1 2063 91 EPIGENETIC CONTROL OF IL-23 EXPRESSION IN KERATINOCYTES IS IMPORTANT FOR CHRONIC SKIN INFLAMMATION. THE CHRONIC SKIN INFLAMMATION PSORIASIS IS CRUCIALLY DEPENDENT ON THE IL-23/IL-17 CYTOKINE AXIS. ALTHOUGH IL-23 IS EXPRESSED BY PSORIATIC KERATINOCYTES AND IMMUNE CELLS, ONLY THE IMMUNE CELL-DERIVED IL-23 IS BELIEVED TO BE DISEASE RELEVANT. HERE WE USE A GENETIC MOUSE MODEL TO SHOW THAT KERATINOCYTE-PRODUCED IL-23 IS SUFFICIENT TO CAUSE A CHRONIC SKIN INFLAMMATION WITH AN IL-17 PROFILE. FURTHERMORE, WE REVEAL A CELL-AUTONOMOUS NUCLEAR FUNCTION FOR THE ACTIN POLYMERIZING MOLECULE N-WASP, WHICH CONTROLS IL-23 EXPRESSION IN KERATINOCYTES BY REGULATING THE DEGRADATION OF THE HISTONE METHYLTRANSFERASES G9A AND GLP, AND H3K9 DIMETHYLATION OF THE IL-23 PROMOTER. THIS MECHANISM MEDIATES THE INDUCTION OF IL-23 BY TNF, A KNOWN INDUCER OF IL-23 IN PSORIASIS. FINALLY, IN KERATINOCYTES OF PSORIATIC LESIONS A DECREASE IN H3K9 DIMETHYLATION CORRELATES WITH INCREASED IL-23 EXPRESSION, SUGGESTING RELEVANCE FOR DISEASE. TAKEN TOGETHER, OUR DATA DESCRIBE A MOLECULAR PATHWAY WHERE EPIGENETIC REGULATION OF KERATINOCYTES CAN CONTRIBUTE TO CHRONIC SKIN INFLAMMATION. 2018 2 5421 26 REGULATION OF INTERLEUKIN-23 EXPRESSION IN HEALTH AND DISEASE. INTERLEUKIN (IL)-23 PLAYS A CENTRAL ROLE IN THE ORCHESTRATION OF INFLAMMATORY RESPONSES. PRODUCED BY DENDRITIC CELLS AND MACROPHAGES, THIS CYTOKINE PROMOTES THE PROTECTION OF THE HOST AGAINST MUCOSAL PATHOGENS THROUGH THE INDUCTION OF IL-17 AND RELATED CYTOKINES BY LYMPHOID CELLS. PRECLINICAL DISEASE MODELS AND ASSOCIATION STUDIES IN HUMANS HAVE ALSO CLEARLY DEMONSTRATED THE IMPLICATION OF IL-23 SIGNALLING PATHWAY IN INFLAMMATORY DISEASES. INDEED, THIS CYTOKINE IS NOW CONSIDERED AS A MAJOR THERAPEUTIC TARGET IN IMMUNE-BASED PATHOLOGIES SUCH AS PSORIASIS, ANKYLOSING SPONDYLITIS OR CROHN'S DISEASE. FURTHERMORE, IN THE CONTEXT OF INFLAMMATION-RELATED CANCER, IL-23 IS THOUGHT TO CONTRIBUTE TO TUMORIGENESIS AND PROGRESSION TO METASTATIC DISEASE. HEREIN, WE REVIEW OUR CURRENT UNDERSTANDING OF IL-23 REGULATION AT THE TRANSCRIPTIONAL AND POST-TRANSCRIPTIONAL LEVELS. WE DISCUSS THE RELEVANCE OF THESE FINDINGS IN THE CONTEXT OF INFECTION, CHRONIC INFLAMMATION AND CANCER. 2016 3 4164 27 MEDIATORS OF CAPILLARY-TO-VENULE CONVERSION IN THE CHRONIC INFLAMMATORY SKIN DISEASE PSORIASIS. PSORIASIS IS A CHRONIC INFLAMMATORY SKIN DISEASE CHARACTERIZED BY EPIDERMAL HYPERPLASIA AND HYPERKERATOSIS, IMMUNE CELL INFILTRATION AND VASCULAR REMODELING. DESPITE THE EMERGING RECOGNITION OF VASCULAR NORMALIZATION AS A POTENTIAL STRATEGY FOR MANAGING PSORIASIS, AN IN-DEPTH DELINEATION OF THE REMODELED DERMAL VASCULATURE HAS BEEN MISSING. IN THIS STUDY, WE EXPLOITED 5' SINGLE-CELL RNA SEQUENCING TO INVESTIGATE THE TRANSCRIPTOMIC ALTERATIONS IN DIFFERENT SUBPOPULATIONS OF BLOOD VASCULAR AND LYMPHATIC ENDOTHELIAL CELLS DIRECTLY ISOLATED FROM PSORIATIC AND HEALTHY HUMAN SKIN. INDIVIDUAL SUBTYPES OF ENDOTHELIAL CELLS UNDERWENT SPECIFIC MOLECULAR REPATTERNING ASSOCIATED WITH CELL ADHESION AND EXTRACELLULAR MATRIX ORGANIZATION. BLOOD CAPILLARIES, IN PARTICULAR, SHOWED UPREGULATION OF THE MELANOMA CELL ADHESION MOLECULE AS WELL AS ITS BINDING PARTNERS AND ADOPTED POSTCAPILLARY VENULE?LIKE CHARACTERISTICS DURING CHRONIC INFLAMMATION THAT ARE MORE PERMISSIVE TO LEUKOCYTE TRANSMIGRATION. WE ALSO IDENTIFIED PSORIASIS-SPECIFIC INTERACTIONS BETWEEN CIS-REGULATORY ENHANCERS AND PROMOTERS FOR EACH ENDOTHELIAL CELL SUBTYPE, REVEALING THE DYSREGULATED GENE REGULATORY NETWORKS IN PSORIASIS. TOGETHER, OUR RESULTS PROVIDE MORE INSIGHTS INTO THE SPECIFIC TRANSCRIPTIONAL RESPONSES AND EPIGENETIC SIGNATURES OF ENDOTHELIAL CELLS LINING DIFFERENT VESSEL COMPARTMENTS IN CHRONIC SKIN INFLAMMATION. 