity for IFNα secretion during infection would hinder an appropriate host response, as evidenced by protection against HIV-mediated CD4+ T cell depletion in a humanized mouse model on administration of IFNα,12 and lead to an inability to appropriately control the infection.13 HIV-infected pDC may also directly facilitate the infection of CD4+ T cells during the acute phase of HIV infection.14 Furthermore, the loss of pDC in circulation correlated with an increase in HIV viral serum titer such that fewer circulating pDC translated into a deficiency in antiviral response.15 Collectively, these results have broader implications for the health of HIV+ patients as loss of pDC function could exacerbate susceptibility to opportunistic viral infection.

In 2015, the Centers for Disease Control and Prevention estimated that 1.2 million people were infected with HIV in the United States and 36.9 million globally. Antiretroviral therapy (ART) is the primary therapy for patients with HIV in the United States and has been since the mid 1990s.16 Although effective, ART therapy can also induce nausea and reduce appetite.17 Furthermore, HIV infection, even when properly controlled by ART, is associated with physical wasting18,19 and anxiety,20,21 both of which can have deleterious effects on the host immune response. The effects of both HIV infection and ART have led to a significant number of patients with HIV using cannabinoid-based therapies such as medical marijuana (Cannabis sativa) and dronabinol (Marinol).22–24

9-Tetrahydrocannabinol">Δ9-Tetrahydrocannabinol (THC, also known as dronabinol or Marinol) is the primary psychoactive cannabinoid in marijuana and is a well-characterized immune modulator.25–27 In mouse models of herpes simplex virus type II,28,29Listeria monocytogenes,29 and influenza virus type A,30,31 THC administration exacerbated disease progression. Although THC has been shown to have suppressive effects on the function of many different immune cell populations, THC-mediated suppression of IFN secretion was demonstrated in all the aforementioned models of disease.32 Suppression of IFN (type I and II) secretion by THC is likely a key mechanism by which viral infections are potentiated.

Currently, the utilization of cannabinoid-based therapies in HIV infection is controversial. Utilization of cannabinoids has been found to reduce the concentration of circulating antiretroviral drugs, and these studies indicated little effect of cannabinoids on retroviral therapy efficacy or immune cell function.23,33 However, in these cases, it is difficult to distinguish between the direct effects of the cannabinoids on leukocyte function and possible confounders. Furthermore, suppression of peripheral IFNα secretion through utilization of medicinal cannabinoids may reduce certain HIV-associated comorbidities, thereby lending potential support for cannabinoid-based therapies. The objective of this study was to determine the effects of THC on IFNα production by pDCs using leukocytes from HIV+ patients on ART and healthy donors as controls.

Back to Top | Article Outline

MATERIALS AND METHODS

PBMC Isolation and Cell Identification

Leukocyte packs were purchased from the Gulf Coast Regional Blood Center (Houston, TX). Blood was diluted 1:1 with Hanks balanced salt solution from Gibco (Grand Island, NY) and layered on 15 mL Ficoll Paque Plus (GE Healthcare Life Sciences, Pittsburgh, PA) in SepMate 50-mL conical tubes by StemCell Technologies (Vancouver, BC, Canada). Leukocytes were centrifuged at ×1300g for 25 minutes at 4°C. The leukocyte layer was resuspended in RPMI Media from Gibco containing 5% Human AB Serum (Sigma-Aldrich, St. Louis, MO), 1% Penicillin-Streptomycin (Gibco), and 0.035% β-mercaptoethanol. pDCs were identified using mouse anti-human antibodies by Miltenyi Biotec GmbH (Bergisch Gladbach, Germany) as CD303+ CD123+ cells.

Back to Top | Article Outline

pDC Purification by Magnetic-Activated Cell Sorting

pDCs were isolated by negative selection using magnetic-activated cell sorting (MACs) isolation kits from Miltenyi Biotec per the manufacturer's instructions. Briefly, PBMC cell concentrations were determined using a coulter cell counter, and the appropriate volume of non-pDC antibody cocktail was incubated with PBMC followed by washing and incubation with magnetic beads. Labeled PBMCs were then passed through a MACS depletion column affixed to a MACS magnet with unstimulated pDC being collected in the flow through. The number of PBMCs in a single leukocyte pack range from 3.0 to 11 × 108 total PBMC with an average of 6 × 108 total PBMC and 0.9–1 × 106 pDC per leukocyte pack containing 6 × 108 total PBMC when accounting for isolation efficiency.

