• Chronic prostatitis/chronic pelvic pain syndrome
• Etiological mechanism
• Prostatitis
• Research progress
• Review

• Humans
• Male
• Prostatitis/etiology
• Prostatitis/epidemiology
• Pelvic Pain/etiology
• Risk Factors
• Chronic Disease
• Chronic Pain/etiology
• Animals
• Syndrome

• Adipose-derived stem cells
• Chronic prostatitis/chronic pelvic pain syndrome
• Click chemistry
• Macrophage
• Small extracellular vesicles

• Prostatitis/therapy
• Prostatitis/pathology
• Prostatitis/metabolism
• Prostatitis/immunology
• Male
• Extracellular Vesicles/transplantation
• Extracellular Vesicles/metabolism
• Macrophages/metabolism
• Macrophages/immunology
• Animals
• Pelvic Pain/therapy
• MicroRNAs/genetics
• MicroRNAs/metabolism
• Mice
• Mesenchymal Stem Cells/metabolism
• Humans
• Adipose Tissue/cytology
• B7-2 Antigen/metabolism
• B7-2 Antigen/genetics

• bayesian-weighted mendelian randomization
• immunophenotypes
• mediation
• metabolites
• prostatitis

• Humans
• Male
• Mendelian Randomization Analysis
• Prostatitis/blood
• Prostatitis/immunology
• Prostatitis/genetics
• Bayes Theorem
• Genome-Wide Association Study
• Risk Factors
• Immunophenotyping
• Polymorphism, Single Nucleotide

• Wuhu Municipal Science and Technology Bureau

• Disease
• Drugs
• Histone deacetylase
• Inflammation
• Review

• Histone Deacetylase Inhibitors/therapeutic use
• Histone Deacetylase Inhibitors/pharmacology
• Humans
• Histone Deacetylases/metabolism
• Inflammation/drug therapy
• Animals
• Anti-Inflammatory Agents/therapeutic use
• Anti-Inflammatory Agents/pharmacology

• Carboxymethyl chitin
• Hollow mesoporous silica nanoparticles
• Immune response
• TAM repolarization

• Humans
• Silicon Dioxide/chemistry
• Hydrogen Peroxide
• Doxorubicin/chemistry
• Neoplasms/drug therapy
• Nanoparticles/chemistry
• alpha-Tocopherol/chemistry
• Interleukin-12
• Macrophages
• Chitin
• Porosity
• Tumor Microenvironment

• IL-1β
• J774A.1
• NO
• TNF-alpha
• histone deacetylase inhibitors
• macrophages
• trichostatin-A
• valproic acid

• AMG487
• CXCR3
• chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS)
• immune
• inflammation

• Acetamides
• Animals
• Autoimmune Diseases
• Cell Differentiation
• Chronic Pain
• Disease Models, Animal
• Humans
• Inflammation
• Macrophages/pathology
• Male
• Mice
• Pelvic Pain/drug therapy
• Pelvic Pain/etiology
• Pelvic Pain/metabolism
• Phenotype
• Prostatitis/pathology
• Pyrimidinones
• Receptors, CXCR3/genetics
• Receptors, CXCR3/therapeutic use

IL-10⁺ regulatory B (Breg) cells play a vital role in regulating the immune responses in experimental autoimmune encephalomyelitis, colitis, and contact hypersensitivity (CHS). Several sti-mulants such as lipopolysaccharide (LPS), CD40 ligand, and IL-21 spur the activation and maturation of IL-10⁺ Breg cells, while the epigenetic mechanism for the IL-10 expression remains largely unknown. It is well accepted that the histone acetylation/deacetylation is an important mechanism that regulates the expression of IL-10. We found that entinostat, an HDAC inhibitor, stimulated the induction of IL-10⁺ Breg cells by LPS in vitro and the formation of IL-10⁺ Breg cells to suppress CHS in vivo. We further demonstrated that entinostat inhibited HDAC1 from binding to the proximal region of the IL-10 expression promoter in splenic B cells, followed by an increase in the binding of NF-κB p65, eventually enhancing the expression of IL-10 in Breg cells.

