1 5594 79 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 2 297 41 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 3 552 22 AUTOINFLAMMATION IN SYNDROMIC HIDRADENITIS SUPPURATIVA: THE ROLE OF AIM2. BACKGROUND: AIM2 IS A KEY CYTOPLASMATIC PATHOGEN-SENSOR THAT DETECTS FOREIGN DNA FROM VIRUSES AND BACTERIA; IT CAN ALSO RECOGNIZE DAMAGED OR ANOMALOUS PRESENCE OF DNA, PROMOTING INFLAMMASOME ASSEMBLY AND ACTIVATION WITH THE SECRETION OF IL-1BETA, THUS SUSTAINING A CHRONIC INFLAMMATORY STATE, POTENTIALLY LEADING TO THE ONSET OF AUTOINFLAMMATORY SKIN DISEASES. GIVEN THE IMPLICATION OF THE IL-1BETA PATHWAY IN THE PATHOGENESIS OF SYNDROMIC HIDRADENITIS SUPPURATIVA (HS), AN AUTOINFLAMMATORY IMMUNE-MEDIATED SKIN CONDITION, THE POTENTIAL INVOLVEMENT OF AIM2 WAS INVESTIGATED. METHODS: SEQUENCING OF THE WHOLE CODING REGION OF THE AIM2 GENE, COMPRISING 5'- AND 3' UTR AND A REGION UPSTREAM OF THE FIRST EXON OF ~800 BP WAS PERFORMED IN TWELVE SYNDROMIC HS PATIENTS. RESULTS: SIX OUT OF TWELVE SYNDROMIC HS PATIENTS CARRIED A HETEROZYGOUS VARIANT C.-208 A >/= C (RS41264459), LOCATED ON THE PROMOTER REGION OF THE AIM2 GENE, WITH A MINOR ALLELE FREQUENCY OF 0.25, WHICH IS MUCH HIGHER THAN THAT REPORTED IN 1000 G AND GNOMAD (0.075 AND 0.094, RESPECTIVELY). THE SAME VARIANT WAS FOUND AT A LOWER ALLELIC FREQUENCY IN SPORADIC HS AND ISOLATED PYODERMA GANGRENOSUM (PG) (0.125 AND 0.065, RESPECTIVELY). CONCLUSION: OUR DATA SUGGEST THAT THIS VARIANT MIGHT PLAY A ROLE IN SUSCEPTIBILITY TO DEVELOP SYNDROMIC FORMS OF HS BUT NOT TO PROGRESS TO SPORADIC HS AND PG. FURTHERMORE, EPIGENETIC AND/OR SOMATIC VARIATIONS COULD AFFECT AIM2 EXPRESSION LEADING TO DIFFERENT, CONTEXT-DEPENDENT RESPONSES. 2023 4 3701 32 INFLAMMATORY RESPONSE TO REGULATED CELL DEATH IN GOUT AND ITS FUNCTIONAL IMPLICATIONS. GOUT, A CHRONIC INFLAMMATORY ARTHRITIS DISEASE, IS CHARACTERIZED BY HYPERURICEMIA AND CAUSED BY INTERACTIONS BETWEEN GENETIC, EPIGENETIC, AND METABOLIC FACTORS. ACUTE GOUT SYMPTOMS ARE TRIGGERED BY THE INFLAMMATORY RESPONSE TO MONOSODIUM URATE CRYSTALS, WHICH IS MEDIATED BY THE INNATE IMMUNE SYSTEM AND IMMUNE CELLS (E.G., MACROPHAGES AND NEUTROPHILS), THE NACHT, LRR, AND PYD DOMAINS-CONTAINING PROTEIN 3 (NLRP3) INFLAMMASOME ACTIVATION, AND PRO-INFLAMMATORY CYTOKINE (E.G., IL-1BETA) RELEASE. RECENT STUDIES HAVE INDICATED THAT THE MULTIPLE PROGRAMMED CELL DEATH PATHWAYS INVOLVED IN THE INFLAMMATORY RESPONSE INCLUDE PYROPTOSIS, NETOSIS, NECROPTOSIS, AND APOPTOSIS, WHICH INITIATE INFLAMMATORY REACTIONS. IN THIS REVIEW, WE EXPLORE THE CORRELATION AND INTERACTIONS AMONG THESE FACTORS AND THEIR ROLES IN THE PATHOGENESIS OF GOUT TO PROVIDE FUTURE RESEARCH DIRECTIONS AND POSSIBILITIES FOR IDENTIFYING POTENTIAL NOVEL THERAPEUTIC TARGETS AND ENHANCING OUR UNDERSTANDING OF GOUT PATHOGENESIS. 