Long Term Delta-9-tetrahydrocannabinol Administration Inhibits Proinflammatory Responses in Minor Salivary Glands of Chronically Simian Immunodeficieny Virus Infected Rhesus Macaques.

Xavier Alvarez,Mahesh Mohan,Karol Sestak,Siddappa N Byrareddy

doi:10.3390/v12070713

Abstract

HIV/SIV-associated oral mucosal disease/dysfunction (HAOMD) (gingivitis/periodontitis/salivary adenitis) represents a major comorbidity affecting HIV patients on anti-retroviral therapy. Using a systems biology approach, we investigated molecular changes (mRNA/microRNA) underlying HAOMD and its modulation by phytocannabinoids (delta-9-tetrahydrocannabinol (∆9-THC)) in uninfected (n = 5) and SIV-infected rhesus macaques untreated (VEH-untreated/SIV; n = 7) or treated with vehicle (VEH/SIV; n = 3) or ∆9-THC (THC/SIV; n = 3). Relative to controls, fewer mRNAs were upregulated in THC/SIV compared to VEH-untreated/SIV macaques. Gene enrichment analysis showed differential enrichment of biological functions involved in anti-viral defense, Type-I interferon, Toll-like receptor, RIG-1 and IL1R signaling in VEH-untreated/SIV macaques. We focused on the anti-ER-stress anterior gradient-2 (AGR2), epithelial barrier protecting and anti-dysbiotic WAP Four-Disulfide Core Domain-2 (WFDC2) and glucocorticoid-induced anti-inflammatory TSC22D3 (TSC22-domain family member-3) that were significantly downregulated in oropharyngeal mucosa (OPM) of VEH-untreated/SIV macaques. All three proteins localized to minor salivary gland acini and secretory ducts and showed enhanced and reduced expression in OPM of THC/SIV and VEH/SIV macaques, respectively. Additionally, inflammation associated miR-21, miR-142-3p and miR-29b showed significantly higher expression in OPM of VEH-untreated/SIV macaques. TSC22D3 was validated as a target of miR-29b. These preliminary translational findings suggest that phytocannabinoids may safely and effectively reduce oral inflammatory responses in HIV/SIV and other (autoimmune) diseases.

Highlights

Innate and adaptive immune functions are maintained in the oral mucosa during acute HIV/SIV infection, these responses become markedly impaired during chronic HIV infection and are not fully restored by combination anti-retroviral therapy [1,2,3,4,5,6]
We demonstrated the anti-inflammatory effects of cannabinoids in the distal gastrointestinal (GI) tract of SIV-infected rhesus macaques [24,25,26], its impact on the upper GI tract, especially on HIV/SIV-induced oral mucosal inflammation, remained to be determined
We demonstrate the ability of miR-29b, a miRNA significantly upregulated in oropharyngeal mucosa (OPM) of SIV-infected rhesus macaques, to post-transcriptionally regulate TSC22D3 expression

Summary

Introduction

Innate and adaptive immune functions are maintained in the oral mucosa during acute HIV/SIV infection, these responses become markedly impaired during chronic HIV infection and are not fully restored by combination anti-retroviral therapy [1,2,3,4,5,6]. In addition to cytokines and transcription factors, recent studies show miRNA-mediated gene regulation to play critical roles in the pathogenesis of periodontitis (PO), Sjogren (Sjs), Oral lichen planus (OLP) and oral malignancy [17,18,19,20]. In this regard, a causal relationship between dysregulated miRNA (miR-146a, miR-30 and miR-155) expression and periodontitis has been proposed for further investigation [21,22,23]. It is striking that miRNA-mediated dysregulation of gene expression in the oral cavity during the course of HIV/SIV infection remains unknown and unaddressed

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Conclusion