• Cancer
• Immune response
• Interleukin-17
• Pathophysiology
• Th17 cells
• Tumor microenvironment

• recurrent spontaneous miscarriage / decidual macrophages / THP-1 / HDAC8 / CD163

• chronic prostatitis
• inflammatory cytokines
• rat model
• resveratrol

• autophagy
• chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS)
• immune
• regulatory T (Treg) cells

• Animals
• Autoimmune Diseases/drug therapy
• Autoimmune Diseases/immunology
• Autoimmune Diseases/pathology
• Autophagy/drug effects
• Autophagy/immunology
• CTLA-4 Antigen/immunology
• Chronic Disease
• Disease Models, Animal
• GATA3 Transcription Factor/biosynthesis
• GATA3 Transcription Factor/immunology
• Male
• Mice
• Mice, Inbred NOD
• Pain Measurement
• Prostatitis/drug therapy
• Prostatitis/immunology
• Prostatitis/pathology
• Rats
• Rats, Sprague-Dawley
• Sirolimus/pharmacology
• T-Lymphocytes, Regulatory/drug effects
• T-Lymphocytes, Regulatory/immunology
• T-Lymphocytes, Regulatory/pathology
• Up-Regulation

• Colitis
• MS-275
• histone H3 acetylation
• vitamin D receptor

• Acetylation/drug effects
• Animals
• Apoptosis/drug effects
• Benzamides/pharmacology
• Cells, Cultured
• Colitis/drug therapy
• Colitis/metabolism
• Colitis/physiopathology
• Colitis, Ulcerative/pathology
• Disease Models, Animal
• Histone Deacetylase Inhibitors/pharmacology
• Histone Deacetylases/metabolism
• Histones/metabolism
• Humans
• Intestinal Mucosa/drug effects
• Intestinal Mucosa/metabolism
• Mice
• Pyridines/pharmacology
• Receptors, Calcitriol/metabolism
• Severity of Illness Index
• Signal Transduction/drug effects
• Vitamin D Deficiency/metabolism

• drug delivery
• liposome
• nanoparticle
• neuroblastoma
• targeted therapy

• CP/CPPS
• EAP
• Foxp3
• Treg cells
• methylation

The rapid and persistent increase of drug-resistant Mycobacterium tuberculosis (Mtb) infections poses increasing global problems in combatting tuberculosis (TB), prompting for the development of alternative strategies including host-directed therapy (HDT). Since Mtb is an intracellular pathogen with a remarkable ability to manipulate host intracellular signaling pathways to escape from host defense, pharmacological reprogramming of the immune system represents a novel, potentially powerful therapeutic strategy that should be effective also against drug-resistant Mtb. Here, we found that host-pathogen interactions in Mtb-infected primary human macrophages affected host epigenetic features by modifying histone deacetylase (HDAC) transcriptomic levels. In addition, broad spectrum inhibition of HDACs enhanced the antimicrobial response of both pro-inflammatory macrophages (Mϕ1) and anti-inflammatory macrophages (Mϕ2), while selective inhibition of class IIa HDACs mainly decreased bacterial outgrowth in Mϕ2. Moreover, chemical inhibition of HDAC activity during differentiation polarized macrophages into a more bactericidal phenotype with a concomitant decrease in the secretion levels of inflammatory cytokines. Importantly, in vivo chemical inhibition of HDAC activity in Mycobacterium marinum-infected zebrafish embryos, a well-characterized animal model for tuberculosis, significantly reduced mycobacterial burden, validating our in vitro findings in primary human macrophages. Collectively, these data identify HDACs as druggable host targets for HDT against intracellular Mtb.

• epigenetic regulation
• histone deacetylases (HDAC)
• host-directed therapy
• human macrophages
• tuberculosis

• ECM protein Tenascin C
• Early postnatal development
• HDAC1
• Microglia
• Phagocytosis
• TLR4

Chronic orofacial pain is a significant health problem requiring identification of regulating processes. Involvement of epigenetic modifications that is reported for hindlimb neuropathic pain experimental models, however, is less well studied in cranial nerve pain models. Three independent observations reported here are the (1) epigenetic profile in mouse trigeminal ganglia (TG) after trigeminal inflammatory compression (TIC) nerve injury mouse model determined by gene expression microarray, (2) H3K9 acetylation pattern in TG by immunohistochemistry, and (3) efficacy of histone deacetylase (HDAC) inhibitors to attenuate development of hypersensitivity. After TIC injury, ipsilateral whisker pad mechanical sensitization develops by day 3 and persists well beyond day 21 in contrast to sham surgery. Global acetylation of H3K9 decreases at day 21 in ipsilateral TG . Thirty-four genes are significantly (p < 0.05) overexpressed in the ipsilateral TG by at least two-fold at either 3 or 21 days post-trigeminal inflammatory compression injury. The three genes most overexpressed three days post-trigeminal inflammatory compression nerve injury are nerve regeneration-associated gene ATF3, up 6.8-fold, and two of its regeneration-associated gene effector genes, Sprr1a and Gal, up 174- and 25-fold, respectively. Although transcription levels of 25 of 32 genes significantly overexpressed three days post-trigeminal inflammatory compression return to constitutive levels by day 21, these three regeneration-associated genes remain significantly overexpressed at the later time point. On day 21, when tissues are healed, other differentially expressed genes include 39 of the top 50 upregulated and downregulated genes. Remarkably, preemptive manipulation of gene expression with two HDAC inhibitors (HDACi's), suberanilohydroxamic acid (SAHA) and MS-275, reduces the magnitude and duration of whisker pad mechanical hypersensitivity and prevents the development of a persistent pain state. These findings suggest that trigeminal nerve injury leads to epigenetic modifications favoring overexpression of genes involved in nerve regeneration and that maintaining transcriptional homeostasis with epigenetic modifying drugs could help prevent the development of persistent pain.