2022 4 2082 36 EPIGENETIC DOWNREGULATION OF SFRP4 CONTRIBUTES TO EPIDERMAL HYPERPLASIA IN PSORIASIS. PSORIASIS IS A CHRONIC RECURRENT INFLAMMATORY SKIN DISORDER CHARACTERIZED BY THE DYSREGULATED CROSS-TALK BETWEEN EPIDERMAL KERATINOCYTES AND IMMUNE CELLS, LEADING TO KERATINOCYTE HYPERPROLIFERATION. SEVERAL STUDIES DEMONSTRATED THAT WNT PATHWAY GENES WERE DIFFERENTIALLY EXPRESSED IN PSORIATIC PLAQUES AND LIKELY WERE INVOLVED IN THE PATHOPHYSIOLOGY OF DISEASE. HOWEVER, THE MOLECULAR MECHANISMS UNDERLYING WNT SIGNALING REGULATION IN EPIDERMAL HYPERPLASIA IN PSORIASIS REMAIN LARGELY UNKNOWN. WE REPORT THAT THE EXPRESSION OF SECRETED FRIZZLED-RELATED PROTEIN (SFRP) 4, A NEGATIVE REGULATOR OF THE WNT SIGNALING PATHWAY, WAS DIMINISHED IN LESIONAL SKIN OF MOUSE MODELS AND PATIENTS WITH PSORIASIS. SFRP4 DIRECTLY INHIBITED EXCESSIVE KERATINOCYTE PROLIFERATION EVOKED BY PROINFLAMMATORY CYTOKINES IN VITRO. PHARMACOLOGICAL INHIBITION OF WNT SIGNALING OR INTRADERMAL INJECTION OF SFRP4 DECREASED THE SEVERITY OF THE PSORIASIFORM SKIN PHENOTYPE IN VIVO, INCLUDING DECREASED ACANTHOSIS AND REDUCED LEUKOCYTE INFILTRATION. MECHANISTICALLY, WE IDENTIFIED THAT ABERRANT PROMOTER METHYLATION RESULTED IN EPIGENETIC DOWNREGULATION OF SFRP4 IN INFLAMED SKIN OF PATIENTS WITH PSORIASIS AND IN THE IL-23-INDUCED MOUSE MODEL. OUR FINDINGS SUGGEST THAT THIS EPIGENETIC EVENT IS CRITICALLY INVOLVED IN THE PATHOGENESIS OF PSORIASIS, AND THE DOWNREGULATION OF SFRP4 BY CPG ISLAND METHYLATION IS ONE POSSIBLE MECHANISM CONTRIBUTING TO THE HYPERPLASIA OF EPIDERMIS IN THE DISEASE. 2015 5 1479 25 DIVERSE TARGETS OF THE TRANSCRIPTION FACTOR STAT3 CONTRIBUTE TO T CELL PATHOGENICITY AND HOMEOSTASIS. STAT3, AN ESSENTIAL TRANSCRIPTION FACTOR WITH PLEIOTROPIC FUNCTIONS, PLAYS CRITICAL ROLES IN THE PATHOGENESIS OF AUTOIMMUNITY. DESPITE RECENT DATA LINKING STAT3 WITH INFLAMMATORY BOWEL DISEASE, EXACTLY HOW IT CONTRIBUTES TO CHRONIC INTESTINAL INFLAMMATION IS NOT KNOWN. USING A T CELL TRANSFER MODEL OF COLITIS, WE FOUND THAT STAT3 EXPRESSION IN T CELLS WAS ESSENTIAL FOR THE INDUCTION OF BOTH COLITIS AND SYSTEMIC INFLAMMATION. STAT3 WAS CRITICAL IN MODULATING THE BALANCE OF T HELPER 17 (TH17) AND REGULATORY T (TREG) CELLS, AS WELL AS IN PROMOTING CD4(+) T CELL PROLIFERATION. WE USED CHROMATIN IMMUNOPRECIPITATION AND MASSIVE PARALLEL SEQUENCING (CHIP-SEQ) TO DEFINE THE GENOME-WIDE TARGETS OF STAT3 IN CD4(+) T CELLS. WE FOUND THAT STAT3 BOUND TO MULTIPLE GENES INVOLVED IN TH17 CELL DIFFERENTIATION, CELL ACTIVATION, PROLIFERATION, AND SURVIVAL, REGULATING BOTH EXPRESSION AND EPIGENETIC MODIFICATIONS. THUS, STAT3 ORCHESTRATES MULTIPLE CRITICAL ASPECTS OF T CELL FUNCTION IN INFLAMMATION AND HOMEOSTASIS. 2010 6 2228 28 EPIGENETIC MODIFICATIONS OF HISTONES IN PERIODONTAL DISEASE. PERIODONTITIS IS A CHRONIC INFECTIOUS DISEASE DRIVEN BY DYSBIOSIS, AN IMBALANCE BETWEEN COMMENSAL BACTERIA AND THE HOST ORGANISM. PERIODONTITIS IS A LEADING CAUSE OF TOOTH LOSS IN ADULTS AND OCCURS IN ABOUT 50% OF THE US POPULATION. IN ADDITION TO THE CLINICAL CHALLENGES ASSOCIATED WITH TREATING PERIODONTITIS, THE PROGRESSION AND CHRONIC NATURE OF THIS DISEASE SERIOUSLY AFFECT HUMAN HEALTH. EMERGING EVIDENCE SUGGESTS THAT PERIODONTITIS IS ASSOCIATED WITH MECHANISMS BEYOND BACTERIA-INDUCED PROTEIN AND TISSUE DEGRADATION. HERE, WE HYPOTHESIZE THAT BACTERIA ARE ABLE TO INDUCE EPIGENETIC MODIFICATIONS IN ORAL EPITHELIAL CELLS MEDIATED BY HISTONE MODIFICATIONS. IN THIS STUDY, WE FOUND THAT DYSBIOSIS IN VIVO LED TO EPIGENETIC MODIFICATIONS, INCLUDING ACETYLATION OF HISTONES AND