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Published on: November 3, 2014
HDAC inhibitors modulate innate immune responses to micro-organisms relevant to chronic mucocutaneous candidiasis
B Rösler1, X Wang1,2, S T Keating1
1Department of Internal Medicine, Radboud Center for Infectious diseases (RCI), Radboud UMC, Nijmegen, the Netherlands.
Abstract:
Signal transducer and activator of transcription 1 (STAT-1) gain-of-function (GOF) mutations cause chronic mucocutaneous candidiasis (CMC), a disease associated with Candida albicans and Staphylococcus aureus infection. Patients suffer from dysegulated immune responses due to aberrant cell programming and function. We investigated the effect of inhibitory molecules targeting histone deacetylases (HDACi) on the immune responses of peripheral blood mononuclear cells (PBMCs) of healthy controls and patients with CMC towards microbes relevant for CMC. PBMCs cells were pretreated with HDACi and challenged with C. albicans or S. aureus. Innate and adaptive cytokines were measured in cell culture supernatants by enzyme-linked immunosorbent assay (ELISA). We assessed the effect of HDAC inhibitors on T helper type 1 (Th1) and Th17 cells and measured STAT-1 and STAT-3 phosphorylation using flow cytometry. Panobinostat, a pan-HDAC inhibitor, strongly inhibits innate and adaptive cytokines upon challenge with C. albicans or S. aureus. Specific inhibitors (entinostat or RGFP966) also had a tendency to lower production of most innate cytokines in CMC patient cells. Entinostat and RGFP966 increased the production of interleukin (IL)-22 specifically after S. aureus challenge in patient cells. In healthy and control cells, entinostat and RGFP966 treatment down-regulated STAT-1 phosphorylation while pSTAT-3 levels remained stable. HDACi modulate cytokine production in response to C. albicans and S. aureus. Pan-inhibitors lower overall cytokine production, whereas specific inhibitors confer a selective effect. Entinostat and RGFP966 are promising therapeutic candidates to treat STAT-1 GOF due to their capacity to restore IL-22 production and decrease STAT-1 phosphorylation; however, their inhibition of innate cytokines poses a possible risk to secondary infections.
Insights
Histone deacetylase inhibitors (HDACi) modulate immune responses in patients with STAT-1 gain-of-function mutations. Specific HDACi like entinostat and RGFP966 show promise for restoring IL-22 production and decreasing STAT-1 phosphorylation, but may increase infection risk.
Area of Science:
- Immunology
- Molecular Biology
- Pharmacology
Background:
- Gain-of-function mutations in Signal Transducer and Activator of Transcription 1 (STAT-1 GOF) lead to immune dysregulation and susceptibility to Candida albicans and Staphylococcus aureus infections.
- Chronic mucocutaneous candidiasis (CMC) is a primary immunodeficiency characterized by impaired host defense against fungal and bacterial pathogens.
Purpose of the Study:
- To investigate the therapeutic potential of histone deacetylase inhibitors (HDACi) in modulating immune responses in STAT-1 GOF patients.
- To evaluate the effects of specific and pan-HDAC inhibitors on cytokine production and STAT phosphorylation in response to microbial challenges.
Main Methods:
- Peripheral blood mononuclear cells (PBMCs) from healthy donors and CMC patients were pre-treated with HDAC inhibitors (panobinostat, entinostat, RGFP966).
- Cells were subsequently challenged with C. albicans or S. aureus.
- Cytokine levels (innate and adaptive) were quantified using ELISA.
- STAT-1 and STAT-3 phosphorylation was assessed via flow cytometry.
Main Results:
- Panobinostat significantly inhibited innate and adaptive cytokine production against both pathogens.
- Specific inhibitors (entinostat, RGFP966) showed a trend towards lowering innate cytokine production in CMC patient cells.
- Entinostat and RGFP966 enhanced Interleukin-22 (IL-22) production specifically after S. aureus challenge in patient cells.
- These specific inhibitors reduced STAT-1 phosphorylation in healthy cells while pSTAT-3 levels remained unchanged.
Conclusions:
- HDAC inhibitors differentially modulate cytokine profiles in response to microbial stimuli.
- Specific HDAC inhibitors like entinostat and RGFP966 demonstrate potential for treating STAT-1 GOF by restoring IL-22 and reducing STAT-1 phosphorylation.
- The immunosuppressive effects of pan-HDAC inhibitors and potential risks of reduced innate immunity warrant careful consideration for therapeutic application.
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