• H3K9 acetylation
• HDAC inhibitor
• Orofacial pain
• epigenetic regulation
• gene microarray
• mechanical allodynia
• mice
• trigeminal

• early life exposure
• environmental factors
• epigenetic modifiers
• inflammation
• uterine fibroids

• R01 ES028615 NIEHS NIH HHS
• R01 HD094378 NICHD NIH HHS

• chronic prostatitis/chronic pelvic pain syndrome (CP/CPPS)
• epigenetic inactivation
• estradiol
• estrogene receptor
• liquid biopsies

The progression of cancer is a result of not only the growth of the malignant cells but also the behavior of other components of the tumor microenvironment (TME). Tumor-associated macrophages (TAMs) are key components of the TME that influence tumor growth and disease progression. TAMs can either inhibit or support tumor growth depending on their polarization to classically-activated macrophages (M1s) or alternatively-activated macrophages (M2s), respectively. Epigenetic regulation plays a significant role in determining this polarization and manipulating the epigenetic regulation in macrophages would provide a means for selectively targeting M2s thereby eliminating tumor-supporting TAMs while sparing tumor-inhibiting M1 TAMs. Many pharmacologic modulators of epigenetic enzymes are currently used clinically and could be repurposed for treating tumors with high TAM infiltrate. While much research involving epigenetic enzymes and their modulators has been performed in M1s, significantly less is known about the epigenetic regulation of M2s. This review highlights the field’s current knowledge of key epigenetic enzymes and their pharmacologic modulators known to influence macrophage polarization.

• epigenetics
• macrophage
• macrophage polarization
• tumor microenvironment
• tumor-associated macrophage

Chronic pain occurs in ~85–90% of chronic pancreatitis (CP) patients. However, as the pathogenesis of CP pain remains to be fully understood, the current therapies for CP pain remain inadequate. Emerging evidence has suggested that the epigenetic modulations of genes are involved in chronic pain. In the present study, intrapancreatic trinitrobenzene sulfonic acid infusions were used to establish a CP model in rats. Mechanical allodynia was measured with von Frey filaments. Immunofluorescent staining analysis was used to observe the expression changes of histone deacetylase 2 (HDAC2) and µ-opioid receptor (MOR), and intrathecal administration of the selective HDAC2 inhibitor AR-42 was used to assess the underlying mechanisms. The expression levels of c-Jun N-terminal kinase (JNK) in the thoracic spinal cord were detected by western blotting, and the mRNA expression levels of interleukin (IL)1-β, IL-6 and tumor necrosis factor (TNF)-α were detected by reverse transcription-quantitative polymerase chain reaction. The results demonstrated that HDAC2 expression was upregulated during the course of CP induction, while MOR activity in the thoracic spinal dorsal horn was significantly suppressed. Intrathecal infusion of AR-42 significantly attenuated CP-induced mechanical allodynia, with rescued MOR activity. Additionally, HDAC2 facilitated the release of inflammatory cytokines, including IL-1β, IL-6 and TNF-α. These results suggested that the underlying mechanisms of HDAC2 regulating MOR activity under CP induction may occur via promoting the release of inflammatory cytokines, thus activating the JNK signaling pathway. The present study suggested that the epigenetic-regulated disturbance of MOR is dependent on the endogenous analgesia system in CP, which may a provide novel therapeutic strategy for treating pain in CP.

