1 3645 133 INCREASED PRESENCE AND DIFFERENTIAL MOLECULAR IMPRINTING OF TRANSIT AMPLIFYING CELLS IN PSORIASIS. PSORIASIS IS A VERY COMMON CHRONIC INFLAMMATORY SKIN DISEASE CHARACTERIZED BY EPIDERMAL THICKENING AND SCALING RESULTING FROM KERATINOCYTE HYPERPROLIFERATION AND IMPAIRED DIFFERENTIATION. PATHOMECHANISTIC STUDIES IN PSORIASIS ARE OFTEN LIMITED BY USING WHOLE SKIN TISSUE BIOPSIES, NEGLECTING THEIR STRATIFICATION AND CELLULAR DIVERSITY. THIS STUDY AIMED AT CHARACTERIZING EPIDERMAL ALTERATIONS IN PSORIASIS AT THE LEVEL OF KERATINOCYTE POPULATIONS. EPIDERMAL CELL POPULATIONS WERE PURIFIED FROM SKIN BIOPSIES OF PSORIASIS PATIENTS AND HEALTHY DONORS USING A NOVEL CELL TYPE-SPECIFIC APPROACH. MOLECULAR CHARACTERIZATION OF THE TRANSIT-AMPLIFYING CELLS (TAC), THE KEY PLAYERS OF EPIDERMAL RENEWAL, WAS PERFORMED USING IMMUNOCYTOFLUORESCENCE-TECHNIQUE AND INTEGRATED MULTISCALE-OMICS ANALYSES. ALREADY TAC FROM NON-LESIONAL PSORIATIC SKIN SHOWED ALTERED METHYLATION AND DIFFERENTIAL EXPRESSION IN 1.7% AND 1.0% OF ALL PROTEIN-CODING GENES, RESPECTIVELY. IN PSORIATIC LESIONS, TAC WERE STRONGLY EXPANDED SHOWING FURTHER INCREASED DIFFERENTIALLY METHYLATED (10-FOLD) AND EXPRESSED (22-FOLD) GENES NUMBERS. IMPORTANTLY, 17.2% OF DIFFERENTIALLY EXPRESSED GENES WERE ASSOCIATED WITH RESPECTIVE GENE METHYLATIONS. COMPARED WITH NON-LESIONAL TAC, PATHWAY ANALYSES REVEALED METABOLIC ALTERATIONS AS ONE FEATURE PREDOMINANTLY CHANGED IN TAC DERIVED FROM ACTIVE PSORIATIC LESIONS. OVERALL, OUR STUDY SHOWED STAGE-SPECIFIC MOLECULAR ALTERATIONS, ALLOWS NEW INSIGHTS INTO THE PATHOGENESIS, AND IMPLIES THE INVOLVEMENT OF EPIGENETIC MECHANISMS IN LESION DEVELOPMENT IN PSORIASIS. KEY MESSAGES: TRANSIT AMPLIFYING CELL (TAC) NUMBERS ARE HIGHLY INCREASED IN PSORIATIC LESIONS PSORIATIC TAC SHOW PROFOUND MOLECULAR ALTERATIONS & STAGE-SPECIFIC IDENTITY TAC FROM UNAFFECTED AREAS ALREADY SHOW FIRST SIGNS OF MOLECULAR ALTERATIONS LESIONAL TAC SHOW A PREFERENCE IN METABOLIC-RELATED ALTERATIONS. 2020 2 2726 27 EXPERIMENTAL PHARMACOLOGICAL MANAGEMENT OF PSORIASIS. PSORIASIS IS A CHRONIC, RELAPSING, IMMUNE-MEDIATED SYSTEMIC DISEASE. ITS PATHOGENESIS IS COMPLEX AND NOT FULLY UNDERSTOOD YET. GENETIC AND EPIGENETIC FACTORS INTERACT WITH MOLECULAR PATHWAYS INVOLVING TNF-ALPHA, IL-23/IL-17 AXIS, AND PECULIAR CYTOKINES, AS IL-36 OR PHOSPHODIESTERASE 4. THIS REVIEW DISCUSSES THE MECHANISMS INVOLVED IN THE DEVELOPMENT OF THE DISEASE, AS WELL AS THE THERAPEUTIC OPTIONS PROPOSED FOLLOWING THE INVESTIGATION OF THE INFLAMMATORY PSORIATIC PATHWAYS. WE PERFORMED A COMPREHENSIVE SEARCH USING THE WORDS "PSORIASIS" AND THE NEWEST MOLECULES CURRENTLY UNDER INVESTIGATION AND APPROVAL. FROM THESE DATA, A NEW SCENARIO IN PSORIASIS IS OCCURRING TO PERSONALIZE THE THERAPIES - ESPECIALLY SYSTEMIC ONES AND THOSE USING SMALL MOLECULES - AND AVOID TOPICAL AND INJECTABLE DRUGS. WE REPORTED THE NEWEST THERAPEUTIC OPPORTUNITIES, INCLUDING THE INHIBITORS OF JANUS KINASE/TYROSINE KINASE 2, PHOSPHODIESTERASE-4 AND IL-36 RECEPTOR. TODAY, MORE THAN 20 MOLECULES ARE UNDER INVESTIGATION FOR THE TREATMENT OF CUTANEOUS PSORIASIS. MOST OF THEM ARE CONSTITUTED BY SMALL MOLECULES OR BIOLOGIC THERAPIES. THIS UNDERLINES HOW PSORIASIS NEEDS SYSTEMIC THERAPIES, DUE TO ITS COMPLEX PATHOGENESIS AND MULTISYSTEMIC INVOLVEMENT. 