Journal article
Differential Effects of Cannabinoid Receptor 2 Agonists on HIV Replication and Inflammatory Activation in Monocyte-Derived Macrophages and Induced Pluripotent Stem Cell-Derived Microglia
Journal of neuroimmune pharmacology, v 20(1), 87
11 Oct 2025
PMID: 41075102
Featured in Collection : UN Sustainable Development Goals @ Drexel
Abstract
Emerging evidence suggests brain-resident myeloid cells, including perivascular macrophages and microglia, provide a reservoir for HIV infection in the central nervous system (CNS), and their inflammatory activation is a proposed pathogenic mechanism in HIV-associated neurocognitive disorders (HAND). We investigated whether cannabinoid receptor 2 (CB
), an immunomodulatory receptor expressed in myeloid cells, regulates viral replication and inflammation in HIV-infected macrophages and microglia. Using the synthetic CB
-specific agonist JWH-133, we found that CB
activation reduced HIV replication in primary human monocyte-derived macrophages (MDMs) and human induced pluripotent stem cell-derived microglia (iMg) at differing doses, corresponding to the basal expression of CNR2, which encodes CB
, and related endocannabinoid transcripts in each cell type. JWH-133 broadly reduced release of cytokines from HIV-infected MDMs but not iMg. RNA-seq revealed that CB
agonism primarily altered interferon and integrated stress response pathways in MDMs while altering homeostatic pathways, including synapse maintenance and phagocytosis, in iMg. Further analyses in iMg revealed that NLRP3 inflammasome activation, but not priming, was reduced by CB
activation, which did not inhibit HIV-induced nuclear factor kB activation. This study identifies key differences in CB
response between myeloid lineage cell types and implicates CB
-specific agonists as promising candidates for the regulation of HIV-associated neuroinflammation.
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Details
- Title
- Differential Effects of Cannabinoid Receptor 2 Agonists on HIV Replication and Inflammatory Activation in Monocyte-Derived Macrophages and Induced Pluripotent Stem Cell-Derived Microglia
- Creators
- Alexander Starr - University of PennsylvaniaSara Rathore - University of PennsylvaniaMarzieh Daniali - Drexel UniversityPeter J Gaskill - Drexel UniversityCagla Akay-Espinoza - University of PennsylvaniaKelly L Jordan-Sciutto (Corresponding Author) - University of Pennsylvania
- Publication Details
- Journal of neuroimmune pharmacology, v 20(1), 87
- Publisher
- Springer Nature
- Number of pages
- 21
- Grant note
- P30AI045008 / NIH HHS T32GM008076 and F31DA054001 / NIH HHS R01DA057337 and R61DA058051 / NIH HHS R21MH129193 / NIH HHS
- Resource Type
- Journal article
- Language
- English
- Academic Unit
- Pharmacology and Physiology
- Web of Science ID
- WOS:001591919400002
- Scopus ID
- 2-s2.0-105018397778
- Other Identifier
- 991022123438704721
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- Collaboration types
- Domestic collaboration
- Web of Science research areas
- Neurosciences
- Pharmacology & Pharmacy