2022 5 5421 27 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 6 6476 26 TOLL-LIKE RECEPTORS, INFECTIONS, AND RHEUMATOID ARTHRITIS. TOLL-LIKE RECEPTORS (TLR) THAT BELONG TO THE GROUP OF PROTEIN RECOGNITION RECEPTOR (PPR) PROVIDE AN INNATE IMMUNE RESPONSE FOLLOWING THE SENSING OF CONSERVED PATHOGEN-ASSOCIATED MICROBIAL PATTERNS (PAMPS) AND CHANGES IN DANGER-ASSOCIATED MOLECULAR PATTERNS (DAMPS) THAT ARE GENERATED AS A CONSEQUENCE OF CELLULAR INJURY. ANALYSIS OF THE TLR PATHWAY HAS MOREOVER OFFERED NEW INSIGHTS INTO THE PATHOGENESIS OF RHEUMATOID ARTHRITIS (RA). INDEED, A DYSFUNCTIONAL TLR-MEDIATED RESPONSE CHARACTERIZES RA PATIENTS AND PARTICIPATES IN ESTABLISHMENT OF A CHRONIC INFLAMMATORY STATE. SUCH AN INAPPROPRIATE TLR RESPONSE HAS BEEN ATTRIBUTED (I) TO THE REPORT OF IMPORTANT ALTERATIONS IN THE MICROBIOTA AND ABNORMAL RESPONSES TO INFECTIOUS AGENTS AS PART OF RA; (II) TO THE ABNORMAL PRESENCE OF TLR-LIGANDS IN THE SERUM AND SYNOVIAL FLUID OF RA PATIENTS; (III) TO THE OVEREXPRESSION OF TLR MOLECULES; (IV) TO THE PRODUCTION OF A LARGE PANEL OF PRO-INFLAMMATORY CYTOKINES DOWNSTREAM OF THE TLR PATHWAY; AND (V) TO GENETIC VARIANTS AND EPIGENETIC FACTORS IN SUSCEPTIBLE RA PATIENTS PROMOTING A HYPER TLR RESPONSE. AS A CONSEQUENCE, THE DEVELOPMENT OF PROMISING THERAPEUTIC STRATEGIES TARGETING TLRS FOR THE TREATMENT AND PREVENTION OF RA IS EMERGING. 2020 7 4961 30 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 8 4164 31 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 9 6891 16 [SIGNAL RECEPTORS OF CONGENITAL IMMUNITY: A NEW MOLECULAR TARGET FOR DIAGNOSTICS AND TREATMENT OF INFLAMMATORY DISEASES]. THE DISCOVERY OF SIGNAL RECEPTORS OF CONGENITAL IMMUNITY (SIGNAL PRR) NOT ONLY PROVIDED A NOVEL VIEW OF BASIC ASPECTS OF PATHOGENESIS OF CHRONIC INFLAMMATORY DISEASES BUT ALSO CREATED A BASIS FOR THE DEVELOPMENT OF ADDITIONAL DIAGNOSTIC CRITERIA FOR THESE PATHOLOGIES AND NEW PHARMACEUTICALS FOR THEIR TREATMENT. REDUCED EXPRESSION AND FUNCTION OF PRR DUE TO MUTATIONS/POLYMORPHISMS OR EPIGENETIC DISTURBANCES OF REGULATION CAN BE REGARDED AS IMMUNODEFICIENT CONDITIONS MANIFEST AS SEVERE INFECTIOUS INFLAMMATORY DISEASES. IN CONTRAST, EXCESSIVE EXPRESSION AND ACTIVATION OF PRR AS A RULE LEADS TO CHRONIC AUTOINFLAMMATORY, AUTOIMMUNE, AND ATOPIC DISEASES INVOLVING ADAPTIVE IMMUNITY AND AGGRESSION AGAINST OWN TISSUES AND CELLS. ASSESSMENT OF CERTAIN MUTATIONS IN PRR GENES, THEIR EXPRESSION AND ACTIVATION PROVIDES A POWERFUL TOOL FOR IN-DEPTH DIAGNOSTICS OF INFLAMMATORY DISEASES. SIMULTANEOUSLY, NEW LINES OF IMMUNOSTIMULATING AND ANTI-INFLAMMATORY THERAPY ARE DEVELOPED BASED ON THE KNOWLEDGE OF MOLECULAR PHYSIOLOGY OF PRR WITH THE USE OF SYNTHETIC AGONISTS AND