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Published on: January 5, 2016
Upregulated IL-32 Expression And Reduced Gut Short Chain Fatty Acid Caproic Acid in People Living With HIV With
Mohamed El-Far1, Madeleine Durand1,2, Isabelle Turcotte1,2
1University of Montreal Hospital Centre (CRCHUM)-Research Centre, Montréal, QC, Canada.
Insights
People living with HIV (PLWH) show increased cardiovascular disease risk due to chronic inflammation. Specific IL-32 isoforms and gut microbiome changes contribute to this HIV-specific inflammatory signature, offering potential therapeutic targets.
Area of Science:
- Immunology
- Cardiovascular Medicine
- Microbiome Research
Background:
- Antiretroviral therapy (ART) reduces HIV progression but doesn't eliminate cardiovascular disease (CVD) risk in people living with HIV (PLWH).
- Chronic inflammation persists in PLWH, contributing to higher CVD rates.
- Novel inflammatory mediators are needed as biomarkers and therapeutic targets for CVD in PLWH.
Purpose of the Study:
- To investigate the expression and role of Interleukin-32 (IL-32) isoforms in subclinical atherosclerosis among PLWH.
- To identify inflammatory signatures associated with CVD in PLWH.
- To explore the link between IL-32, gut microbiome, and CVD risk in PLWH.
Main Methods:
- Compared IL-32 isoform expression in peripheral blood of PLWH with and without subclinical atherosclerosis versus HIV- controls.
- Analyzed plasma levels of IL-18, IL-1β, and TRAIL.
- Performed in vitro studies on macrophage activation and analyzed gut microbiome and short-chain fatty acid (SCFA) profiles.
Main Results:
- All IL-32 isoforms were higher in PLWH; IL-32D and IL-32θ were upregulated in PLWH with atherosclerosis.
- Upregulation of IL-32 isoforms correlated with increased IL-18/IL-1β and decreased TRAIL, forming an HIV-specific inflammatory signature.
- IL-32 isoforms were associated with altered gut microbiome and reduced caproic acid, which inhibited IL-32 production.
Conclusions:
- Identified a unique atherosclerotic inflammatory signature in PLWH involving specific IL-32 isoforms.
- Demonstrated that caproic acid, a gut metabolite, can regulate this inflammatory signature.
- Suggests IL-32 and caproic acid as potential therapeutic targets for preventing CVD in ART-treated PLWH.
Abstract:
Despite the success of antiretroviral therapy (ART), people living with HIV (PLWH) are still at higher risk for cardiovascular diseases (CVDs) that are mediated by chronic inflammation. Identification of novel inflammatory mediators with the inherent potential to be used as CVD biomarkers and also as therapeutic targets is critically needed for better risk stratification and disease management in PLWH. Here, we investigated the expression and potential role of the multi-isoform proinflammatory cytokine IL-32 in subclinical atherosclerosis in PLWH (n=49 with subclinical atherosclerosis and n=30 without) and HIV- controls (n=25 with subclinical atherosclerosis and n=24 without). While expression of all tested IL-32 isoforms (α, β, γ, D, ϵ, and θ) was significantly higher in peripheral blood from PLWH compared to HIV- controls, IL-32D and IL-32θ isoforms were further upregulated in HIV+ individuals with coronary artery atherosclerosis compared to their counterparts without. Upregulation of these two isoforms was associated with increased plasma levels of IL-18 and IL-1β and downregulation of the atheroprotective protein TRAIL, which together composed a unique atherosclerotic inflammatory signature specific for PLWH compared to HIV- controls. Logistic regression analysis demonstrated that modulation of these inflammatory variables was independent of age, smoking, and statin treatment. Furthermore, our in vitro functional data linked IL-32 to macrophage activation and production of IL-18 and downregulation of TRAIL, a mechanism previously shown to be associated with impaired cholesterol metabolism and atherosclerosis. Finally, increased expression of IL-32 isoforms in PLWH with subclinical atherosclerosis was associated with altered gut microbiome (increased pathogenic bacteria; Rothia and Eggerthella species) and lower abundance of the gut metabolite short-chain fatty acid (SCFA) caproic acid, measured in fecal samples from the study participants. Importantly, caproic acid diminished the production of IL-32, IL-18, and IL-1β in human PBMCs in response to bacterial LPS stimulation. In conclusion, our studies identified an HIV-specific atherosclerotic inflammatory signature including specific IL-32 isoforms, which is regulated by the SCFA caproic acid and that may lead to new potential therapies to prevent CVD in ART-treated PLWH.