DOWNREGULATION OF DNA METHYLTRANSFERASE 1. IN ADDITION, IN VITRO EXPOSURE OF ORAL EPITHELIAL CELLS TO LIPOPOLYSACCHARIDES RESULTED IN HISTONE MODIFICATIONS, ACTIVATION OF TRANSCRIPTIONAL COACTIVATORS, SUCH AS P300/CBP, AND ACCUMULATION OF NUCLEAR FACTOR-KAPPAB (NF-KAPPAB). GIVEN THAT ORAL EPITHELIAL CELLS ARE THE FIRST LINE OF DEFENSE FOR THE PERIODONTIUM AGAINST BACTERIA, WE ALSO EVALUATED WHETHER ACTIVATION OF PATHOGEN RECOGNITION RECEPTORS INDUCED HISTONE MODIFICATIONS. WE FOUND THAT ACTIVATION OF THE TOLL-LIKE RECEPTORS 1, 2, AND 4 AND THE NUCLEOTIDE-BINDING OLIGOMERIZATION DOMAIN PROTEIN 1 INDUCED HISTONE ACETYLATION IN ORAL EPITHELIAL CELLS. OUR FINDINGS CORROBORATE THE EMERGING CONCEPT THAT EPIGENETIC MODIFICATIONS PLAY A ROLE IN THE DEVELOPMENT OF PERIODONTITIS. 2016 7 6202 36 THE INFLAMMATORY RESPONSE IN PSORIASIS: A COMPREHENSIVE REVIEW. PSORIASIS IS A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE CHARACTERIZED BY AN EXCESSIVELY ABERRANT HYPERPROLIFERATION OF KERATINOCYTES. THE PATHOGENESIS OF PSORIASIS IS COMPLEX AND THE EXACT MECHANISM REMAINS ELUSIVE. HOWEVER, PSORIASIS IS THOUGHT TO RESULT FROM A COMBINATION OF GENETIC, EPIGENETIC, AND ENVIRONMENTAL INFLUENCES. RECENT STUDIES HAVE IDENTIFIED THAT EPIGENETIC FACTORS INCLUDING DYSREGULATED DNA METHYLATION LEVELS, ABNORMAL HISTONE MODIFICATION AND MICRORNAS EXPRESSIONS ARE INVOLVED IN THE DEVELOPMENT OF PSORIASIS. THE INTERPLAY OF IMMUNE CELLS AND CYTOKINES IS ANOTHER CRITICAL FACTOR IN THE PATHOGENESIS OF PSORIASIS. THESE FACTORS OR PATHWAYS INCLUDE TH1/TH2 HOMEOSTASIS, THE TH17/TREG BALANCE AND THE IL-23/TH17 AXIS. TH17 IS BELIEVED PARTICULARLY IMPORTANT IN PSORIASIS DUE TO ITS PRO-INFLAMMATORY EFFECTS AND ITS INVOLVEMENT IN AN INTEGRATED INFLAMMATORY LOOP WITH DENDRITIC CELLS AND KERATINOCYTES, CONTRIBUTING TO AN OVERPRODUCTION OF ANTIMICROBIAL PEPTIDES, INFLAMMATORY CYTOKINES, AND CHEMOKINES THAT LEADS TO AMPLIFICATION OF THE IMMUNE RESPONSE. IN ADDITION, OTHER PATHWAYS AND SIGNALING MOLECULES HAVE BEEN FOUND TO BE INVOLVED, INCLUDING TH9, TH22, REGULATORY T CELLS, GAMMADELTA T CELLS, CD8(+) T CELLS, AND THEIR RELATED CYTOKINES. UNDERSTANDING THE PATHOGENESIS OF PSORIASIS WILL ALLOW US TO DEVELOP INCREASINGLY EFFICIENT TARGETED TREATMENT BY BLOCKING RELEVANT INFLAMMATORY SIGNALING PATHWAYS AND MOLECULES. THERE IS NO CURE FOR PSORIASIS AT THE PRESENT TIME, AND MUCH OF THE TREATMENT INVOLVES MANAGING THE SYMPTOMS. THE BIOLOGICS, WHILE LACKING THE ADVERSE EFFECTS ASSOCIATED WITH SOME OF THE TRADITIONAL MEDICATIONS SUCH AS CORTICOSTEROIDS AND METHOTREXATE, HAVE THEIR OWN SET OF SIDE EFFECTS, WHICH MAY INCLUDE REACTIVATION OF LATENT INFECTIONS. SIGNIFICANT CHALLENGES REMAIN IN DEVELOPING SAFE AND EFFICACIOUS NOVEL TARGETED THERAPIES THAT DEPEND ON A BETTER UNDERSTANDING OF THE IMMUNOLOGICAL DYSFUNCTION IN PSORIASIS. 2016 8 6293 23 THE PRO- AND ANTI-INFLAMMATORY POTENTIAL OF IL-12: THE DUAL ROLE OF TH1 CELLS. THE DIFFERENTIATION OF T-HELPER (TH) LYMPHOCYTES INTO VARIOUS TYPES OF T-HELPER EFFECTOR AND MEMORY CELLS WITH DISTINCT FUNCTIONS DEPENDING ON THE TYPE OF CONCOMITANT SIGNALS THEY RECEIVE UPON ACTIVATION IS A CRITICAL EVENT DETERMINING THE COURSE OF AN IMMUNE REACTION. TH1 CELLS CHARACTERIZED BY THE EXPRESSION OF IFN-GAMMA AND THE RECENTLY DESCRIBED TH17 CELLS PROMOTE INFLAMMATION AND ARE CRITICALLY INVOLVED IN THE INDUCTION AND MAINTENANCE OF AUTOIMMUNITY, WHEREAS THE SECRETION OF IL-4 IS A HALLMARK OF TH2 CELLS MEDIATING PROTECTION FROM PARASITES AND ALLERGY. ORIGINAL STIMULATION IN THE PRESENCE OF IL-12 RESULTS IN THE IMPRINTING OF TH1 MEMORY CELLS FOR THE EXPRESSION OF IFN-GAMMA BY EXPRESSION OF THE TRANSCRIPTION FACTOR T-BET AND EPIGENETIC MODIFICATION OF THE IFNGAMMA GENE. IT HAS BEEN DEMONSTRATED THAT TH1 CELLS ARE POTENT INDUCERS OF INFLAMMATION. HOWEVER, IN THE CHRONIC PHASE OF SUCH INFLAMMATION, THE REGULATORY POTENTIAL OF IL-12 AND TH1 CELLS THEMSELVES MAY PLAY AN IMPORTANT ROLE IN LIMITING IMMUNOPATHOLOGY. 