Back to Top | Article Outline

Gene Expression Analysis

RNA was isolated using Qiagen RNeasy kits (Germantown, MD) per the manufacturer's instructions. Briefly, cells were lysed using lysing buffer containing β-mercaptoethanol and stored at −20°C. Lysates were then purified and treated with DNAse from Promega SV Total RNA Isolation Kit (Madison, WI). RNA concentrations were determined by Nanodrop (Thermo-Fisher Scientific, Waltham, MA). Reverse transcriptase–polymerase chain reaction (RT-PCR) was performed using High-Capacity cDNA RT-PCR kit by Applied Biosystems (Foster City, CA). cDNA was frozen at −20°C. Gene analysis was determined by real-time quantitative PCR (Qt-PCR) using TaqMan probes for CNR1 (Hs00275634_m1) and CNR2 (Hs00275635_m1) by Life Technologies (Compendia Bioscience, Ann Arbor, MI) with 18sRNA as a loading control.

Back to Top | Article Outline

Treatment With Cannabinoids or Vehicle Control and Cell Stimulation

THC was supplied by the National Institute of Drug Abuse. Purified, unstimulated pDCs or PBMCs were treated with either Δ9-THC, cannabidiol (CBD), or vehicle control (–0.026% ethanol). The appropriate concentrations were prepared in complete RPMI. The prepared cell suspensions and appropriate treatments were added to flat bottom 96-well tissue culture plates. Cells were then incubated at 37°C and 5% CO2 for 30 minutes. After incubation, cells were stimulated with CpG-ODN type A 2216 (15 μg/mL) (InvivoGen; San Diego, CA).

Back to Top | Article Outline

IFNα Capture Assay

Secretion of IFNα was determined using the IFNα capture assay by Miltenyi Biotec per the manufacturer's directions. Treated cells were bound with IFNα capture reagent and placed into warm media and incubated under continuous motion for 30 minutes. Cells were then washed and incubated with IFNα detection antibody. Cells were fixed using CytoFix buffer by BD Biosciences (San Jose, CA), and IFNα secreting pDC were quantified by flow cytometry.

Back to Top | Article Outline

Phospho-IRF-7 Detection

Treated PBMCs were washed, and pDCs were stained as described. pIRF7 levels were determined using Phosflow antibodies and the harsh detergent method by BD Biosciences. In brief, cells were fixed using BD Cytofix buffer for 10 minutes at 37°C then permeabilized using ×1 of Perm buffer IV, stained for 1 hour under continuous motion using Fluorescence Activated Cell Sorting (FACS) buffer and 5% Human AB Serum, washed 3X with ×0.5 perm buffer, and analyzed by flow cytometry.

Back to Top | Article Outline

IFNΑ2 Gene Expression by PrimeFlow

PrimeFlow RNA assay (eBiosciences; San Diego, CA) was performed per manufacturer's directions. Treated PBMCs were fixed, permeabilized, and bound with IFNΑ2 probe. The mRNA signal was then amplified and detected using Alexa Fluor 647 detection probes (Thermo-Fisher Scientific, Waltham, MA). Relative gene expression was determined using flow cytometry.

Back to Top | Article Outline

Measuring Secreted IFNα

IFNα secretion was determined using the LEGENDplex cytometric bead array by BioLegend per the manufacturer's directions. Detection beads were sonicated and incubated with media from purified pDC. The BD Canto II was used for data acquisition and accompanying LEGENDplex software was used for analysis.

Back to Top | Article Outline

Data Analysis

GraphPad Prism 5.0 was used for statistical analysis. Where appropriate, samples were normalized to 0 μM THC + CpG, which was considered 100% maximum response for each individual donor, and the appropriate statistical test was performed (Figs. 2–5).

FIGURE 2

FIGURE 2

FIGURE 3

FIGURE 3

FIGURE 4

FIGURE 4

FIGURE 5

FIGURE 5

Back to Top | Article Outline

HIV+ Donor Recruitment and Data Management

HIV+ donors voluntarily enrolled in the Mid-Michigan HIV consortium (MMHC) under the institutional review board–approved protocol (IRB # 11-202) and into the MMHC Registry. Donors were recruited from clinics attended by Dr. Peter Gulick; HIV+ were males between the ages of 31 and 71 with an average age of 54.4 years. Donors received the standard of care and were not asked to change any lifestyle habits to participate. All subject questionnaires and their abstracted medical record data for the MMHC are managed using the Research Electronic Data Capture (REDCap) (Vanderbilt University), which supports 21 CFR Part 11 compliance for clinical research and trial data and HIPAA guidelines.

