Class I histone deacetylase inhibition improves pancreatitis outcome by limiting leukocyte recruitment and acinar‐to‐ductal metaplasia

Abstract

BACKGROUND AND PURPOSEPancreatitis is a common inflammation of the pancreas with rising incidence in many countries. Despite improvements in diagnostic techniques, the disease is associated with high risk of severe morbidity and mortality and there is an urgent need for new therapeutic interventions. In this study, we evaluated whether histone deacetylases (HDACs), key epigenetic regulators of gene transcription, are involved in the development of the disease. EXPERIMENTAL APPROACHWe analysed HDAC regulation during cerulein-induced acute, chronic and autoimmune pancreatitis using different transgenic mouse models. The functional relevance of class I HDACs was tested with the selective inhibitor MS-275 in vivo upon pancreatitis induction and in vitro in activated macrophages and primary acinar cell explants. KEY RESULTSHDAC expression and activity were up-regulated in a time-dependent manner following induction of pancreatitis, with the highest abundance observed for class I HDACs. Class I HDAC inhibition did not prevent the initial acinar cell damage. However, it effectively reduced the infiltration of inflammatory cells, including macrophages and T cells, in both acute and chronic phases of the disease, and directly disrupted macrophage activation. In addition, MS-275 treatment reduced DNA damage in acinar cells and limited acinar de-differentiation into acinar-to-ductal metaplasia in a cell-autonomous manner by impeding the EGF receptor signalling axis. CONCLUSIONS AND IMPLICATIONSThese results demonstrate that class I HDACs are critically involved in the development of acute and chronic forms of pancreatitis and suggest that blockade of class I HDAC isoforms is a promising target to improve the outcome of the disease. IntroductionAbnormal activity of histone deacetylases (HDACs), a family of enzymes involved in the epigenetic control of gene transcription, has been implicated in the aetiology and development of several malignancies. However, recent evidence indicates that HDACs are also involved in the development of inflammatory diseases, highlighting the potential of targeting the activity of HDACs as a therapeutic approach to improve the outcome of rheumatoid arthritis (Choo et al., 2010(Choo et al., , 2013, neuritis (Zhang et al., 2010;Zhang and Schluesener, 2013), cholitis (Felice et al., 2015) and autoimmunity (Hancock et al., 2012).HDACs control the acetylation status of histone and non-histone proteins, thus regulating the expression of target genes (reviewed in Delcuve et al., 2012). The complexity of acetylation-based epigenetic regulation is reflected by the size of the mammalian HDAC family, composed of 11 zinc-dependent enzymes divided into three subfamilies (classes I, II and IV) and seven NAD-dependent enzymes in a fourth (sirtuin) subfamily (class III), with non-redundant functions.The function of HDAC subfamilies in the pathophysiology of pancreatitis, a highly debilitating inflammatory disease with a potentially lethal outcome, has not been thoroughly investigated. During pancreatitis, the ...

The role of the interleukin‐1 family in trained immunity

“…Since trained immunity is characterized by metabolic and epigenetic rewiring of innate immune cells, using epigenetic drugs such as lysine methyltransferase‐ or histone deacetylase (HDAC) inhibitors could, for example, prove a valuable treatment strategy. Epigenetic drugs are slowly spreading from oncology into other fields, and there have already been several small studies in which the efficacy of HDAC inhibitors for treating inflammatory diseases was investigated . In one of these studies, HDAC inhibition yielded clinical benefits for patients with the IL‐1‐driven Schnitzler syndrome .…”

“…Epigenetic drugs are slowly spreading from oncology into other fields, and there have already been several small studies in which the efficacy of HDAC inhibitors for treating inflammatory diseases was investigated. [91][92][93] In one of these studies, HDAC inhibition yielded clinical benefits for patients with the IL-1-driven Schnitzler syndrome. 91 As for the metabolic reprogramming of trained cells, there are examples of animal models in which metabolic inhibitors have been used to treat inflammatory diseases.…”

Inhibition of Class I Histone Deacetylases Abrogates Tumor Growth FactorβExpression and Development of Fibrosis during Chronic Pancreatitis

“…Houston,TX) was injected intraperitoneally at 20 mg/kg every 2nd day for 2 weeks, starting concomitantly (preventive regimen) or 1 week after the beginning of cerulein injections (therapeutic regimen). The concentration of MS-275 was chosen based on previously published in vivo studies using the inhibitor in mice (Dalgard et al, 2008;Nguyên et al, 2008;Murphy et al, 2014;Bombardo et al, 2017). Control animals received 10% dimethylsulfoxide injections.…”

“…In this study, we evaluated whether administration of MS-275 (also known as entinostat), a selective inhibitor of class 1 histone deacetylases (HDACs), counteracts the development of pancreatic fibrosis using the widespread murine model of cerulein-induced chronic pancreatitis. The rationale for this approach was 3-fold: 1) development of fibrosis activates a substantial gene regulation, which is prominently orchestrated by epigenetic mechanisms (McDonnell et al, 2014;Weigel et al, 2015;Yang and Schwartz, 2015;Moran-Salvador and Mann, 2017); 2) HDACs are critical epigenetic regulators, and expression of class 1 HDACs is significantly upregulated during the course of chronic pancreatitis (Bombardo et al, 2017); and 3) pharmacologic inhibitors of HDAC activity, originally developed as anticancer agents, are currently being investigated for their antifibrotic properties in different fibrotic diseases (recently reviewed in Pang and Zhuang, 2010;Royce et al, 2014;Chen et al, 2015;Schuetze et al, 2016).…”

Ca²⁺-Activated K⁺ Channel K_Ca3.1 as a Therapeutic Target for Immune Disorders

“…Histone deacetylase inhibitors are expected to be potentially therapeutic against autoimmune diseases such as type I diabetes, MS, pancreatitis, and IBD. [34][35][36][37] For instance, HDAC isoforms such as HDAC2, HDAC3, and HDAC6 are involved in chronic intestinal inflammation, and pan-HDAC inhibitors (HDACis) suppress pro-inflammatory cytokine production such as IL-6, tumor necrosis factor α (TNF-α), and interferon γ (IFN-γ). 37) In K Ca 3.1-expressing breast and prostate cancer cells, pharmacological and small interfering RNA (siRNA)- mediated inhibition of HDAC2 and HDAC3 resulted in the down-regulation of K Ca 3.1.…”