2007 9 4756 37 NOVEL THERAPEUTIC TARGET(S) FOR PSORIATIC DISEASE. PSORIASIS AND PSORIATIC ARTHRITIS, TOGETHER KNOWN AS PSORIATIC DISEASE, IS HIGHLY PREVALENT CHRONIC RELAPSING INFLAMMATORY DISEASE AFFECTING SKIN, JOINTS OR BOTH AND IS ASSOCIATED WITH SEVERAL COMORBIDITIES SUCH AS CARDIOVASCULAR, METABOLIC, PSYCHIATRIC, RENAL DISEASE ETC. THE ETIOPATHOGENESIS OF PSORIASIS IS COMPLEX AND MAINLY DRIVEN BY ABERRANT IMMUNE RESPONSE OWING TO THE GENETIC SUSCEPTIBILITY AND VARIOUS ENVIRONMENTAL FACTORS SUCH AS TRAUMA, INFECTIONS AND DRUGS. RECENT ADVANCES IN UNDERSTANDING MOLECULAR AND CELLULAR PATHWAYS HAVE IDENTIFIED TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA), INTERLEUKIN-17 (IL-17), IL-23, IL-22 AS MAJOR CONTRIBUTORS IN PSORIASIS PATHOGENESIS. ADVANCES IN THE KNOWLEDGE OF PATHOPHYSIOLOGY, THE INTERACTION OF AUTOINFLAMMATION AND CLINICAL PHENOTYPES HAVE LED TO THE DEVELOPMENT OF HIGHLY EFFECTIVE TARGETED THERAPEUTIC AGENTS WHICH INCLUDE TNF-ALPHA, IL-17, IL-23, IL-1 ALPHA/BETA OR IL-36 INHIBITORS OR RECEPTOR BLOCKERS, SMALL MOLECULE DRUGS LIKE PHOSPHODIESTERASE-4 INHIBITORS (APREMILAST), JANUS KINASE (JAK) INHIBITORS, RETINOIC ACID RECEPTOR-RELATED ORPHAN RECEPTOR GAMMAT (RORGAMMAT) INHIBITORS. THESE NOVEL DRUGS HAVE PROMISED THE POTENTIAL OF IMPROVED DISEASE CONTROL. IN RECENT YEARS, THE TRANSITION FROM BIOLOGICS TO BIOSIMILARS ESPECIALLY WITH TNF-ALPHA INHIBITORS HAD SIGNIFICANT IMPACT ON DECREASING HEALTH CARE COST AND INCREASING THERAPEUTIC OPTIONS TO THE PATIENTS. HOWEVER, SELECTION OF RIGHT TREATMENT FOR AN INDIVIDUAL PATIENT STILL REMAINS CHALLENGING. MOREOVER, INTERPLAY BETWEEN DIFFERENT EPIGENETIC MECHANISMS SUCH AS THE DNA METHYLATION, CHROMATIN MODIFICATIONS AND NONCODING RNA REGULATION HAS RECENTLY BEEN STARTED TO BE DECIPHERED. ENZYMES INHIBITORS INVOLVED IN EPIGENETIC PATHWAYS SUCH AS DNA METHYLTRANSFERASES AND HISTONE DEACETYLASES DEMONSTRATED TO RESTORE NORMAL EPIGENETIC PATTERNS IN CLINICAL SETTINGS AND HAVE PROVIDED THE POTENTIAL AS NOVEL THERAPEUTIC TARGETS FOR PSORIASIS. IN THIS REVIEW, WE WILL DISCUSS NOVEL BIOLOGIC AGENTS AND NEWER THERAPEUTIC APPROACHES IN TREATMENT OF PSORIATIC DISEASE. 2022 10 911 22 CHRONIC EXPOSURE TO TNF REPROGRAMS CELL SIGNALING PATHWAYS IN FIBROBLAST-LIKE SYNOVIOCYTES BY ESTABLISHING LONG-TERM INFLAMMATORY MEMORY. FIBROBLAST-LIKE SYNOVIOCYTES (FLS) PLAY A CRITICAL ROLE IN THE PATHOGENESIS OF RHEUMATOID ARTHRITIS (RA). CHRONIC INFLAMMATION INDUCES TRANSCRIPTOMIC AND EPIGENETIC MODIFICATIONS THAT IMPARTS A PERSISTENT CATABOLIC PHENOTYPE TO THE FLS, DESPITE THEIR DISSOCIATION FROM THE INFLAMMATORY ENVIRONMENT. WE ANALYZED HIGH THROUGHPUT GENE EXPRESSION AND CHROMATIN ACCESSIBILITY DATA FROM HUMAN AND MOUSE FLS FROM OUR AND OTHER STUDIES AVAILABLE ON PUBLIC REPOSITORIES, WITH THE GOAL OF IDENTIFYING THE PERSISTENTLY REPROGRAMMED SIGNALING PATHWAYS DRIVEN BY CHRONIC INFLAMMATION. WE FOUND THAT THE GENE EXPRESSION CHANGES INDUCED BY SHORT-TERM TUMOR NECROSIS FACTOR-ALPHA (TNF) TREATMENT WERE LARGELY SUSTAINED IN THE FLS EXPOSED TO CHRONIC INFLAMMATION. THESE CHANGES THAT INCLUDED BOTH ACTIVATION AND REPRESSION OF GENE EXPRESSION, WERE ACCOMPANIED BY THE REMODELING OF CHROMATIN ACCESSIBILITY. THE SUSTAINED ACTIVATED GENES (SAGS) INCLUDED ESTABLISHED PRO-INFLAMMATORY SIGNALING COMPONENTS KNOWN TO ACT AT MULTIPLE LEVELS OF NF-KAPPAB, STAT AND AP-1 SIGNALING CASCADES. INTERESTINGLY, THE SUSTAINED REPRESSED GENES (SRGS) INCLUDED CRITICAL MEDIATORS AND TARGETS OF THE BMP SIGNALING PATHWAY. WE THUS IDENTIFIED SUSTAINED REPRESSION OF BMP SIGNALING AS A UNIQUE CONSTITUENT OF THE LONG-TERM INFLAMMATORY MEMORY INDUCED BY CHRONIC INFLAMMATION. WE POSTULATE THAT SIMULTANEOUS TARGETING OF THESE ACTIVATED AND REPRESSED SIGNALING PATHWAYS MAY BE NECESSARY TO COMBAT RA PERSISTENCE. 