Back to Top | Article Outline

RESULTS

Profile of CNR1 and CNR2 Expression in pDC and PBMC From HIV+ Donors Versus Healthy Donors

The profile of cannabinoid receptor (CNR1 and CNR2) expression has not previously been characterized in human pDC and was therefore investigated using purified pDC and compared with PBMC from healthy donors (Fig. 1A). Purified pDC were found to exhibit a very similar profile of CNR1 and CNR2 expression compared with other PBMC such that CNR2 mRNA levels were more highly expressed than CNR1 (Fig. 1B). These studies were extended to also quantify CNR1 and CNR2 levels in HIV+ donors. PBMC from HIV+ donors showed significantly augmented CB1 mRNA levels compared with healthy donors (Figs. 1C, D). By contrast, CB2 mRNA levels were similar in PBMC from healthy versus HIV+ donors (Figs. 1C, D). A sufficient amount of blood could not be collected from HIV+ donors to quantify CNR1 and CNR2 mRNA expression levels in purified pDC by RT/Qt-PCR.

FIGURE 1

FIGURE 1

Back to Top | Article Outline

pDCs From HIV+ Donors Are More Sensitive to THC-Mediated Suppression of IFNα Secretion Compared With Healthy Donors

HIV infection reduces both the number of circulating pDC and the ability for the remaining pDC to secrete IFNα.8,15,34 To extend the previous observations, PBMCs from HIV+ patients were treated with CpG-ODN, and the number of IFNα-secreting pDCs were quantified using the IFNα capture assay. THC is known to suppress IFN secretion in infection and inflammatory conditions.32 Here, the effects of THC on IFNα secretion were determined in CpG-ODN–induced human primary pDC.

pDC were identified as CD303+ CD123+ cells (Fig. 2A), and secretion of IFNα was then quantified by flow cytometry (Fig. 2B). The induction of IFNα+ pDC after CpG-ODN treatment from HIV+ donors was comparable with pDC from healthy donors (Fig. 2C). Treatment of PBMCs with THC decreased the number of IFNα-secreting pDC from both healthy and HIV+ donors (Figs. 2D, E). Conversely, the closely related cannabinoid congener CBD, which possesses low affinity for both CB1 and CB2, produced no effect on the percentage of IFNα-secreting cells in response to CpG-ODN activation (Figs. 2D, E). Neither THC nor CBD exhibited cytotoxic effects on pDC at any of the concentrations used in these determinations.

HIV infection, and associated disease states, can cause prolonged stimulation of host immune cells and a chronic inflammatory state which can alter immune cell function. To determine possible differences in THC sensitivity of pDC between HIV+ and healthy donors, PBMCs from HIV+ donors were treated with THC and activated with CpG-ODN, as previously described. Treatment with THC significantly suppressed the number of IFNα-secreting pDCs from HIV+ donors (Fig. 2E), and the degree of suppression was greater than the suppression in pDC from healthy donors (Fig. 2F), indicating more pronounced sensitivity to cannabinoid-mediated suppression in pDC from HIV+ donors.

Back to Top | Article Outline

Δ9-THC Directly Suppressed Secretion of IFNα in Healthy Donors

Given that pDCs are a minor population within the PBMC (Fig. 2A), studies were conducted to determine whether THC acts directly on pDC to suppress IFNα production or indirectly through bystander cell effects. The aforementioned studies were repeated using highly purified pDC (Fig. 3A) which showed that treatment with THC decreased the percent of IFNα-secreting pDCs in a manner comparable with that observed in the PBMC preparation (Fig. 3B), indicating THC acts directly on pDC.

To determine whether THC also suppressed the quantity of total secreted IFNα, LEGENDplex cytometric bead array was used to quantify the amount of IFNα in the cell culture supernatants from purified healthy pDC preparations. THC treatment significantly suppressed the amount of IFNα secreted by the highly purified pDC (Fig. 3C).

