Cannabinoids shift the basal ganglia microRNA m 6 A methylation profile towards an anti-inflammatory phenotype in SIV-infected rhesus macaques

Chioma M Okeoma; Lakmini S Premadasa; Chen S Tan; Ionita C Ghiran; Mahesh Mohan

doi:10.1038/s42003-025-09049-w

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Cannabinoids shift the basal ganglia microRNA m 6 A methylation profile towards an anti-inflammatory phenotype in SIV-infected rhesus macaques

Chioma M Okeoma, Lakmini S Premadasa, Chen S Tan, Ionita C Ghiran and Mahesh Mohan

Communications biology, Vol.8(1), 1659

11/24/2025

DOI: 10.1038/s42003-025-09049-w

PMCID: PMC12644866

PMID: 41286161

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Abstract

Epitranscriptomic modifications [N6-methyladenosine (m6A)] regulate various diseases, including cancer and inflammation. Despite their functional relevance in neural development and differentiation, the role of m6A modifications in HIV neuropathogenesis is unknown. Using anti-N6-methyladenosine (m6A) antibody-immunoprecipitation and microarray profiling, we identified m6A modifications in miRNAs in basal ganglia (BG) of uninfected (VEH) and SIV-infected Rhesus macaques (RMs) on combination anti-retroviral therapy (ART) and either VEH-treated (VEH/SIV/ART) or THC:CBD-treated (THC:CBD/SIV/ART). HIV/SIV infection promoted an overall hypomethylated miRNA m6A profile. While THC:CBD did not significantly impact the overall hypomethylated m6A profile, specific miRNAs predicted to target proinflammatory genes showed marked m6A hypomethylation compared to VEH-treated RMs. Additionally, specific BG m6A-modified miRNAs were detected in BG-derived extracellular vesicles. Mechanistically, the DRACH motif in the miR-194-5p seed region was significantly m6A hypomethylated in THC:CBD/SIV/ART RMs. Unlike wild-type, in-vitro transfected m6A-modified miR-194-5p mimics failed to downregulate STAT1 protein expression. Further, compared to VEH/SIV/ART RMs, THC:CBD significantly reduced m6A methylation of 44 miRNAs directly involved in regulating CNS network genes. Our findings indicate that m6A epi-transcriptomic marks in the seed nucleotides can impair miRNA function and that cannabinoids may preserve it by reducing m6A methylation levels, thus providing a mechanistic explanation underlying their anti-neuroinflammatory effects in HIV/SIV infection.

Phenotype

Adenosine - analogs & derivatives

Adenosine - metabolism

Animals

Anti-Inflammatory Agents - pharmacology

Basal Ganglia - drug effects

Basal Ganglia - metabolism

Cannabinoids - pharmacology

Macaca mulatta

Male

Methylation

MicroRNAs - genetics

MicroRNAs - metabolism

Simian Acquired Immunodeficiency Syndrome - drug therapy

Simian Acquired Immunodeficiency Syndrome - genetics

Simian Acquired Immunodeficiency Syndrome - metabolism

Simian Acquired Immunodeficiency Syndrome - virology

Simian Immunodeficiency Virus

Details

Title: Subtitle: Cannabinoids shift the basal ganglia microRNA m 6 A methylation profile towards an anti-inflammatory phenotype in SIV-infected rhesus macaques
Creators: Chioma M Okeoma - New York Medical College
Lakmini S Premadasa - Texas Biomedical Research Institute
Chen S Tan - University of Iowa
Ionita C Ghiran - Beth Israel Deaconess Medical Center
Mahesh Mohan - Texas Biomedical Research Institute
Resource Type: Journal article
Publication Details: Communications biology, Vol.8(1), 1659
DOI: 10.1038/s42003-025-09049-w
PMID: 41286161
PMCID: PMC12644866
eISSN: 2399-3642
Publisher: Springer Nature
Grant note: R01DA042348 / U.S. Department of Health & Human Services | National Institutes of Health (NIH) S10OD032443 / U.S. Department of Health & Human Services | National Institutes of Health (NIH) R21/R33DA053643 / U.S. Department of Health & Human Services | National Institutes of Health (NIH) R01CA218500 / U.S. Department of Health & Human Services | National Institutes of Health (NIH) R01DA052845 / U.S. Department of Health & Human Services | National Institutes of Health (NIH) R01TR218500 / U.S. Department of Health & Human Services | National Institutes of Health (NIH) R01DA050169 / U.S. Department of Health & Human Services | National Institutes of Health (NIH) P30AI161943 / U.S. Department of Health & Human Services | National Institutes of Health (NIH) S10OD028732 / U.S. Department of Health & Human Services | National Institutes of Health (NIH) P51OD111033 / U.S. Department of Health & Human Services | National Institutes of Health (NIH)
Language: English
Date published: 11/24/2025
Academic Unit: Microbiology and Immunology; Infectious Diseases; Iowa Neuroscience Institute; Internal Medicine
Record Identifier: 9985035031602771

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