• COPD
• acetylation
• acetylomics
• asthma
• chemoproteomics
• histone deacetylase
• inhibitor
• selectivity

The present study aimed to determine the expression and mediation of interleukin-17 (IL-17) and chemokine ligand 2 (CCL2) in a rat model with experimental autoimmune prostatitis (EAP). A total of 44 Sprague Dawley (SD) rats were used in the present study. Of these, a total of 20 two-month-old SD rats were randomly divided into a normal control (n=10) and a model group (EAP group, n=10). The remaining 24 two-month old SD rats were treated in the same way as EAP rats and subsequently randomly divided into a tacrolimus group (n=8), a celecoxib group (n=8) and a normal saline (NS) control group (n=8). Rats in the EAP and normal control groups underwent the Von Frey filaments behavioral test; rats in the tacrolimus, celecoxib and normal saline groups received a pain test following intervention treatment. Prostate tissues of SD rats in each group were harvested for reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot analysis to observe the expression of IL-17 and CCL2. In the pain-reaction test, the occurrence of abnormal pain in the EAP group was significantly higher compared with the control group (P<0.001). The celecoxib group experienced a significant decrease in pain at day 10 compared with the NS group (P<0.01), while the decrease in pain experienced by the tacrolimus group was only significant at day 30 (P<0.001) and the pain experienced by the NS group decreased slightly over this same period. Results of RT-qPCR and western blot analysis indicated that, compared with the control group, the expression of IL-17 and CCL2 in the prostate tissue of EAP rats was significantly upregulated 50 days following modeling (P<0.05). On day 30 following intervention, the expression of IL-17 and CCL2 in the prostate of rats in the tacrolimus and celecoxib groups was significantly downregulated compared with the NS group (P<0.05). Therefore, the results of the current study demonstrate that IL-17 and CCL2 serve a vital role in the morbidity of the experimental autoimmune prostatitis and may also have a mediation effect on pelvic pain associated with chronic prostatitis.

• chemokine ligand 2
• interleukin-17
• mechanical pain sense
• prostatitis

Entinostat, a class I-selective histone deacetylase inhibitor, has shown promising activity in ENCORE 301, a randomized, placebo-controlled, phase II trial of exemestane with or without entinostat in women with locally recurrent or metastatic estrogen receptor-positive breast cancer progressing on a nonsteroidal aromatase inhibitor. ENCORE 301 showed an 8.3-mo improvement in median overall survival among patients who received entinostat. We investigated the impact of entinostat on immune subsets with CD40, HLA-DR, and immune checkpoint receptor expression analyses in 34 patient blood samples from ENCORE 301. We found that entinostat significantly decreased granulocytic and monocytic MDSCs at cycle 1 day 15. MDSC CD40 was significantly downregulated by entinostat. A significant increase in HLA-DR expression on CD14⁺ monocytes by entinostat was observed. Entinostat did not impact T-cell subsets or T-cell immune checkpoint receptor expression. Our findings suggest that a significant interplay between this epigenetic regimen and host immune homeostatic mechanisms may impact therapeutic outcome.

• Breast cancer
• HLA-DR
• entinostat
• exemestane
• histone deacetylase inhibitors
• immune checkpoint receptor
• immune subsets
• monocyte
• myeloid-derived suppressor cell
• regulatory T cell

Our understanding of epigenetics in complex diseases is rapidly advancing and increasingly influencing the practice of medicine. Much is known about disruption of chromatin-modifying enzymes in malignant disease, but knowledge of irregular epigenetics in immune-driven disorders is just emerging. Epigenetic factors, such as DNA or histone modifications, are indispensable for precise gene expression in diverse immune cell types. Thus a disruption of epigenetic landscapes likely has a large impact on immune homeostasis. Moreover, the low concordance rates for most autoimmune diseases suggest that epigenetics contribute to immune tolerance disturbance. Here we review the important role of epigenetics for initiation, maintenance, tolerance, and training of immune responses. We discuss evolving evidence that DNA/histone modifications and chromatin-modifying enzymes are altered in immune-based diseases. Furthermore, we explore the potential of small molecules targeting epigenetic machinery, some of which are already used in oncology, as a way to reset the immune response in disease.

Epigenetic modifications, like histone acetylation, are essential for regulating gene expression within cells. Cancer cells acquire pathological epigenetic modifications resulting in gene expression patterns that facilitate and sustain tumorigenesis. Epigenetic manipulation therefore is emerging as a novel targeted therapy for cancer. Histone Acetylases (HATs) and Histone Deacetylases (HDACs) regulate histone acetylation and hence gene expression. Histone deacetylase (HDAC) inhibitors are well known to affect cancer cell viability and biology and are already in use for the treatment of cancer patients. Immunotherapy can lead to clinical benefit in selected cancer patients, especially in patients with limited disease after tumor debulking. HDAC inhibitors can potentially synergize with immunotherapy by elimination of tumor cells. The direct effects of HDAC inhibitors on immune cell function, however, remain largely unexplored. Initial data have suggested HDAC inhibitors to be predominantly immunosuppressive, but more recent reports have challenged this view. In this review we will discuss the effects of HDAC inhibitors on tumor cells and different immune cell subsets, synergistic interactions and possible mechanisms. Finally, we will address future challenges and potential application of HDAC inhibitors in immunocombination therapy of cancer.