Back to Top | Article Outline

THC Directly Suppressed IFNα mRNA Levels by Impairment of Interferon Regulatory Factor 7 Phosphorylation

To determine whether the suppression of IFNα by THC was tied to decreased IFNα mRNA levels, PrimeFlow, a flow cytometry–based method that allows quantification of gene-specific mRNA levels on a per cell basis, was employed (Fig. 4A). THC suppressed the transcription of IFNΑ2, a member of the IFNα gene cassette, in healthy pDC in a manner that paralleled the decrease of secreted IFNα (Fig. 4B).

Honda et al35 demonstrated that phosphorylation of IFN regulatory factor 7 (IRF-7) is a master regulatory event of type I IFN responses. In this study, THC treatment suppressed the phosphorylation of IRF-7 in pDC from healthy and HIV+ donors in a concentration-dependent manner. Treatment with CBD had no effect on healthy pDC, but suppressed pIRF7 in pDC from HIV+ donors (Figs. 4D, E). IFNα mRNA expression is dependent on nuclear translocation of pIRF-7, which is in turn controlled, at least in part, through osteopontin.36 Treatment with both THC and CBD had no significant effect on osteopontin levels in pDC from healthy donors (Fig. 4C).

Back to Top | Article Outline

THC-Suppressed TLR-9–Mediated Induction of Costimulatory Molecule CD83 on pDC From Healthy and HIV+ Donors

CD83 is a surface protein on myeloid lineage cells, including pDCs, which serves as a costimulatory molecule to drive other immune cell activation.37–41 We found that CD83 is expressed early during pDC activation by CpG-ODN (within 6 hours) and that THC suppressed the number of pDC expressing surface CD83 in both healthy and HIV+ donors (Figs. 5A, B). Treatment with CBD did not alter CD83 expression by pDC from healthy donors (Fig. 5A) but did suppress CD83 expression in pDC from HIV+ donors (Fig. 5B).

Back to Top | Article Outline

DISCUSSION

Presented here is the first report of cannabinoid receptor expression and modulation by THC of pDC function. pDC expression of the canonical cannabinoid receptors (CNR1 and CNR2) was found to be comparable with other PBMC, with greater expression of CNR2 than CNR1. We also observed that treatment with THC, and not CBD, caused a concentration-dependent suppression of IFNα secretion by pDC in healthy donors but did have an effect at higher concentrations in pDC from HIV+ donors. Because CBD has much lower affinity for both CB1 and CB2 than THC, suppression of pDC secretion of IFNα by THC suggests the involvement of cannabinoid receptors rather than nonspecific mechanisms. Moreover, THC impaired IFNα secretion by purified pDC, ruling out the possibility for a bystander effect by other cell types. The direct suppression by THC of pDC-secreted IFNα is in agreement with previous findings showing pDC modulation by the endogenous cannabinoid, anandamide.42

The mechanism underlying the modulation of immune cell function by cannabinoids has been partially elucidated by our and other laboratory results.25,27,43 Here, we provide evidence that THC suppresses the phosphorylation of IRF-7, the master regulator of IFNα secretion, in pDC and that this suppression results in the loss of IFNα gene transcription. IRF-7 can be phosphorylated by Interleukin-1 Receptor Associated Kinase 1 & 4 (IRAK 1/4),44 phosphoinositide 3-kinase,45 and IκB kinase-α.46 PI3K signaling in particular has been identified in modulation of the innate immune cell response and is a putative target for the development of therapeutics.47 Activation of the cannabinoid receptors has been shown to directly modulate mTOR-AKT-PI3K signaling in neuronal cell differentiation and survival48,49 and disrupt T-cell stimulation by keratinocytes through suppression of the same pathway.50 Given the critical role of PI3K in IFNα secretion in pDC and the conservation of cannabinoid receptor-mediated suppression of mTOR-AKT-PI3K signaling across different cell types, the suppression of the mTOR-AKT-PI3K signaling axis is likely a means by which IFNα secretion is suppressed in pDC by THC. However, a comprehensive phosphoproteomic approach will be needed to elucidate the complexity surrounding the cannabinoid-mediated modulation of this signaling pathway.