2020 11 2493 24 EPIGENETICS AND CHROMATIN REMODELING PLAY A ROLE IN LUNG DISEASE. EPIGENETICS IS DEFINED AS HERITABLE CHANGES THAT AFFECT GENE EXPRESSION WITHOUT ALTERING THE DNA SEQUENCE. EPIGENETIC REGULATION OF GENE EXPRESSION IS FACILITATED THROUGH DIFFERENT MECHANISMS SUCH AS DNA METHYLATION, HISTONE MODIFICATIONS AND RNA-ASSOCIATED SILENCING BY SMALL NON-CODING RNAS. ALL THESE MECHANISMS ARE CRUCIAL FOR NORMAL DEVELOPMENT, DIFFERENTIATION AND TISSUE-SPECIFIC GENE EXPRESSION. THESE THREE SYSTEMS INTERACT AND STABILIZE ONE ANOTHER AND CAN INITIATE AND SUSTAIN EPIGENETIC SILENCING, THUS DETERMINING HERITABLE CHANGES IN GENE EXPRESSION. HISTONE ACETYLATION REGULATES DIVERSE CELLULAR FUNCTIONS INCLUDING INFLAMMATORY GENE EXPRESSION, DNA REPAIR AND CELL PROLIFERATION. TRANSCRIPTIONAL COACTIVATORS POSSESS INTRINSIC HISTONE ACETYLTRANSFERASE ACTIVITY AND THIS ACTIVITY DRIVES INFLAMMATORY GENE EXPRESSION. ELEVEN CLASSICAL HISTONE DEACETYLASES (HDACS) ACT TO REGULATE THE EXPRESSION OF DISTINCT SUBSETS OF INFLAMMATORY/IMMUNE GENES. THUS, LOSS OF HDAC ACTIVITY OR THE PRESENCE OF HDAC INHIBITORS CAN FURTHER ENHANCE INFLAMMATORY GENE EXPRESSION BY PRODUCING A GENE-SPECIFIC CHANGE IN HAT ACTIVITY. FOR EXAMPLE, HDAC2 EXPRESSION AND ACTIVITY ARE REDUCED IN LUNG MACROPHAGES, BIOPSY SPECIMENS, AND BLOOD CELLS FROM PATIENTS WITH SEVERE ASTHMA AND SMOKING ASTHMATICS, AS WELL AS IN PATIENTS WITH CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). THIS MAY ACCOUNT, AT LEAST IN PART, FOR THE ENHANCED INFLAMMATION AND REDUCED STEROID RESPONSIVENESS SEEN IN THESE PATIENTS. OTHER PROTEINS, PARTICULARLY TRANSCRIPTION FACTORS, ARE ALSO ACETYLATED AND ARE TARGETS FOR DEACETYLATION BY HDACS AND SIRTUINS, A RELATED FAMILY OF 7 PREDOMINANTLY PROTEIN DEACETYLASES. THUS THE ACETYLATION/DEACETYLATION STATUS OF NF-KAPPAB AND THE GLUCOCORTICOID RECEPTOR CAN ALSO AFFECT THE OVERALL EXPRESSION PATTERN OF INFLAMMATORY GENES AND REGULATE THE INFLAMMATORY RESPONSE. UNDERSTANDING AND TARGETING SPECIFIC ENZYMES INVOLVED IN THIS PROCESS MIGHT LEAD TO NEW THERAPEUTIC AGENTS, PARTICULARLY IN SITUATIONS IN WHICH CURRENT ANTI-INFLAMMATORY THERAPIES ARE SUBOPTIMAL. 2011 12 5937 29 TARGETING HISTONE DEACETYLASE ACTIVITY IN RHEUMATOID ARTHRITIS AND ASTHMA AS PROTOTYPES OF INFLAMMATORY DISEASE: SHOULD WE KEEP OUR HATS ON? CELLULAR ACTIVATION, PROLIFERATION AND SURVIVAL IN CHRONIC INFLAMMATORY DISEASES IS REGULATED NOT ONLY BY ENGAGEMENT OF SIGNAL TRANS-DUCTION PATHWAYS THAT MODULATE TRANSCRIPTION FACTORS REQUIRED FOR THESE PROCESSES, BUT ALSO BY EPIGENETIC REGULATION OF TRANSCRIPTION FACTOR ACCESS TO GENE PROMOTER REGIONS. HISTONE ACETYL TRANSFERASES COORDINATE THE RECRUITMENT AND ACTIVATION OF TRANSCRIPTION FACTORS WITH CONFORMATIONAL CHANGES IN HISTONES THAT ALLOW GENE PROMOTER EXPOSURE. HISTONE DEACETYLASES (HDACS) COUNTERACT HISTONE ACETYL TRANSFERASE ACTIVITY THROUGH THE TARGETING OF BOTH HISTONES AS WELL AS NONHISTONE SIGNAL TRANSDUCTION PROTEINS IMPORTANT IN INFLAMMATION. NUMEROUS STUDIES HAVE INDICATED THAT DEPRESSED HDAC ACTIVITY IN PATIENTS WITH INFLAMMATORY AIRWAY DISEASES MAY CONTRIBUTE TO LOCAL PROINFLAMMATORY CYTOKINE PRODUCTION AND DIMINISH PATIENT RESPONSES TO