2021 3 1570 37 DNA METHYLATION PATTERNS IN CD4(+) T-CELLS SEPARATE PSORIASIS PATIENTS FROM HEALTHY CONTROLS, AND SKIN PSORIASIS FROM PSORIATIC ARTHRITIS. BACKGROUND: PSORIASIS IS AN AUTOIMMUNE/INFLAMMATORY DISORDER PRIMARILY AFFECTING THE SKIN. CHRONIC JOINT INFLAMMATION TRIGGERS THE DIAGNOSIS OF PSORIATIC ARTHRITIS (PSA) IN APPROXIMATELY ONE-THIRD OF PSORIASIS PATIENTS. ALTHOUGH JOINT DISEASE TYPICALLY FOLLOWS THE ONSET OF SKIN PSORIASIS, IN AROUND 15% OF CASES IT IS THE INITIAL PRESENTATION, WHICH CAN RESULT IN DIAGNOSTIC DELAYS. THE PATHOPHYSIOLOGICAL MECHANISMS UNDERLYING PSORIASIS AND PSA ARE NOT YET FULLY UNDERSTOOD, BUT THERE IS EVIDENCE POINTING TOWARDS EPIGENETIC DYSREGULATION INVOLVING CD4(+) AND CD8(+) T-CELLS. OBJECTIVES: THE AIM OF THIS STUDY WAS TO INVESTIGATE DISEASE-ASSOCIATED DNA METHYLATION PATTERNS IN CD4(+) T-CELLS FROM PSORIASIS AND PSA PATIENTS THAT MAY REPRESENT POTENTIAL DIAGNOSTIC AND/OR PROGNOSTIC BIOMARKERS. METHODS: PBMCS WERE COLLECTED FROM 12 PATIENTS WITH CHRONIC PLAQUE PSORIASIS AND 8 PSA PATIENTS, AND 8 HEALTHY CONTROLS. CD4(+) T-CELLS WERE SEPARATED THROUGH FACS SORTING, AND DNA METHYLATION PROFILING WAS PERFORMED (ILLUMINA EPIC850K ARRAYS). BIOINFORMATIC ANALYSES, INCLUDING GENE ONTOLOGY (GO) AND KEGG PATHWAY ANALYSIS, WERE PERFORMED USING R. TO IDENTIFY GENES UNDER THE CONTROL OF INTERFERON (IFN), THE INTERFEROME DATABASE WAS CONSULTED, AND DNA METHYLATION SCORES WERE CALCULATED. RESULTS: NUMBERS AND PROPORTIONS OF CD4(+) T-CELL SUBSETS (NAIVE, CENTRAL MEMORY, EFFECTOR MEMORY, CD45RA RE-EXPRESSING EFFECTOR MEMORY CELLS) DID NOT VARY BETWEEN CONTROLS, SKIN PSORIASIS AND PSA PATIENTS. 883 DIFFERENTIALLY METHYLATED POSITIONS (DMPS) AFFECTING 548 GENES WERE IDENTIFIED BETWEEN CONTROLS AND "ALL" PSORIASIS PATIENTS. PRINCIPAL COMPONENT AND PARTIAL LEAST-SQUARES DISCRIMINANT ANALYSIS SEPARATED CONTROLS FROM SKIN PSORIASIS AND PSA PATIENTS. GO ANALYSIS CONSIDERING PROMOTER DMPS DELIVERED HYPERMETHYLATION OF GENES INVOLVED IN "REGULATION OF WOUND HEALING, SPREADING OF EPIDERMAL CELLS", "NEGATIVE REGULATION OF CELL-SUBSTRATE JUNCTION ORGANIZATION" AND "NEGATIVE REGULATION OF FOCAL ADHESION ASSEMBLY". COMPARING CONTROLS AND "ALL" PSORIASIS, A MAJORITY OF DMPS MAPPED TO IFN-RELATED GENES (69.2%). NOTABLY, DNA METHYLATION PROFILES ALSO DISTINGUISHED SKIN PSORIASIS FROM PSA PATIENTS (2,949 DMPS/1,084 GENES) THROUGH GENES AFFECTING "CAMP-DEPENDENT PROTEIN KINASE INHIBITOR ACTIVITY" AND "CAMP-DEPENDENT PROTEIN KINASE REGULATOR ACTIVITY". TREATMENT WITH CYTOKINE INHIBITORS (IL-17/TNF) CORRECTED DNA METHYLATION PATTERNS OF IL-17/TNF-ASSOCIATED GENES, AND METHYLATION SCORES CORRELATED WITH SKIN DISEASE ACTIVITY SCORES (PASI). CONCLUSION: DNA METHYLATION PROFILES IN CD4(+) T-CELLS DISCRIMINATE BETWEEN SKIN PSORIASIS AND PSA. DNA METHYLATION SIGNATURES MAY BE APPLIED FOR QUANTIFICATION OF DISEASE ACTIVITY AND PATIENT STRATIFICATION TOWARDS INDIVIDUALIZED TREATMENT. 