pDC from HIV+ donors were found to be more sensitive to suppression by THC compared with pDC from healthy donors. This increased cannabinoid sensitivity may be linked to the significantly higher expression of CNR1 mRNA, and therefore a greater number of CB1 receptors, in PBMC from HIV+ donors compared with healthy donors. The higher expression of CNR1 mRNA might be linked to the chronic inflammatory state experienced by many HIV+ patients, as activation of T cells results in the upregulation of CNR1 and not CNR2.51 Patients with HIV, even those successfully treated by ART, experience a variety of inflammatory conditions (eg, “Leaky Gut Syndrome”) that can lead to systemic inflammation and higher levels of circulating inflammatory cytokines.52,53 It is tempting to speculate that higher levels of inflammatory cytokines lead to increased expression of CNR1, but proinflammatory cytokines can induce expression of both CNR1 and CNR2.54 Furthermore, it is noteworthy that in the current studies, CB1 and CB2 expression was quantified solely at the mRNA level (CNR1 and CNR2, respectively). Additional studies will be needed to confirm these findings at the protein level.

pDC can stimulate other immune cells by secretion of IFNα and through the expression of costimulatory molecules (CD83, CD86, CD80, and HLA-DR).55 Expression of CD83 by pDC has been associated with stimulation of both T and B cells.4 Here, we show that THC can impair CD83 surface expression by pDC within 6 hours after activation by CpG-ODN. Similarly, when CD83 signaling is ablated, dendritic cell induction of T-cell expansion was significantly reduced.38,39 Therefore, our results indicate that cannabinoid-based therapies may diminish pDC activation of the adaptive immune response by suppressing both the secretion of IFNα and the expression of a key costimulatory molecule, CD83. Future studies will reveal whether the suppression of CD83 by THC contributes to a functional deficit in pDC-mediated T-cell effector function.

The use of cannabis remains controversial in both healthy and HIV+ populations. The results presented here suggest that THC directly impairs pDC function, which may further compromise patients with HIV in responding to opportunistic viral infections. However, the actual implications of these results are mixed. HIV-Associated Neurocognitive Disorders (HAND) affect patients with HIV56,57 regardless of ART, and these neurocognitive deficits have been linked with a chronic neuroinflammatory state.52,58 pDCs have been implicated in neuroinflammatory disease,42,59–61 and elevated levels of IFNα in neuronal tissue have been associated with neuroinflammation and neurodegeneration.62,63 Although the direct role of pDC on IFNα levels in the CNS is unclear, the suppression of pDC activation may be protective against neuroinflammation associated with prolonged HIV infection. Furthermore, and consistent with the premise of medicinal marijuana use as potentially neuroprotective, cannabinoids have been shown to help maintain the integrity of the blood–brain barrier in patients with HIV,64 potentially reducing the migration of inflammatory cells from the periphery to the brain.

The data generated from HIV+ donors presented in this article were generated using PBMC provided by male donors exclusively, which comprise 80% of patients with HIV in the United States. However, over 240,000 women are infected with HIV in the United States, and modulation of pDC activity is of particular interest for these patients. Women progress more quickly than men from the establishment of HIV infection to the development of AIDS.65 Interestingly, pDC from women have an augmented IFN response compared with men when stimulated through Toll-like Receptor-7,66 and this difference may underlie the accelerated development of AIDS.65 Collectively, the presented data imply that the use of cannabinoids may be also beneficial for suppressing the activity of the cells, which play a role in the persistent activation of the immune system of patients with HIV who have been successfully treated by ART.

Back to Top | Article Outline

ACKNOWLEDGMENTS

The authors thank Linda Dale for coordinating blood collection from HIV+ donors.