CORTICOSTEROID TREATMENT. RECENT OBSERVATIONS THAT HDAC ACTIVITY IS DEPRESSED IN RHEUMATOID ARTHRITIS PATIENT SYNOVIAL TISSUE HAVE PREDICTED THAT STRATEGIES RESTORING HDAC FUNCTION MAY BE THERAPEUTIC IN THIS DISEASE AS WELL. PHARMACOLOGICAL INHIBITORS OF HDAC ACTIVITY, HOWEVER, HAVE DEMONSTRATED POTENT THERAPEUTIC EFFECTS IN ANIMAL MODELS OF ARTHRITIS AND OTHER CHRONIC INFLAMMATORY DISEASES. IN THE PRESENT REVIEW WE ASSESS AND RECONCILE THESE OUTWARDLY PARADOXICAL STUDY RESULTS TO PROVIDE A WORKING MODEL FOR HOW ALTERATIONS IN HDAC ACTIVITY MAY CONTRIBUTE TO PATHOLOGY IN RHEUMATOID ARTHRITIS, AND HIGHLIGHT KEY QUESTIONS TO BE ANSWERED IN THE PRECLINICAL EVALUATION OF COMPOUNDS MODULATING THESE ENZYMES. 2008 13 2591 30 EPIGENETICS OF PSORIASIS. PSORIASIS IS A CHRONIC AND RECURRENT INFLAMMATORY SKIN DISEASE, INVOLVING THE RAPID PROLIFERATION AND ABNORMAL DIFFERENTIATION OF KERATINOCYTES AND ACTIVATION OF T CELLS. IT IS GENERALLY ACCEPTED THAT THE CENTRAL PATHOGENESIS OF PSORIASIS IS A T CELL-DOMINANT IMMUNE DISORDER AFFECTED BY MULTIPLE FACTORS INCLUDING GENETIC SUSCEPTIBILITY, ENVIRONMENTAL FACTORS, INNATE AND ADAPTIVE IMMUNE RESPONSES, ETC. HOWEVER, THE EXACT ETIOLOGY IS LARGELY UNKNOWN. IN RECENT YEARS, EPIGENETIC INVOLVEMENTS, SUCH AS THE DNA METHYLATION, CHROMATIN MODIFICATIONS, AND NONCODING RNA REGULATION ARE REPORTED TO BE CRITICAL FOR THE PATHOGENESIS OF PSORIASIS. HOWEVER, THE INTERPLAY BETWEEN THESE FACTORS HAS ONLY RECENTLY BEEN STARTED TO BE UNRAVELED. NOTABLY, INHIBITORS OF ENZYMES THAT WORK IN EPIGENETIC MODIFICATIONS, SUCH AS DNA METHYLTRANSFERASES AND HISTONE DEACETYLASES, ARE BEGINNING TO APPEAR IN THE CLINICAL SETTING TO RESTORE NORMAL EPIGENETIC PATTERNS (GENERALI ET AL. IN J AUTOIMMUN 83:51-61, 2017), PROVIDING NOVEL THERAPEUTIC POTENTIAL AS NOVEL TREATMENT TARGETS FOR PSORIASIS. INDEED, MEDICATIONS PREVIOUSLY USED TO TREAT AUTOIMMUNE DISEASES HAVE LATER BEEN DISCOVERED TO EXERT THEIR ACTION VIA EPIGENETIC MECHANISMS. HEREIN, WE REVIEW THE FINDINGS ON EPIGENETICS ASSOCIATED WITH PSORIASIS, AND DISCUSS FUTURE PERSPECTIVES IN THIS FIELD. 2020 14 6057 21 THE DARK SIDE OF REGULATORY T CELLS IN PSORIASIS. PSORIASIS IS A HEREDITARY DISEASE ELICITED BY CHRONIC ACTIVATION OF CUTANEOUS T CELLS. DELINEATING THE MECHANISTIC INTERPLAY OF THE CELL SUBSETS INVOLVED IS KEY TO DEVELOPING THE NEXT GENERATION OF EFFECTIVE TREATMENTS. IN THIS ISSUE, BOVENSCHEN ET AL. REPORT THAT REGULATORY T CELLS MAINTAIN A FINE BALANCE BETWEEN THE TRANSCRIPTION FACTORS FOXP3 AND RORGAMMAT. IN PATIENTS WITH PSORIASIS, TREGS READILY TURN INTO IL-17-EXPRESSING CELLS, THUS POTENTIALLY PERPETUATING THE INFLAMMATORY PROCESS THAT CHARACTERIZES THE DISEASE. RESULTS DEMONSTRATING THAT THE HISTONE/PROTEIN DEACETYLATION INHIBITOR TRICHOSTATIN A CAN BLOCK THIS CONVERSION SUGGEST THAT AN EPIGENETIC MODIFICATION MAY UNDERLIE REGULATORY T-CELL PLASTICITY. 2011 15 297 32 AIM2 AND PSORIASIS. PSORIASIS IS A CHRONIC INFLAMMATORY SKIN DISEASE OCCURRING WORLDWIDE, WITH MULTIPLE SYSTEMIC COMPLICATIONS, WHICH SERIOUSLY AFFECT THE QUALITY OF LIFE AND PHYSICAL AND MENTAL HEALTH OF PATIENTS. THE PATHOGENESIS OF PSORIASIS IS RELATED TO THE ENVIRONMENT, GENETICS, EPIGENETICS, AND DYSREGULATION OF IMMUNE CELLS SUCH AS T CELLS, DENDRITIC CELLS (DCS), AND NONIMMUNE CELLS SUCH AS KERATINOCYTES. ABSENT IN MELANOMA 2 (AIM2), A SUSCEPTIBILITY GENE LOCUS FOR PSORIASIS, HAS BEEN STRONGLY LINKED TO THE GENETIC AND EPIGENETIC ASPECTS OF PSORIASIS AND INCREASED IN EXPRESSION IN PSORIATIC KERATINOCYTES. AIM2 WAS FOUND TO BE ACTIVATED IN AN INFLAMMASOME-DEPENDENT WAY TO RELEASE IL-1BETA AND IL-18 TO MEDIATE INFLAMMATION, AND TO PARTICIPATE IN IMMUNE REGULATION IN PSORIASIS, OR IN AN INFLAMMASOME-INDEPENDENT WAY BY REGULATING THE FUNCTION OF REGULATORY T(TREG) CELLS OR PROGRAMMING CELL DEATH IN KERATINOCYTES AS WELL AS CONTROLLING THE PROLIFERATIVE STATE OF DIFFERENT CELLS. AIM2 MAY ALSO PLAY A ROLE IN THE RECURRENCE OF PSORIASIS BY TRAINED IMMUNITY. IN THIS REVIEW, WE WILL ELABORATE ON THE CHARACTERISTICS OF AIM2 AND HOW AIM2 MEDIATES THE DEVELOPMENT OF PSORIASIS. 