2023 4 4452 22 MOLECULAR MECHANISMS AND MANAGEMENT OF A CUTANEOUS INFLAMMATORY DISORDER: PSORIASIS. PSORIASIS IS A COMPLEX CHRONIC INFLAMMATORY CUTANEOUS DISORDER. TO DATE, ROBUST MOLECULAR MECHANISMS OF PSORIASIS HAVE BEEN REPORTED. AMONG DIVERSE ABERRANT IMMUNOPATHOGENETIC MECHANISMS, THE CURRENT MODEL EMPHASIZES THE ROLE OF TH1 AND THE IL-23/TH17 AXIS, SKIN-RESIDENT IMMUNE CELLS AND MAJOR SIGNAL TRANSDUCTION PATHWAYS INVOLVED IN PSORIASIS. THE MULTIPLE GENETIC RISK LOCI FOR PSORIASIS HAVE BEEN RAPIDLY REVEALED WITH THE ADVENT OF A NOVEL TECHNOLOGY. MOREOVER, IDENTIFYING EPIGENETIC MODIFICATIONS COULD BRIDGE THE GAP BETWEEN GENETIC AND ENVIRONMENTAL RISK FACTORS IN PSORIASIS. THIS REVIEW WILL PROVIDE A BETTER UNDERSTANDING OF THE PATHOGENESIS OF PSORIASIS BY UNRAVELING THE COMPLICATED INTERPLAY AMONG IMMUNOLOGICAL ABNORMALITIES, GENETIC RISK FOCI, EPIGENETIC MODIFICATION AND ENVIRONMENTAL FACTORS OF PSORIASIS. WITH ADVANCES IN MOLECULAR BIOLOGY, DIVERSE NEW TARGETS ARE UNDER INVESTIGATION TO MANAGE PSORIASIS. THE RECENT ADVANCES IN TREATMENT MODALITIES FOR PSORIASIS BASED ON TARGETED MOLECULES ARE ALSO DISCUSSED. 2017 5 631 28 BIOLOGICAL AND SYNTHETIC TARGET DMARDS IN PSORIATIC ARTHRITIS. PSORIATIC ARTHRITIS (PSA) IS A CHRONIC MULTI-FACETED IMMUNE-MEDIATED SYSTEMIC DISORDER, CHARACTERIZED BY ARTICULAR, CUTANEOUS, ENTHESIS, NAIL AND SPINE INVOLVEMENT. ARTICULAR MANIFESTATIONS OF PSA ARE PARTICULARLY COMMON AND HIGHLY DISABLING FOR PATIENTS, WHILE THE HETEROGENEOUS CLINICAL SUBSETS OF THE DISEASE ARE CHALLENGING FOR CLINICIANS. IN RECENT YEARS, RESEARCH HAS MADE MANY ADVANCES IN UNDERSTANDING THE PATHOGENESIS OF THE DISEASE FROM GENETIC, EPIGENETIC AND MOLECULAR POINTS OF VIEW. NEW DRUGS ARE NOW AVAILABLE FOR THE TREATMENT OF THIS CONDITION, AND, IN PARTICULAR, TNF-ALFA INHIBITORS, HISTORICALLY THE FIRST BIOLOGICALS APPROVED IN PSA, ARE NOW JUXTAPOSED BY NEW BIOLOGICAL DISEASE MODIFYING ANTI-RHEUMATIC DRUGS (BDMARDS) WITH DIFFERENT MODES OF ACTION. TARGETING IL-12/IL-23 P40 COMMON SUBUNIT WITH USTEKINUMAB, IL-17A WITH SECUKINUMAB AND IXEKIZUMAB, T CELLS CO-STIMULATION WITH ABATACEPT, IS NOW POSSIBLE, SAFE AND EFFECTIVE. MOREOVER, TARGETED SYNTHETIC MOLECULES WITH ORAL ADMINISTRATION ARE AVAILABLE, WITH THE POSSIBILITY TO INTERFERE WITH PHOSPHODIESTERASE-4 AND JAK/STAT PATHWAYS. INDEED, NEW DRUGS ARE UNDER DEVELOPMENT, WITH THE POSSIBILITY TO TARGET SELECTIVELY IL-17 RECEPTOR, IL-23, AND OTHER KEY MOLECULAR TARGETS IN THE PATHOGENESIS OF THIS CONDITION. IN THIS NARRATIVE REVIEW, WE PROVIDE AN UP-TO-DATE OVERVIEW OF THE CURRENT APPLICATION OF BIOLOGICAL AND TARGETED SYNTHETIC DMARDS IN THE FIELD OF PSA, WITH PARTICULAR REGARD TO THE CLINICAL SIGNIFICANCE OF THIS POSSIBILITY TO TARGET A HIGHER NUMBER OF DISTINCT IMMUNE-PATHWAYS. 2019 6 4883 29 OVERVIEW OF THE MOLECULAR DETERMINANTS CONTRIBUTING TO THE EXPRESSION OF PSORIASIS AND PSORIATIC ARTHRITIS PHENOTYPES. PSORIASIS AND PSORIATIC ARTHRITIS ARE MULTIFACTORIAL CHRONIC DISORDERS WHOSE ETIOPATHOGENESIS ESSENTIALLY DERIVES FROM THE ALTERATION OF SEVERAL SIGNALLING PATHWAYS AND THE CO-OCCURRENCE OF GENETIC, EPIGENETIC AND NON-GENETIC SUSCEPTIBILITY FACTORS THAT ALTOGETHER AFFECT THE FUNCTIONAL AND STRUCTURAL PROPERTY OF THE SKIN. ALTHOUGH SHARED AND DIFFERENTIAL