Back to Top | Article Outline

REFERENCES

1. Barchet W, Blasius A, Cella M, et al. Plasmacytoid dendritic cells. Immunologic Res. 2005;32:75–83.
2. Colonna M, Trinchieri G, Liu YJ. Plasmacytoid dendritic cells in immunity. Nat Immunol. 2004;5:1219–1226.
3. Gilliet M, Cao W, Liu YJ. Plasmacytoid dendritic cells: sensing nucleic acids in viral infection and autoimmune diseases. Nat Rev Immunol. 2008;8:594–606.
4. Swiecki M, Colonna M. The multifaceted biology of plasmacytoid dendritic cells. Nat Rev Immunol. 2015;15:471–485.
5. Gerosa F, Gobbi A, Zorzi P, et al. The reciprocal interaction of NK cells with plasmacytoid or myeloid dendritic cells profoundly affects innate resistance functions. J Immunol. 2005;174:727–734.
6. Megjugorac NJ, Young HA, Amrute SB, et al. Virally stimulated plasmacytoid dendritic cells produce chemokines and induce migration of T and NK cells. J Leukoc Biol. 2004;75:504–514.
7. Havenar-Daughton C, Kolumam GA, Murali-Krishna K. Cutting Edge: the direct action of type I IFN on CD4 T cells is critical for sustaining clonal expansion in response to a viral but not a bacterial infection. J Immunol. 2006;176:3315–3319.
8. Anthony DD, Yonkers NL, Post AB, et al. Selective impairments in dendritic cell-associated function distinguish hepatitis C virus and HIV infection. J Immunol. 2004;172:4907–4916.
9. Cha L, Berry CM, Nolan D, et al. Interferon-alpha, immune activation and immune dysfunction in treated HIV infection. Clin Translational Immunol. 2014;3:e10.
10. Kwa S, Kannanganat S, Nigam P, et al. Plasmacytoid dendritic cells are recruited to the colorectum and contribute to immune activation during pathogenic SIV infection in rhesus macaques. Blood. 2011;118:2763–2773.
11. Donaghy H, Gazzard B, Gotch F, et al. Dysfunction and infection of freshly isolated blood myeloid and plasmacytoid dendritic cells in patients infected with HIV-1. Blood. 2003;101:4505–4511.
12. Lapenta C, Santini SM, Proietti E, et al. Type I interferon is a powerful inhibitor of in vivo HIV-1 infection and preserves human CD4+ T cells from virus-induced depletion in SCID mice transplanted with human cells. Virology. 1999;263:78–88.
13. Feldman S, Stein D, Amrute S, et al. Decreased interferon-α production in HIV-infected patients correlates with numerical and functional deficiencies in circulating type 2 dendritic cell precursors. Clin Immunol. 2001;101:201–210.
14. Loré K, Smed-Sörensen A, Vasudevan J, et al. Myeloid and plasmacytoid dendritic cells transfer HIV-1 preferentially to antigen-specific CD4+ T cells. J Exp Med. 2005;201:2023–2033.
15. Donaghy H, Pozniak A, Gazzard B, et al. Loss of blood CD11c+ myeloid and CD11c− plasmacytoid dendritic cells in patients with HIV-1 infection correlates with HIV-1 RNA virus load. Blood. 2001;98:2574–2576.
16. Palella FJ Jr, Delaney KM, Moorman AC, et al. Declining morbidity and mortality among patients with advanced human immunodeficiency virus infection. N Engl J Med. 1998;338:853–860.
17. Ammassari A, Murri R, Pezzotti P, et al. Self-reported symptoms and medication side effects influence adherence to highly active antiretroviral therapy in persons with HIV infection. J Acquir Immune Defic Syndr. 2001;28:445–449.
18. Tang AM, Forrester J, Spiegelman D, et al. Weight loss and survival in HIV-positive patients in the era of highly active antiretroviral therapy. J Acquir Immune Defic Syndr. 2002;31:230–236.
19. Wanke C, Silva M, Knox T, et al. Weight loss and wasting remain common complications in individuals infected with human immunodeficiency virus in the era of highly active antiretroviral therapy. Clin Infect Dis. 2000;31:803–805.
20. Ciesla JA, Roberts JE. Meta-analysis of the relationship between HIV infection and risk for depressive disorders. Am J Psychiatry. 2001;158:725–730.
21. Calcagni E, Elenkov I. Stress system activity, innate and T helper cytokines, and susceptibility to immune-related diseases. Ann N Y Acad Sci. 2006;1069:62–76.