2023 16 6274 28 THE P300/CBP INHIBITOR A485 NORMALIZES PSORIATIC FIBROBLAST GENE EXPRESSION IN VITRO AND REDUCES PSORIASIS-LIKE SKIN INFLAMMATION IN VIVO. PSORIASIS IS A CHRONIC INFLAMMATORY SKIN DISEASE THAT OFTEN RECURS AT THE SAME LOCATIONS, INDICATING POTENTIAL EPIGENETIC CHANGES IN LESIONAL SKIN CELLS. IN THIS STUDY, WE DISCOVERED THAT FIBROBLASTS ISOLATED FROM PSORIATIC SKIN LESIONS RETAIN AN ABNORMAL PHENOTYPE EVEN AFTER SEVERAL PASSAGES IN CULTURE. TRANSCRIPTOMIC PROFILING REVEALED THE UPREGULATION OF SEVERAL GENES, INCLUDING THE EXTRA DOMAIN A SPLICE VARIANT OF FIBRONECTIN AND ITGA4 IN PSORIATIC FIBROBLASTS. A PHENOTYPIC LIBRARY SCREENING OF SMALL-MOLECULE EPIGENETIC MODIFIER DRUGS REVEALED THAT SELECTIVE CBP/P300 INHIBITORS WERE ABLE TO RESCUE THE PSORIATIC FIBROBLAST PHENOTYPE, REDUCING THE EXPRESSION LEVELS OF EXTRA DOMAIN A SPLICE VARIANT OF FIBRONECTIN AND ITGA4. IN THE IMIQUIMOD-INDUCED MOUSE MODEL OF PSORIASIS-LIKE SKIN INFLAMMATION, SYSTEMIC TREATMENT WITH A485, A POTENT CBP/P300 BLOCKER, SIGNIFICANTLY REDUCED SKIN INFLAMMATION, IMMUNE CELL RECRUITMENT, AND INFLAMMATORY CYTOKINE PRODUCTION. OUR FINDINGS INDICATE THAT EPIGENETIC REPROGRAMMING MIGHT REPRESENT A NEW APPROACH FOR THE TREATMENT AND/OR PREVENTION OF RELAPSES OF PSORIASIS. 2023 17 4961 29 PATHOGENESIS OF PSORIASIS IN THE "OMIC" ERA. PART II. GENETIC, GENOMIC AND EPIGENETIC CHANGES IN PSORIASIS. PSORIASIS IS A MULTIFACTORIAL DISEASE IN WHICH GENETIC, ENVIRONMENTAL AND EPIGENETIC FACTORS REGULATING GENE EXPRESSION PLAY A KEY ROLE. IN THE "GENOMIC ERA", GENOME-WIDE ASSOCIATION STUDIES TOGETHER WITH TARGET GENOTYPING PLATFORMS PERFORMED IN DIFFERENT ETHNIC POPULATIONS HAVE FOUND MORE THAN 50 GENETIC SUSCEPTIBLE MARKERS ASSOCIATED WITH THE RISK OF PSORIASIS WHICH HAVE BEEN IDENTIFIED SO FAR. UP TILL NOW, THE STRONGEST ASSOCIATION WITH THE RISK OF THE DISEASE HAS BEEN PROVED FOR HLA-C*06 GENE. THE MAJORITY OF OTHER PSORIASIS RISK SNPS ARE SITUATED NEAR THE GENES ENCODING MOLECULES INVOLVED IN ADAPTIVE AND INNATE IMMUNITY, AND SKIN BARRIER FUNCTION. MANY CONTEMPORARY STUDIES INDICATE THAT THE EPIGENETIC CHANGES: HISTONE MODIFICATION, PROMOTER METHYLATIONS, LONG NON-CODING AND MICRO-RNA HYPEREXPRESSION ARE CONSIDERED AS FACTORS CONTRIBUTING TO PSORIASIS PATHOGENESIS AS THEY REGULATE ABNORMAL KERATINOCYTE DIFFERENTIATION AND PROLIFERATION, ABERRANT KERATINOCYTES - INFLAMMATORY CELLS COMMUNICATION, NEOANGIOGENESIS AND CHRONIC INFLAMMATION. THE CIRCULATING MIRNAS DETECTED IN THE BLOOD MAY BECOME SPECIFIC MARKERS IN THE DIAGNOSIS, PROGNOSIS AND RESPONSE TO THE TREATMENT OF THE DISEASE. THE INHIBITION OF EXPRESSION IN SELECTED MIRNAS MAY BE A NEW PROMISING THERAPY OPTION FOR PATIENTS WITH PSORIASIS. 