HDAC inhibitors modulate innate immune responses to micro-organisms relevant to chronic mucocutaneous candidiasis

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.

Chronic Mucocutaneous Candidiasis in Early Life: Insights Into Immune Mechanisms and Novel Targeted Therapies

“…Inhibition of histone acetylation is thought to affect the adaptive and innate immune systems. Indeed, HDAC inhibitors were found to rescue STAT3-mediated pathways in STAT1 GOF patients (49). Moreover, in-vitro treatment with HDAC inhibitors resulted in increased IL-22 production in response to Candida spp.…”

“…Moreover, in-vitro treatment with HDAC inhibitors resulted in increased IL-22 production in response to Candida spp. (49).…”

Post-Translational Modifications in Atopic Dermatitis: Current Research and Clinical Relevance

“…Interestingly, the lysine-acetylation of STAT could activate STAT phosphorylation directly, except JAK-induced phosphorylation ( Krämer et al, 2009 ; Zhuang, 2013 ). It is promising that HDAC inhibitors provide synergistic effects on JAK inhibitors in AD treatment ( Quintás-Cardama et al, 2012 ; Rösler et al, 2018 ; Su et al, 2021 ).…”

Central metabolic interactions of immune cells and microbes: prospects for defeating infections

“…Histone deacetylase inhibitors (HDACi), some of which are approved for cancer treatment, also reduce inflammation in fungal and bacterial infections [117]. Histone deacetylase inhibitors (HDACi), some of which are approved for cancer treatment, also reduce inflammation in fungal and bacterial infections [117].…”

“…Another approach is to control chromatin modification enzymes. Histone deacetylase inhibitors (HDACi), some of which are approved for cancer treatment, also reduce inflammation in fungal and bacterial infections [117]. Whether this is solely due to changes in histone acetylation and gene expression, or also involves the many non-histone targets of HDACs, awaits confirmation.…”