Cannabinoid enhancement of lncRNA MMP25-AS1/MMP25 interaction reduces neutrophil infiltration and intestinal epithelial injury in HIV/SIV infection
Lakmini S. Premadasa, Eunhee Lee, Marina McDew-White, Xavier Alvarez, Sahana Jayakumar, Binhua Ling, Chioma M. Okeoma, Siddappa N. Byrareddy, Smita Kulkarni, Mahesh Mohan
Lakmini S. Premadasa, Eunhee Lee, Marina McDew-White, Xavier Alvarez, Sahana Jayakumar, Binhua Ling, Chioma M. Okeoma, Siddappa N. Byrareddy, Smita Kulkarni, Mahesh Mohan
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Research Article AIDS/HIV

Cannabinoid enhancement of lncRNA MMP25-AS1/MMP25 interaction reduces neutrophil infiltration and intestinal epithelial injury in HIV/SIV infection

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.

Authors

Lakmini S. Premadasa, Eunhee Lee, Marina McDew-White, Xavier Alvarez, Sahana Jayakumar, Binhua Ling, Chioma M. Okeoma, Siddappa N. Byrareddy, Smita Kulkarni, Mahesh Mohan

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Figure 1

Changes in the colonic epithelial lncRNA landscape in response to HIV/SIV infection and THC administration.

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Changes in the colonic epithelial lncRNA landscape in response to HIV/SI...
Volcano plots show the relationship between fold-change (x axis) and statistical significance (y axis) of DE lncRNAs in the CE of VEH/SIV (n = 5) (A) and THC/SIV (n = 6) (B) relative to control (n = 6) RMs and VEH/SIV relative to THC/SIV RMs (C). The negative log of statistical significance (P value) (base 10) is plotted on the y axis, and the log of the fold-change (base 2) is plotted on the x axis. Notable DE lncRNAs are shown in the volcano plots. The total number of DE (up- and downregulated) lncRNAs in each treatment group is shown (D). Venn diagram illustrates the overlap between the DE lncRNAs (black, upregulated; red, downregulated) in the 3 treatment groups (E). Distribution of the 6 classes of lncRNAs based on the genomic region of origin within each comparison (F).