SUSCEPTIBILITY GENES AND MOLECULAR PATHWAYS ARE KNOWN TO CONTRIBUTE TO THE ONSET OF PATHOLOGICAL PHENOTYPES, FURTHER RESEARCH IS NEEDED TO DISSECT THE MOLECULAR CAUSES OF PSORIATIC DISEASE AND ITS PROGRESSION TOWARDS PSORIATIC ARTHRITIS. THIS REVIEW WILL THEREFORE BE ADDRESSED TO EXPLORE DIFFERENCES AND SIMILARITIES IN THE ETIOPATHOGENESIS AND PROGRESSION OF BOTH DISORDERS, WITH A PARTICULAR FOCUS ON GENES INVOLVED IN THE MAINTENANCE OF THE SKIN STRUCTURE AND INTEGRITY (KERATINS AND COLLAGENS), MODULATION OF PATTERNS OF RECOGNITION (THROUGH TOLL-LIKE RECEPTORS AND DECTIN-1) AND IMMUNO-INFLAMMATORY RESPONSE (BY NLRP3-DEPENDENT INFLAMMASOME) TO MICROBIAL PATHOGENS. IN ADDITION, SPECIAL EMPHASIS WILL BE GIVEN TO THE CONTRIBUTION OF EPIGENETIC ELEMENTS (METHYLATION PATTERN, NON-CODING RNAS, CHROMATIN MODIFIERS AND 3D GENOME ORGANIZATION) TO THE ETIOPATHOGENESIS AND PROGRESSION OF PSORIASIS AND PSORIATIC ARTHRITIS. THE EVIDENCE DISCUSSED IN THIS REVIEW HIGHLIGHTS HOW THE KNOWLEDGE OF PATIENTS' CLINICAL AND (EPI)GENOMIC MAKE-UP COULD BE HELPFUL FOR IMPROVING THE AVAILABLE THERAPEUTIC STRATEGIES FOR PSORIASIS AND PSORIATIC ARTHRITIS TREATMENT. 2020 7 2063 27 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 8 4756 33 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 9 6343 24 THE ROLE OF EPIGENETICS AND IMMUNOLOGICAL IMBALANCE IN THE ETIOPATHOGENESIS OF PSORIASIS AND PSORIATIC ARTHRITIS. PSORIASIS (PS) AND PSORIATIC ARTHRITIS (PSA) REPRESENT A CLINICAL AND IMMUNOPATHOGENIC CONTINUUM, CALLED PSORIATIC DISEASE, CUMULATIVELY AFFECTING APPROXIMATELY 3% OF THE GENERAL POPULATION. PSORIATIC DISEASE IS A CHRONIC INFLAMMATORY DISORDER AFFECTING THE SKIN AND MUSCULOSKELETAL SYSTEM. THE IMMUNO-PATHOGENESIS IS CHARACTERIZED BY AN ACTIVATION OF THE TNF/IL-23/IL-17 CYTOKINE AXIS, LEADING TO AN IMMUNOLOGIC IMBALANCE OF T-CELLS RESIDENT IN ALL AFFECTED TISSUES, MAINLY ENTHESES. IN THE MAJORITY OF CASES, SKIN PS PREDATES RHEUMATOLOGICAL MANIFESTATIONS. SECONDARY TO THE HIGHER INCIDENCE AND THE AVAILABILITY OF MOUSE MODELS, THERE IS STRONGER DATA AVAILABLE ON SKIN PS, AND DATA ARE, IN MOST CASES, RELEVANT ALSO TO PSA. IN A WIDELY ACCEPTED MODEL, ENVIRONMENTAL TRIGGER FACTORS LIKE INFECTIONS OR TRAUMA ARE CAPABLE OF INITIATING AN INFLAMMATORY CASCADE, ULTIMATELY CREATING A SUSTAINED STATE OF CHRONIC INFLAMMATION IN GENETICALLY SUSCEPTIBLE INDIVIDUALS. BESIDES WELL-KNOWN GENETIC SUSCEPTIBILITY LOCI, EPIGENETIC DNA MODIFICATIONS, WHICH ARE ASSOCIATED WITH PS DEVELOPMENT HAVE BEEN CHARACTERIZED RECENTLY AND WILL BE DISCUSSED IN THIS ARTICLE. THE CURRENT EVIDENCE IS PROMISING IN THE POSSIBILITY TO PROVIDE NEW THERAPEUTIC AVENUES AND FILL THE UNMET NEED OF PATIENTS, FOR WHOM CURRENT TREATMENTS EITHER DO NOT ALLOW THE DISEASE TO BE CONTROLLED OR MUST BE CONTINUED FOR LIFE. 2019 10 4962 31 PATHOGENESIS OF PSORIATIC ARTHRITIS. PSORIATIC ARTHRITIS (PSA) IS A CHRONIC INFLAMMATORY ARTHROPATHY INVOLVING SYNOVIAL AND ENTHESEAL STRUCTURES, ASSOCIATED WITH PSORIASIS OR SIMILAR CONDITIONS. THE ETIOPATHOGENETIC MECHANISMS UNDERLYING PSA REMAIN UNCLARIFIED. THE MOST ACCREDITED HYPOTHESIS INVOLVES A COMPLEX INTERACTION AMONG GENETIC, ENVIRONMENTAL, AND