The interaction of innate immune cells with pathogens leads to changes in gene expression that elicit our body's first line of defense against infection. Although signaling pathways and transcription factors have a central role, it is becoming increasingly clear that epigenetic factors, in the form of DNA or histone modifications, as well as noncoding RNAs, are critical for generating the necessary cell lineage as well as context‐specific gene expression in diverse innate immune cell types. Much of the epigenetic landscape is set during cellular differentiation; however, pathogens and other environmental triggers also induce changes in histone modifications that can either promote tolerance or ‘train’ innate immune cells for a more robust antigen‐independent secondary response. Here we review the important contribution of epigenetic factors to the initiation, maintenance and training of innate immune responses. In addition, we explore how pathogens have hijacked these mechanisms for their benefit and the potential of small molecules targeting chromatin machinery as a way to boost or subdue the innate immune response in disease.

The March 2015 issue contains a Special Feature on the epigenetic mechanisms underlying health and disease. Epigenetic modifications to chromatin influence the transcriptional status of our genes. Thus, understanding the epigenetic mechanisms that regulate immune cell fate are of great importance as they will provide insight into not only how to boost immune responses but also alter harmful ones such as autoimmunity and cancer. Immunology and Cell Biology thanks the coordinators of this Special Feature ‐ Rhys Allan ‐ for his planning and input.

• Animals
• Chromatin Assembly and Disassembly
• Chronic Pain/drug therapy
• Chronic Pain/genetics
• Chronic Pain/metabolism
• DNA Methylation
• Disease Models, Animal
• Epigenesis, Genetic
• Gene Expression Regulation
• Histone Deacetylase Inhibitors/therapeutic use
• Histones/metabolism
• Humans
• Inflammation/drug therapy
• Inflammation/genetics
• Inflammation/metabolism
• Mice
• Neuralgia/genetics
• Neuralgia/metabolism
• RNA, Untranslated/genetics
• RNA, Untranslated/metabolism
• Translational Research, Biomedical
• Visceral Pain/genetics
• Visceral Pain/metabolism

• R01 DE021804 NIDCR NIH HHS
• R01 NS060735 NINDS NIH HHS
• DE021804 NIDCR NIH HHS
• NS060735 NINDS NIH HHS

• Animal models
• DNA methylation
• Epigenetic drugs
• Epigenetics
• Histone modifications
• Multiple sclerosis

• R01 DK051413 NIDDK NIH HHS

• Acute Disease
• Animals
• Cell Proliferation/drug effects
• Cells, Cultured
• Cytokines/immunology
• Cytokines/metabolism
• Disease Models, Animal
• Forkhead Transcription Factors/genetics
• Forkhead Transcription Factors/metabolism
• Graft Rejection/drug therapy
• Graft Rejection/immunology
• Graft Rejection/mortality
• Graft vs Host Disease/drug therapy
• Graft vs Host Disease/immunology
• Graft vs Host Disease/mortality
• Histone Deacetylase Inhibitors/pharmacology
• Hydroxamic Acids/pharmacology
• Liver Transplantation/adverse effects
• Liver Transplantation/mortality
• Male
• Postoperative Complications/drug therapy
• Postoperative Complications/immunology
• Postoperative Complications/mortality
• RNA, Messenger/metabolism
• Rats
• Rats, Inbred BN
• Rats, Inbred Lew
• Spleen/cytology
• Spleen/immunology
• T-Lymphocytes, Regulatory/drug effects
• T-Lymphocytes, Regulatory/immunology
• Treatment Failure

• nerve regeneration
• macrophage
• origin
• polarization
• function
• nerve injury
• nerve repair
• tissue engineering
• neural regeneration

• Adult
• Animals
• Asthma/diagnosis
• Cattle
• Cytoplasmic Granules/drug effects
• Diagnosis, Differential
• Eosinophils/drug effects
• Eosinophils/ultrastructure
• Food Hypersensitivity/diagnosis
• Food Hypersensitivity/etiology
• Food Hypersensitivity/pathology
• Humans
• In Vitro Techniques
• Ketotifen/pharmacology
• Male
• Microscopy, Electron
• Milk/adverse effects
• Monocytes/ultrastructure