22. Haney M, Gunderson EW, Rabkin J, et al. Dronabinol and marijuana in HIV-positive marijuana smokers: caloric intake, mood, and sleep. J Acquir Immune Defic Syndr. 2007;45:545–554.
23. Abrams DI, Hilton JF, Leiser RJ, et al. Short-term effects of cannabinoids in patients with HIV-1 Infection: A randomized, placebo-controlled clinical trial. Ann Intern Med. 2003;139:258–266.
24. Abrams DI. Potential interventions for HIV/AIDS wasting: an overview. J Acquir Immune Defic Syndr. 2000;25:S74–S80.
25. Klein TW, Newton C, Friedman H. Cannabinoid receptors and immunity. Immunol Today. 1998;19:373–381.
26. Massi P, Vaccani A, Parolaro D. Cannabinoids, immune system and cytokine network. Curr Pharm Des. 2006;12:3135–3146.
27. Tanasescu R, Constantinescu CS. Cannabinoids and the immune system: an overview. Immunobiology. 2010;215:588–597.
28. Mishkin E, Cabral G. Delta-9-tetrahydrocannabinol decreases host resistance to herpes simplex virus type 2 vaginal infection in the B6C3F1 mouse. J Gen Virol. 1985;66:2539–2549.
29. Morahan P, Klykken P, Smith S, et al. Effects of cannabinoids on host resistance to Listeria monocytogenes and herpes simplex virus. Infect Immun. 1979;23:670–674.
30. Buchweitz JP, Karmaus PW, Harkema JR, et al. Modulation of airway responses to influenza A/PR/8/34 by Δ9-tetrahydrocannabinol in C57BL/6 mice. J Pharmacol Exp Ther. 2007;323:675–683.
31. Buchweitz JP, Karmaus PW, Williams KJ, et al. Targeted deletion of cannabinoid receptors CB1 and CB2 produced enhanced inflammatory responses to influenza A/PR/8/34 in the absence and presence of Δ9-tetrahydrocannabinol. J Leukoc Biol. 2008;83:785–796.
32. Croxford JL, Yamamura T. Cannabinoids and the immune system: potential for the treatment of inflammatory diseases? J Neuroimmunol. 2005;166:3–18.
33. Kosel BW, Aweeka FT, Benowitz NL, et al. The effects of cannabinoids on the pharmacokinetics of indinavir and nelfinavir. AIDS. 2002;16:543–550.
34. Brown KN, Trichel A, Barratt-Boyes SM. Parallel loss of myeloid and plasmacytoid dendritic cells from blood and lymphoid tissue in simian AIDS. J Immunol. 2007;178:6958–6967.
35. Honda K, Yanai H, Negishi H, et al. IRF-7 is the master regulator of type-I interferon-dependent immune responses. Nature. 2005;434:772–777.
36. Shinohara ML, Lu L, Bu J, et al. Osteopontin expression is essential for interferon-α production by plasmacytoid dendritic cells. Nat Immunol. 2006;7:498–506.
37. Fujimoto Y, Tedder TF. CD83: a regulatory molecule of the immune system with great potential for therapeutic application. J Med Dental Sci. 2006;53:85.
38. Hirano N, Butler MO, Xia Z, et al. Engagement of CD83 ligand induces prolonged expansion of CD8+ T cells and preferential enrichment for antigen specificity. Blood. 2006;107:1528–1536.
39. Pinho MP, Migliori IK, Flatow EA, et al. Dendritic cell membrane CD83 enhances immune responses by boosting intracellular calcium release in T lymphocytes. J Leukoc Biol. 2014;95:755–762.
40. Zhou L-J, Tedder TF. Human blood dendritic cells selectively express CD83, a member of the immunoglobulin superfamily. J Immunol. 1995;154:3821–3835.
41. Lechmann M, Berchtold S, Steinkasserer A, et al. CD83 on dendritic cells: more than just a marker for maturation. Trends Immunol. 2002;23:273–275.
42. Chiurchiu V, Cencioni MT, Bisicchia E, et al. Distinct modulation of human myeloid and plasmacytoid dendritic cells by anandamide in multiple sclerosis. Ann Neurol. 2013;73:626–636.
43. Kaplan BLF, Rockwell CE, Kaminski NE. Evidence for cannabinoid receptor-dependent and-independent mechanisms of action in leukocytes. J Pharmacol Exp Ther. 2003;306:1077–1085.
44. Honda K, Yanai H, Mizutani T, et al. Role of a transductional-transcriptional processor complex involving MyD88 and IRF-7 in Toll-like receptor signaling. Proc Natl Acad Sci U S A. 2004;101:15416–15421.
45. Guiducci C, Ghirelli C, Marloie-Provost MA, et al. PI3K is critical for the nuclear translocation of IRF-7 and type I IFN production by human plasmacytoid predendritic cells in response to TLR activation. J Exp Med. 2008;205:315–322.