IMMUNOLOGICAL FACTORS. ENVIRONMENTAL AGENTS, PARTICULARLY TRAUMA, MECHANICAL STRESS, AND SMOKE HAVE BEEN CITED AS POSSIBLE FACTORS IN TRIGGERING THE DISEASE IN GENETICALLY PREDISPOSED SUBJECTS. LIKE OTHER FORMS OF SPONDYLOARTHROPATHIES, PSA SHOWS SEVERAL GENETIC ASSOCIATIONS WITH THE MAJOR HISTOCOMPATIBILITY COMPLEX (MHC) CLASS I ALLELES LOCATED ON CHROMOSOME 6P21.3, PARTICULARLY THE HUMAN LEUKOCYTE ANTIGEN (HLA)-B27 IN AXIAL PHENOTYPES. RECENT STUDIES HAVE DEMONSTRATED THAT THE MOST COMMON EPIGENETIC MECHANISMS THAT REGULATE GENE EXPRESSION IN PSA ARE REPRESENTED BY DNA METHYLATION, PARENT OF ORIGIN EFFECT OR GENOMIC IMPRINTING, EXPRESSION OR ACTIVITY OF EPIGENETIC MODIFYING ENZYMES, AND RNA INTERFERENCE (RNAI) BY MICRORNAS (MIRNAS). THE MECHANISMS UNDERLYING PSA PATHOGENESIS ACTIVATE THE INNATE AND ADAPTIVE IMMUNE SYSTEM AND OVEREXPRESSION OF TNF ASSOCIATED WITH AMPLIFICATION OF THE IL-23/IL-17 AXIS. IN RECENT YEARS, MORE PSA SUSCEPTIBILITY GENES AND EPIGENETIC MECHANISMS HAVE BEEN IDENTIFIED. ADVANCES IN THE KNOWLEDGE OF INNATE AND ADAPTIVE IMMUNE MECHANISMS UNDERLYING PSA HAVE CONTRIBUTED TO A BETTER UNDERSTANDING OF THE HETEROGENEOUS CLINICAL EXPRESSION OF THE DISEASE AND, THUS, TO THERAPY STRATEGIES. THE COMPLEXITY OF THE PATHOGENETIC ASPECTS INVOLVING MULTIPLE CYTOKINES, CELL LINES, AND MOLECULES NEEDS TO BE FURTHER INVESTIGATED TO ADVANCE PERSONALIZED THERAPEUTIC STRATEGIES AND TO IMPROVE OUTCOMES OF PATIENTS AFFECTED BY PSA. 2019 11 5309 30 PSORIASIS PATHOGENESIS AND TREATMENT. RESEARCH ON PSORIASIS PATHOGENESIS HAS LARGELY INCREASED KNOWLEDGE ON SKIN BIOLOGY IN GENERAL. IN THE PAST 15 YEARS, BREAKTHROUGHS IN THE UNDERSTANDING OF THE PATHOGENESIS OF PSORIASIS HAVE BEEN TRANSLATED INTO TARGETED AND HIGHLY EFFECTIVE THERAPIES PROVIDING FUNDAMENTAL INSIGHTS INTO THE PATHOGENESIS OF CHRONIC INFLAMMATORY DISEASES WITH A DOMINANT IL-23/TH17 AXIS. THIS REVIEW DISCUSSES THE MECHANISMS INVOLVED IN THE INITIATION AND DEVELOPMENT OF THE DISEASE, AS WELL AS THE THERAPEUTIC OPTIONS THAT HAVE ARISEN FROM THE DISSECTION OF THE INFLAMMATORY PSORIATIC PATHWAYS. OUR DISCUSSION BEGINS BY ADDRESSING THE INFLAMMATORY PATHWAYS AND KEY CELL TYPES INITIATING AND PERPETUATING PSORIATIC INFLAMMATION. NEXT, WE DESCRIBE THE ROLE OF GENETICS, ASSOCIATED EPIGENETIC MECHANISMS, AND THE INTERACTION OF THE SKIN FLORA IN THE PATHOPHYSIOLOGY OF PSORIASIS. FINALLY, WE INCLUDE A COMPREHENSIVE REVIEW OF WELL-ESTABLISHED WIDELY AVAILABLE THERAPIES AND NOVEL TARGETED DRUGS. 2019 12 297 30 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 13 3068 37 GENOME-WIDE DNA METHYLATION PROFILING IDENTIFIES DIFFERENTIAL METHYLATION IN UNINVOLVED PSORIATIC EPIDERMIS. PSORIASIS IS A CHRONIC INFLAMMATORY SKIN DISEASE WITH BOTH LOCAL AND SYSTEMIC COMPONENTS. GENOME-WIDE APPROACHES HAVE IDENTIFIED MORE THAN 60 PSORIASIS-SUSCEPTIBILITY LOCI, BUT GENES ARE ESTIMATED TO EXPLAIN ONLY ONE-THIRD OF THE HERITABILITY IN PSORIASIS, SUGGESTING ADDITIONAL, YET UNIDENTIFIED, SOURCES OF HERITABILITY. EPIGENETIC MODIFICATIONS HAVE BEEN LINKED TO PSORIASIS AND ALTERED DNA METHYLATION PATTERNS IN PSORIATIC VERSUS HEALTHY SKIN HAVE BEEN REPORTED IN WHOLE-SKIN