ANTAGONISTS OF SIGNAL PRR. 2011 10 2063 23 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 11 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 12 6353 18 THE ROLE OF GENETIC AND EPIGENETIC REGULATION IN INTESTINAL FIBROSIS IN INFLAMMATORY BOWEL DISEASE: A DESCENDING PROCESS OR A PROGRAMMED CONSEQUENCE? INFLAMMATORY BOWEL DISEASES (IBDS) ARE A GROUP OF CHRONIC DISEASES CHARACTERIZED BY RECURRING PERIODS OF EXACERBATION AND REMISSION. FIBROSIS OF THE INTESTINE IS ONE OF THE MOST COMMON COMPLICATIONS OF IBD. BASED ON CURRENT ANALYSES, IT IS EVIDENT THAT GENETIC FACTORS AND MECHANISMS, AS WELL AS EPIGENETIC FACTORS, PLAY A ROLE IN THE INDUCTION AND PROGRESSION OF INTESTINAL FIBROSIS IN IBD. KEY GENETIC FACTORS AND MECHANISMS THAT APPEAR TO BE SIGNIFICANT INCLUDE NOD2, TGF-BETA, TLRS, IL23R, AND ATG16L1. DEOXYRIBONUCLEIC ACID (DNA) METHYLATION, HISTONE MODIFICATION, AND RIBONUCLEIC ACID (RNA) INTERFERENCE ARE THE PRIMARY EPIGENETIC MECHANISMS. GENETIC AND EPIGENETIC MECHANISMS, WHICH SEEM TO BE IMPORTANT IN THE PATHOPHYSIOLOGY AND PROGRESSION OF IBD, MAY POTENTIALLY BE USED IN TARGETED THERAPY IN THE FUTURE. THEREFORE, THE AIM OF THIS STUDY WAS TO GATHER AND DISCUSS SELECTED MECHANISMS AND GENETIC FACTORS, AS WELL AS EPIGENETIC FACTORS. 2023 13 6210 23 THE INTERPLAY BETWEEN KERATINOCYTES AND IMMUNE CELLS IN THE PATHOGENESIS OF PSORIASIS. PSORIASIS IS A CHRONIC INFLAMMATORY SKIN DISEASE RESULTING FROM GENETIC, EPIGENETIC, ENVIRONMENTAL, AND LIFESTYLE FACTORS. TO DATE, SEVERAL IMMUNOPATHOGENIC MECHANISMS OF PSORIASIS HAVE BEEN ELUCIDATED, AND, IN THE CURRENT MODEL, THE CROSS TALK BETWEEN AUTOREACTIVE T CELLS AND RESIDENT KERATINOCYTES GENERATES INFLAMMATORY AND IMMUNE CIRCUITS RESPONSIBLE FOR THE INITIATION, PROGRESSION, AND PERSISTENCE OF THE DISEASE. SEVERAL AUTOANTIGENS DERIVED FROM KERATINOCYTES (I.E., LL37 CATHELECIDIN/NUCLEIC ACID COMPLEXES, NEWLY GENERATED LIPID ANTIGENS) HAVE BEEN IDENTIFIED, WHICH MAY TRIGGER INITIAL ACTIVATION OF T CELLS, PARTICULARLY IL-17-PRODUCING T CELLS, T HELPER (TH)1 AND TH22 CELLS. HENCE, LYMPHOKINES RELEASED IN SKIN LESIONS ARE PIVOTAL FOR KERATINOCYTE ACTIVATION AND PRODUCTION OF INFLAMMATORY MOLECULES, WHICH IN TURN LEAD TO AMPLIFICATION OF THE LOCAL IMMUNE RESPONSES. INTRINSIC GENETIC ALTERATIONS OF KERATINOCYTES IN THE ACTIVATION OF SIGNAL TRANSDUCTION PATHWAYS DEPENDENT ON T-CELL-DERIVED CYTOKINES ARE ALSO FUNDAMENTAL. THE CURRENT REVIEW EMPHASIZES THE ABERRANT INTERPLAY OF IMMUNE CELLS AND SKIN-RESIDENT KERATINOCYTES IN ESTABLISHING AND SUSTAINING INFLAMMATORY AND IMMUNE RESPONSES IN PSORIASIS. 