2020 18 5279 25 PROMOTER-SPECIFIC RELEVANCE OF HISTONE MODIFICATIONS INDUCED BY DEXAMETHASONE DURING THE REGULATION OF PRO-INFLAMMATORY MEDIATORS. GLUCOCORTICOSTEROIDS (GCS) ARE WIDELY USED TO TREAT DIFFERENT KINDS OF CHRONIC INFLAMMATORY AND IMMUNE DISEASES THROUGH TRANSCRIPTIONAL REGULATION OF INFLAMMATORY GENES. MODULATION OF GENE EXPRESSION BY GCS IS KNOWN TO OCCUR THROUGH DIVERSE MECHANISMS OF VARYING RELEVANCE TO SPECIFIC CLASSES OF GENES. EPIGENETIC MODIFICATIONS ARE INDEED A PIVOTAL REGULATORY FEATURE OF GLUCOCORTICOID RECEPTOR AND OTHER TRANSCRIPTION FACTORS. IN THIS STUDY, HISTONE POST-TRANSLATIONAL MODIFICATIONS WERE INVESTIGATED FOR THEIR INVOLVEMENT IN THE REGULATION OF SELECTED PRO-INFLAMMATORY GENES - EXPRESSED IN HUMAN MONOCYTE-DERIVED MACROPHAGES - IN RESPONSE TO TREATMENT WITH SYNTHETIC GC DEXAMETHASONE (DEX). WE SHOW THAT HISTONE TAIL ACETYLATION STATUS IS MODIFIED FOLLOWING DEX ADMINISTRATION, THROUGH DISTINCT AND ALTERNATIVE MECHANISMS AT THE PROMOTERS OF INTERLEUKIN-8 AND INTERLEUKIN-23. IN ADDITION TO HISTONE H3 ACETYLATION, OUR RESULTS DEMONSTRATE THAT H3 LYSINE 4 TRIMETHYLATION IS AFFECTED FOLLOWING DRUG TREATMENT. 2014 19 2070 21 EPIGENETIC CONTROL OF SKIN IMMUNITY. EPIGENETICS HAS BEEN WELL UNDERSTOOD FOR ITS ROLE IN CELL DEVELOPMENT; HOWEVER, IT IS NOW KNOWN TO REGULATE MANY PROCESSES INVOLVED IN IMMUNE CELL ACTIVATION IN A VARIETY OF CELLS. THE SKIN MAINTAINS HOMEOSTASIS VIA CROSSTALK BETWEEN IMMUNE AND NON-IMMUNE CELLS. DISRUPTION OF NORMAL EPIGENETIC REGULATION IN THESE CELLS MAY ALTER THE TRANSCRIPTION OF IMMUNE-REGULATORY FACTORS AND AFFECT THE IMMUNOLOGICAL BALANCE IN THE SKIN. THIS REVIEW SUMMARIZES RECENT EVIDENCE FOR THE EPIGENETIC REGULATION OF SKIN IMMUNITY. MUCH OF WHAT IS KNOWN ABOUT EPIGENETIC INVOLVEMENT IN SKIN IMMUNITY IS ASSOCIATED WITH DNA METHYLATION. THIS REVIEW FOCUSES ON EPIGENETIC REGULATION OF HISTONE MODIFICATION AND CHROMATIN REMODELING AND DESCRIBES THEIR ROLE IN THE TRANSCRIPTIONAL REGULATION OF IMMUNE-REGULATORY FACTORS. WHILE MUCH IS STILL UNKNOWN REGARDING THE REGULATION OF SKIN IMMUNITY VIA HISTONE MODIFICATION OR CHROMATIN REMODELING, THESE PROCESSES MAY UNDERLIE THE PATHOGENESIS OF CHRONIC CUTANEOUS IMMUNE DISORDERS. 2023 20 141 28 ABERRANT DNA METHYLATION OF MTOR PATHWAY GENES PROMOTES INFLAMMATORY ACTIVATION OF IMMUNE CELLS IN DIABETIC KIDNEY DISEASE. DNA METHYLATION HAS BEEN IMPLICATED IN THE PATHOGENESIS OF DIABETIC KIDNEY DISEASE (DKD), BUT THE UNDERLYING MECHANISMS REMAIN UNCLEAR. IN THIS STUDY, WE TESTED THE HYPOTHESIS THAT ABERRANT DNA METHYLATION IN PERIPHERAL IMMUNE CELLS CONTRIBUTES TO DKD PROGRESSION. WE SHOWED THAT LEVELS OF DNA METHYLTRANSFERASE 1 (DNMT1), A KEY ENZYME FOR DNA METHYLATION, WERE INCREASED ALONG WITH INFLAMMATORY ACTIVITY OF PERIPHERAL BLOOD MONONUCLEAR CELLS IN DKD PATIENTS. INHIBITION OF DNMT1 WITH 5-AZA-2'-DEOXYCYTIDINE (5-AZA) MARKEDLY INCREASED THE PROPORTION OF CD4(+)CD25(+) REGULATORY T CELLS IN PERIPHERAL BLOOD MONONUCLEAR CELLS IN CULTURE AND IN DIABETIC ANIMALS. ADOPTIVE TRANSFER OF IMMUNE CELLS FROM 5-AZA-TREATED ANIMALS SHOWED BENEFICIAL EFFECTS ON THE HOST IMMUNE SYSTEM, RESULTING IN A SIGNIFICANT IMPROVEMENT OF DKD. USING GENOME-WIDE DNA METHYLATION ASSAYS, WE IDENTIFIED THE DIFFERENTIALLY METHYLATED CYTOSINES IN THE PROMOTER REGIONS OF MAMMALIAN TARGET OF RAPAMYCIN (MTOR) REGULATORS IN PERIPHERAL BLOOD MONONUCLEAR CELLS OF DIABETIC PATIENTS. FURTHER, MRNA ARRAYS CONFIRMED THE CONSISTENT INDUCTION OF GENES EXPRESSED IN THE MTOR PATHWAY. IMPORTANTLY, DOWN-REGULATION OF DNMT1 EXPRESSION VIA RNA INTERFERENCE RESULTED IN PROMINENT CYTOSINE DEMETHYLATION OF MTOR NEGATIVE REGULATORS AND SUBSEQUENT DECREASE OF MTOR ACTIVITY. LASTLY, MODULATION OF MTOR RESULTED IN CHANGES IN THE EFFECT OF 5-AZA ON DIABETIC IMMUNE CELLS. THUS, UP-REGULATION OF DNMT1 IN DIABETIC IMMUNE CELLS INDUCES ABERRANT CYTOSINE METHYLATION OF THE UPSTREAM REGULATORS OF MTOR, LEADING TO PATHOGENIC ACTIVATION OF THE MTOR PATHWAY AND CONSEQUENT INFLAMMATION IN DIABETIC KIDNEYS. HENCE, THIS STUDY HIGHLIGHTS THERAPEUTIC POTENTIAL OF TARGETING EPIGENETIC EVENTS IN IMMUNE SYSTEM FOR TREATING DKD. 2019