BIOPSIES. IN THIS STUDY, FOCUSING ON EPIGENETIC MODIFICATIONS IN THE PSORIATIC UNINVOLVED SKIN, WE COMPARED THE LESIONAL AND NON-LESIONAL EPIDERMIS FROM PSORIASIS PATIENTS WITH EPIDERMIS FROM HEALTHY CONTROLS. WE PERFORMED AN EXHAUSTIVE GENOME-WIDE DNA METHYLATION PROFILING USING REDUCED REPRESENTATION BISULFITE SEQUENCING, WHICH INTERROGATES THE METHYLATION STATUS OF APPROXIMATELY 3-4 MILLION CPG SITES. MORE THAN 2,000 STRONGLY DIFFERENTIALLY METHYLATED SITES WERE IDENTIFIED AND A STRIKING OVERREPRESENTATION OF THE WNT AND CADHERIN PATHWAYS AMONG THE DIFFERENTIALLY METHYLATED SITES WAS FOUND. IN PARTICULAR, WE OBSERVE A STRONG DIFFERENTIAL METHYLATION IN SEVERAL PSORIASIS CANDIDATE GENES. A SUBSTANTIAL NUMBER OF DIFFERENTIALLY METHYLATED SITES PRESENT IN THE UNINVOLVED VERSUS HEALTHY EPIDERMIS SUGGESTS THE PRESENCE OF A PRE-PSORIATIC STATE IN THE CLINICALLY HEALTHY SKIN TYPE. OUR EXPLORATORY STUDY REPRESENTS A STARTING POINT FOR IDENTIFYING BIOMARKERS FOR PSORIASIS-PRONE SKIN BEFORE DISEASE ONSET. 2018 14 4319 25 MICRORNAS IN AXIAL SPONDYLARTHRITIS: AN OVERVIEW OF THE RECENT PROGRESSES IN THE FIELD WITH A FOCUS ON ANKYLOSING SPONDYLITIS AND PSORIATIC ARTHRITIS. PURPOSE OF REVIEW: TO HIGHLIGHT THE RECENT DISCOVERIES AND LINES OF EVIDENCE ON THE ROLE OF MICRORNAS IN ANKYLOSING SPONDYLITIS (AS) AND PSORIATIC ARTHRITIS (PSA), FOCUSING ON THEIR EXPRESSION PROFILING AND MECHANISMS OF ACTION. RECENT FINDINGS: AS AND PSA ARE CHRONIC INFLAMMATORY MUSCULOSKELETAL DISEASES WITH AXIAL MANIFESTATIONS AND REPRESENT AN EXCELLENT MODEL FOR STUDYING MICRORNAS CONTRIBUTION TO THE DISEASE PATHOGENESIS, PARTICULARLY THROUGH IMMUNOMODULATION, INFLAMMATION, AND BONE REMODELLING, OR THEIR VALUE AS CANDIDATE DIAGNOSTIC AND PROGNOSTIC BIOMARKERS. MICRORNAS ARE SINGLE-STRANDED NUCLEOTIDES ABLE TO REGULATE GENE EXPRESSION. THEY ARE A KEY COMPONENT OF THE EPIGENETIC MACHINERY, INVOLVED IN PHYSIOLOGICAL AND PATHOLOGICAL PROCESSES. THE CONTRIBUTION OF MICRORNAS IN AS AND PSA (SUCH AS MIR-29A IN REGULATING BONE METABOLISM) IS HIGHLIGHTED BY SEVERAL WORKS IN THE FIELD BUT THEIR UTILITY AS POSSIBLE MARKERS MUST BE STILL CONFIRMED, PARTICULARLY IN LARGER PATIENTS' COHORTS. 2021 15 1571 45 DNA METHYLATION PATTERNS IN CD8(+) T CELLS DISCERN PSORIASIS FROM PSORIATIC ARTHRITIS AND CORRELATE WITH CUTANEOUS DISEASE ACTIVITY. BACKGROUND: PSORIASIS IS A T CELL-MEDIATED CHRONIC AUTOIMMUNE/INFLAMMATORY DISEASE. WHILE SOME PATIENTS EXPERIENCE DISEASE LIMITED TO THE SKIN (SKIN PSORIASIS), OTHERS DEVELOP JOINT INVOLVEMENT (PSORIATIC ARTHRITIS; PSA). IN THE ABSENCE OF DISEASE- AND/OR OUTCOME-SPECIFIC BIOMARKERS, AND AS ARTHRITIS CAN PRECEDE SKIN MANIFESTATIONS, DIAGNOSTIC AND THERAPEUTIC DELAYS ARE COMMON AND CONTRIBUTE TO DISEASE BURDEN AND DAMAGE ACCRUAL. OBJECTIVE: ALTERED EPIGENETIC MARKS, INCLUDING DNA METHYLATION, CONTRIBUTE TO EFFECTOR T CELL PHENOTYPES AND ALTERED CYTOKINE EXPRESSION IN AUTOIMMUNE/INFLAMMATORY DISEASES. THIS PROJECT AIMED AT THE IDENTIFICATION OF DISEASE-/OUTCOME-SPECIFIC DNA METHYLATION SIGNATURES IN CD8(+) T CELLS FROM PATIENTS WITH PSORIASIS AND PSA AS COMPARED TO HEALTHY CONTROLS. METHOD: PERIPHERAL BLOOD CD8(+) T CELLS FROM NINE