Cannabinoid Enhancement of Lncrna MMP25-AS1/MMP25 Interaction Reduces Neutrophil Infiltration and Intestinal Epithelial Injury in HIV/SIV Infection

Authors

Lakmini S. Premadasa, Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas, USA.
Eunhee Lee, Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas, USA.
Marina McDew-White, Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas, USA.
Xavier Alvarez, Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas, USA.Follow
Sahana Jayakumar, Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas, USA.
Binhua Ling, Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas, USA.
Chioma M. Okeoma, Department of Pathology, Microbiology and Immunology, New York Medical College, Valhalla, New York, USA.
Siddappa N. Byrareddy, Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, USA.
Smita Kulkarni, Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas, USA.
Mahesh Mohan, Southwest National Primate Research Center, Texas Biomedical Research Institute, San Antonio, Texas, USA.

Author Type(s)

Faculty

DOI

10.1172/jci.insight.167903

Journal Title

JCI Insight

Document Type

Article

Publication Date

4-10-2023

Department

Pathology, Microbiology and Immunology

Abstract

Intestinal epithelial barrier dysfunction, a hallmark of HIV/SIV infection, persists despite viral suppression by combination antiretroviral therapy (cART). Emerging evidence suggests a critical role for long noncoding RNAs (lncRNAs) in maintaining epithelial homeostasis. We simultaneously profiled lncRNA/mRNA expression exclusively in colonic epithelium (CE) of SIV-infected rhesus macaques (RMs) administered vehicle (VEH) or Δ-9-tetrahydrocannabinol (THC). Relative to controls, fewer lncRNAs were up- or downregulated in CE of THC/SIV compared with VEH/SIV RMs. Importantly, reciprocal expression of the natural antisense lncRNA MMP25-AS1 (up 2.3-fold) and its associated protein-coding gene MMP25 (attracts neutrophils by inactivating alpha-1 anti-trypsin/SERPINA1) (down 2.2-fold) was detected in CE of THC/SIV RMs. Computational analysis verified 2 perfectly matched complementary regions and an energetically stable (normalized binding free energy = -0.2626) MMP25-AS1/MMP25 duplex structure. MMP25-AS1 overexpression blocked IFN-γ-induced MMP25 mRNA and protein expression in vitro. Elevated MMP25 protein expression in CE of VEH/SIV but not THC/SIV RMs was associated with increased infiltration by myeloperoxidase/CD11b++ neutrophils (transendothelial migration) and epithelial CD47 (transepithelial migration) expression. Interestingly, THC administered in combination with cART increased MMP25-AS1 and reduced MMP25 mRNA/protein expression in jejunal epithelium of SIV-infected RMs. Our findings demonstrate that MMP25-AS1 is a potentially unique epigenetic regulator of MMP25 and that low-dose THC can reduce neutrophil infiltration and intestinal epithelial injury potentially by downregulating MMP25 expression through modulation of MMP25-AS1.

Recommended Citation

Premadasa, L. S., Lee, E., McDew-White, M., Alvarez, X., Jayakumar, S., Ling, B., Okeoma, C. M., Byrareddy, S. N., Kulkarni, S., & Mohan, M. (2023). Cannabinoid Enhancement of Lncrna MMP25-AS1/MMP25 Interaction Reduces Neutrophil Infiltration and Intestinal Epithelial Injury in HIV/SIV Infection. JCI Insight, 8 (7). https://doi.org/10.1172/jci.insight.167903