46. Hoshino K, Sugiyama T, Matsumoto M, et al. IκB kinase-α is critical for interferon-α production induced by Toll-like receptors 7 and 9. Nature. 2006;440:949–953.
47. Weichhart T, Säemann M. The PI3K/Akt/mTOR pathway in innate immune cells: emerging therapeutic applications. Ann Rheum Dis. 2008;67(suppl 3):iii70–iii74.
48. Gomez O, Sanchez-Rodriguez A, Le M, et al. Cannabinoid receptor agonists modulate oligodendrocyte differentiation by activating PI3K/Akt and the mammalian target of rapamycin (mTOR) pathways. Br J Pharmacol. 2011;163:1520–1532.
49. Molina-Holgado E, Vela JM, Arévalo-Marti[Combining Acute Accent]n A, et al. Cannabinoids promote oligodendrocyte progenitor survival: involvement of cannabinoid receptors and phosphatidylinositol-3 kinase/Akt signaling. J Neurosci. 2002;22:9742–9753.
50. Chiurchiù V, Rapino C, Talamonti E, et al. Anandamide suppresses proinflammatory T cell responses in vitro through Type-1 cannabinoid receptor–mediated mTOR inhibition in human keratinocytes. J Immunol. 2016;197:3545–3553.
51. Börner C, Bedini A, Höllt V, et al. Analysis of promoter regions regulating basal and interleukin-4-inducible expression of the human CB1 receptor gene in T lymphocytes. Mol Pharmacol. 2008;73:1013–1019.
52. Ipp H, Zemlin A. The paradox of the immune response in HIV infection: when inflammation becomes harmful. Clinica Chim Acta. 2013;416:96–99.
53. Kaul M. HIV-1 associated dementia: update on pathological mechanisms and therapeutic approaches. Curr Opin Neurol. 2009;22:315.
54. Jean-Gilles L, Braitch M, Latif ML, et al. Effects of pro-inflammatory cytokines on cannabinoid CB1 and CB2 receptors in immune cells. Acta Physiol. 2015;214:63–74.
55. Jarrossay D, Napolitani G, Colonna M, et al. Specialization and complementarity in microbial molecule recognition by human myeloid and plasmacytoid dendritic cells. Eur J Immunol. 2001;31:3388–3393.
56. Heaton RK, Franklin DR, Ellis RJ, et al. HIV-associated neurocognitive disorders before and during the era of combination antiretroviral therapy: differences in rates, nature, and predictors. J Neurovirol. 2011;17:3–16.
57. Rumbaugh JA, Tyor W. HIV-associated neurocognitive disorders five new things. Neurol Clin Pract. 2015;5:224–231.
58. Gannon P, Khan MZ, Kolson DL. Current understanding of HIV-associated neurocognitive disorders pathogenesis. Curr Opin Neurol. 2011;24:275.
59. Longhini AL, von Glehn F, Brandão CO, et al. Plasmacytoid dendritic cells are increased in cerebrospinal fluid of untreated patients during multiple sclerosis relapse. J neuroinflammation. 2011;8:2.
60. McMahon EJ, Bailey SL, Miller SD. CNS dendritic cells: critical participants in CNS inflammation? Neurochem Int. 2006;49:195–203.
61. Pashenkov M, Huang YM, Kostulas V, et al. Two subsets of dendritic cells are present in human cerebrospinal fluid. Brain. 2001;124:480–492.
62. Sas AR, Bimonte-Nelson H, Smothers CT, et al. Interferon-α causes neuronal dysfunction in encephalitis. J Neurosci. 2009;29:3948–3955.
63. Sas AR, Bimonte-Nelson HA, Tyor WR. Cognitive dysfunction in HIV encephalitic SCID mice correlates with levels of Interferon-α in the brain. AIDS. 2007;21:2151–2159.
64. Lu TS, Avraham HK, Seng S, et al. Cannabinoids inhibit HIV-1 Gp120-mediated insults in brain microvascular endothelial cells. J Immunol. 2008;181:6406–6416.
65. Meier A, Chang JJ, Chan ES, et al. Sex differences in the Toll-like receptor–mediated response of plasmacytoid dendritic cells to HIV-1. Nat Med. 2009;15:955–959.
66. Berghöfer B, Frommer T, Haley G, et al. TLR7 ligands induce higher IFN-α production in females. J Immunol. 2006;177:2088–2096.
Keywords:

plasmacytoid dendritic cells; interferon-α; cannabinoid receptors; 9-tetrahydrocannabinol">Δ9-tetrahydrocannabinol; medical marijuana; interferon regulatory factor 7

Copyright © 2017 Wolters Kluwer Health, Inc. All rights reserved.