HEALTHY CONTROLS, 10 PSORIASIS, AND SEVEN PSA PATIENTS WERE COLLECTED TO ANALYZE DNA METHYLATION MARKS USING ILLUMINA HUMAN METHYLATION EPIC BEADCHIPS (>850,000 CPGS PER SAMPLE). BIOINFORMATIC ANALYSIS WAS PERFORMED USING R (MINFI, LIMMA, CHAMP, AND DMRCATE PACKAGES). RESULTS: DNA METHYLATION PROFILES IN CD8(+) T CELLS DIFFERENTIATE HEALTHY CONTROLS FROM PSORIASIS PATIENTS [397 DIFFERENTIALLY METHYLATED POSITIONS (DMPS); 9 DIFFERENTIALLY METHYLATED REGIONS (DMRS) WHEN >/=CPGS PER DMR WERE CONSIDERED; 2 DMRS FOR >/=10 CPGS]. FURTHERMORE, PATIENTS WITH SKIN PSORIASIS CAN BE DISCRIMINATED FROM PSA PATIENTS [1,861 DMPS, 20 DMRS (>/=5 CPGS PER REGION), 4 DMRS (>/=10 CPGS PER REGION)]. GENE ONTOLOGY (GO) ANALYSES CONSIDERING GENES WITH >/=1 DMP IN THEIR PROMOTER DELIVERED METHYLATION DEFECTS IN SKIN PSORIASIS AND PSA PRIMARILY AFFECTING THE BMP SIGNALING PATHWAY AND ENDOPEPTIDASE REGULATOR ACTIVITY, RESPECTIVELY. GO ANALYSIS OF GENES ASSOCIATED WITH DMRS BETWEEN SKIN PSORIASIS AND PSA DEMONSTRATED AN ENRICHMENT OF GABAERGIC NEURON AND CORTEX NEURON DEVELOPMENT PATHWAYS. TREATMENT WITH CYTOKINE BLOCKERS ASSOCIATED WITH DNA METHYLATION CHANGES [2,372 DMPS; 1,907 DMPS WITHIN PROMOTERS, 7 DMRS (>/=5 CPG PER REGIONS)] AFFECTING TRANSFORMING GROWTH FACTOR BETA RECEPTOR AND TRANSMEMBRANE RECEPTOR PROTEIN SERINE/THREONINE KINASE SIGNALING PATHWAYS. LASTLY, A METHYLATION SCORE INCLUDING TNF AND IL-17 PATHWAY ASSOCIATED DMPS INVERSE CORRELATES WITH SKIN DISEASE ACTIVITY SCORES (PASI). CONCLUSION: PATIENTS WITH SKIN PSORIASIS EXHIBIT DNA METHYLATION PATTERNS IN CD8(+) T CELLS THAT ALLOW DIFFERENTIATION FROM PSA PATIENTS AND HEALTHY INDIVIDUALS, AND REFLECT CLINICAL ACTIVITY OF SKIN DISEASE. THUS, DNA METHYLATION PROFILING PROMISES POTENTIAL AS DIAGNOSTIC AND PROGNOSTIC TOOL TO BE USED FOR MOLECULAR PATIENT STRATIFICATION TOWARD INDIVIDUALIZED TREATMENT. 2021 16 118 33 A SUBSET OF METHYLATED CPG SITES DIFFERENTIATE PSORIATIC FROM NORMAL SKIN. PSORIASIS IS A CHRONIC INFLAMMATORY IMMUNE-MEDIATED DISORDER AFFECTING THE SKIN AND OTHER ORGANS INCLUDING JOINTS. OVER 1,300 TRANSCRIPTS ARE ALTERED IN PSORIATIC INVOLVED SKIN COMPARED WITH NORMAL SKIN. HOWEVER, TO OUR KNOWLEDGE, GLOBAL EPIGENETIC PROFILING OF PSORIATIC SKIN IS PREVIOUSLY UNREPORTED. HERE, WE DESCRIBE A GENOME-WIDE STUDY OF ALTERED CPG METHYLATION IN PSORIATIC SKIN. WE DETERMINED THE METHYLATION LEVELS AT 27,578 CPG SITES IN SKIN SAMPLES FROM INDIVIDUALS WITH PSORIASIS (12 INVOLVED, 8 UNINVOLVED) AND 10 UNAFFECTED INDIVIDUALS. CPG METHYLATION OF INVOLVED SKIN DIFFERED FROM NORMAL SKIN AT 1,108 SITES. TWELVE MAPPED TO THE EPIDERMAL DIFFERENTIATION COMPLEX, UPSTREAM OR WITHIN GENES THAT ARE HIGHLY UPREGULATED IN PSORIASIS. HIERARCHICAL CLUSTERING OF 50 OF THE TOP DIFFERENTIALLY METHYLATED (DM) SITES SEPARATED PSORIATIC FROM NORMAL SKIN SAMPLES WITH UNINVOLVED SKIN EXHIBITING INTERMEDIATE METHYLATION. CPG SITES WHERE METHYLATION WAS CORRELATED WITH GENE EXPRESSION ARE REPORTED. SITES WITH INVERSE CORRELATIONS BETWEEN METHYLATION AND NEARBY GENE EXPRESSION INCLUDE THOSE OF KYNU, OAS2, S100A12, AND SERPINB3, WHOSE STRONG TRANSCRIPTIONAL UPREGULATION IS AN IMPORTANT DISCRIMINATOR OF PSORIASIS. PYROSEQUENCING OF BISULFITE-TREATED DNA FROM SKIN BIOPSIES AT THREE DM LOCI CONFIRMED EARLIER FINDINGS AND REVEALED REVERSION OF METHYLATION LEVELS TOWARD THE NON-PSORIATIC STATE AFTER 1 MONTH OF ANTI-TNF-ALPHA THERAPY. 2012 17 2082 37 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 18 5594 25 ROLES OF AIM2 GENE AND AIM2 INFLAMMASOME IN THE PATHOGENESIS AND TREATMENT OF PSORIASIS. PSORIASIS IS AN IMMUNE-MEDIATED CHRONIC INFLAMMATORY SKIN DISEASE CAUSED BY A COMBINATION OF ENVIRONMENTAL INCENTIVES, POLYGENIC GENETIC CONTROL, AND IMMUNE REGULATION. THE INFLAMMATION-RELATED GENE ABSENT IN MELANOMA 2 (AIM2) WAS IDENTIFIED AS A SUSCEPTIBILITY GENE FOR PSORIASIS. AIM2 INFLAMMASOME FORMED FROM THE COMBINATION OF AIM2, PYD-LINKED APOPTOSIS-ASSOCIATED SPECK-LIKE PROTEIN (ASC) AND CASPASE-1 PROMOTES THE MATURATION AND RELEASE OF INFLAMMATORY CYTOKINES SUCH AS IL-1BETA AND IL-18, AND TRIGGERS AN INFLAMMATORY RESPONSE. STUDIES SHOWED THE GENETIC AND EPIGENETIC ASSOCIATIONS BETWEEN AIM2 GENE AND PSORIASIS. AIM2 GENE HAS AN ESSENTIAL ROLE IN THE OCCURRENCE AND DEVELOPMENT OF PSORIASIS, AND THE INHIBITORS OF AIM2 INFLAMMASOME WILL BE NEW THERAPEUTIC TARGETS FOR PSORIASIS. IN THIS REVIEW, WE SUMMARIZED THE ROLES OF THE AIM2 GENE AND AIM2 INFLAMMASOME IN PATHOGENESIS AND TREATMENT OF PSORIASIS, HOPEFULLY PROVIDING A BETTER UNDERSTANDING AND NEW INSIGHT INTO THE ROLES OF AIM2 GENE AND AIM2 INFLAMMASOME IN PSORIASIS. 2022 19 6274 30 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 20 1879 27 EMERGING ROLES OF NON-CODING RNAS IN PSORIASIS PATHOGENESIS. PSORIASIS IS A COMPLEX GENETIC SKIN DISORDER TYPICALLY MANIFESTED BY RED, SCALY, AND ITCHY PLAQUES MOST COMMONLY OVER THE SCALP, TRUNK, ELBOWS, AND KNEES. HISTOPATHOLOGICAL FEATURES INCLUDE THICKENING OF THE EPIDERMAL LAYER DUE TO HYPER-PROLIFERATION AND ABNORMAL DIFFERENTIATION OF EPIDERMAL KERATINOCYTES ALONG WITH INFILTRATION OF IMMUNE CELLS IN THE PSORIATIC SKIN. IT IS A CHRONIC INFLAMMATORY RELAPSING DISEASE, AND THERE IS CURRENTLY NO PERMANENT CURE FOR PSORIASIS. PROPER MEDICATIONS CAN REDUCE THE SEVERITY OF THE DISEASE AND IMPROVE THE QUALITY OF LIFE OF THE PATIENTS. WHILE THE GENETIC COMPONENTS OF PSORIASIS PATHOGENESIS ARE WELL EXPLORED, THE FULL UNDERSTANDING OF ITS EPIGENETIC COMPONENT REMAINS ELUSIVE. NON-CODING RNAS (NCRNAS) ARE DOCUMENTED TO REGULATE VARIOUS EPIGENETIC PROCESSES THAT LEAD TO THE PATHOGENESIS OF DIFFERENT DISEASES INCLUDING PSORIASIS. IN THIS REVIEW, WE HAVE DISCUSSED THE MOLECULAR INTERPLAY OF DIFFERENT NCRNAS IN PSORIASIS PATHOGENESIS. THE ROLES OF MICRORNAS (MIRNAS) IN PSORIASIS ARE PRETTY WELL STUDIED, WHEREAS THE ROLES OF LONG NONCODING RNAS (LNCRNAS) AND CIRCULAR RNAS (CIRCRNAS) ARE EMERGING. THIS REVIEW PROVIDES IDEAS COVERING SOME OF THE LATEST FINDINGS OF DIFFERENT MODES OF FUNCTIONS PLAYED BY THOSE DIFFERENT NCRNAS DOCUMENTED IN THE LITERATURE. AS AN EVER-EVOLVING TOPIC, SOME WORKS ARE STILL ONGOING AS WELL AS THERE ARE SEVERAL FIELDS THAT NEED RIGOROUS SCIENTIFIC VENTURES. WE HAVE PROPOSED THE AREAS WHICH CLAIM MORE EXPLORATIONS TO BETTER UNDERSTAND THE ROLES PLAYED BY THE NCRNAS IN PSORIASIS PATHOGENESIS. 2023