2018 14 2591 35 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 15 5998 20 THE ABERRANT EPIGENETIC MODIFICATIONS IN THE PATHOGENESIS OF PSORIASIS. PSORIASIS IS A CHRONIC AND RECURRENT INFLAMMATORY SKIN DISEASE THAT IS CHARACTERIZED BY ABNORMAL KERATINOCYTE PROLIFERATION, VASCULAR HYPERPLASIA, AND INFILTRATION OF INFLAMMATORY CELLS INTO THE DERMIS AND EPIDERMIS. IT IS GENERALLY ACCEPTED THAT THE CENTRAL PATHOGENESIS OF PSORIASIS IS DYSFUNCTION OF T LYMPHOCYTES, WHICH ARE AFFECTED BY THE COMPLEX INTERPLAY BETWEEN GENETIC AND ENVIRONMENTAL FACTORS, INCLUDING TRAUMA, INFECTIONS, STRESS, DRUGS, SMOKING, AND ALCOHOL CONSUMPTION (NESTLE ET AL., 2009). THE ENVIRONMENTALLY INDUCED EPIGENETIC CHANGES, INCLUDING DNA METHYLATION, HISTONE MODIFICATION, AND MICRORNAS, HAVE BEEN SHOWN TO BE INVOLVED IN THE PATHOGENESIS OF THIS DISEASE (ZHANG ET AL., 2012). 2018 16 5505 24 RHEUMATOID ARTHRITIS AND ALZHEIMER'S DISEASE: GENETIC AND EPIGENETIC LINKS IN INFLAMMATORY REGULATION. CONTROVERSIAL DATA ARE AVAILABLE ABOUT THE RELATIONSHIP BETWEEN ALZHEIMER'S DISEASE (AD) AND RHEUMATOID ARTHRITIS (RA). AN INVERSE RELATIONSHIP BETWEEN AD AND RA, DUE TO DIFFERENT FACTORS, WAS PREVIOUSLY DESCRIBED. SIMILARLY TO RA, AD PATHOGENESIS IS MULTIFACTORIAL AND DIFFERENT FINDINGS SUPPORT THE INFLAMMATORY PATHOGENETIC HYPOTHESIS. SEVERAL INFLAMMATORY MEDIATORS ARE INVOLVED IN THE DISEASE ONSET AND PROGRESSION REGULATED BY GENETIC AND EPIGENETIC MECHANISMS. AMONG THEM, INTELEUKIN-6 (IL-6) AND INTERLEUKIN-1 (IL-1) AS PRO-INFLAMMATORY SOLUBLE FACTORS PRODUCED BY MONOCYTES-MACROPHAGES AND TUMOR NECROSIS FACTOR ALPHA (TNF-ALPHA) PRODUCED BY ACTIVATED MACROPHAGES AND MONONUCLEAR CELLS REPRESENT KEY MOLECULES IN THE INDUCTION AND MAINTENANCE OF CHRONIC INFLAMMATION IN RA. IN PARTICULAR A LINK WITH THE T ALLELE OF THE SNP 3953 T/C IN THE IL-1 GENE AND AN OVEREXPRESSION OF MIR-146A APPEARS TO BE COMMON TO BOTH RA AND AD. IN THIS REVIEW WE WILL DISCUSS THE GENETIC AND EPIGENETIC REGULATION OF THE INFLAMMATORY CASCADE IN RA AND AD TO FIND OUT THE POSSIBLE LINKS BETWEEN RA AND AD ONSET. 2012 17 5566 32 ROLE OF INFLAMMATION IN THE DEVELOPMENT OF COLORECTAL CANCER. CHRONIC INFLAMMATION CAN LEAD TO THE DEVELOPMENT OF MANY DISEASES, INCLUDING CANCER. INFLAMMATORY BOWEL DISEASE (IBD) THAT INCLUDES BOTH ULCERATIVE COLITIS (UC) AND CROHNMP'S DISEASE (CD) ARE RISK FACTORS FOR THE DEVELOPMENT OF COLORECTAL CANCER (CRC). MANY CYTOKINES PRODUCED PRIMARILY BY THE GUT IMMUNE CELLS EITHER DURING OR IN RESPONSE TO LOCALIZED INFLAMMATION IN THE COLON AND RECTUM ARE KNOWN TO STIMULATE THE COMPLEX INTERACTIONS BETWEEN THE DIFFERENT CELL TYPES IN THE GUT ENVIRONMENT RESULTING IN ACUTE INFLAMMATION. SUBSEQUENTLY, CHRONIC INFLAMMATION, TOGETHER WITH GENETIC AND EPIGENETIC CHANGES, HAVE BEEN SHOWN TO LEAD TO THE DEVELOPMENT AND PROGRESSION OF CRC. VARIOUS CELL TYPES PRESENT IN THE COLON, SUCH AS ENTEROCYTES, PANETH CELLS, GOBLET CELLS, AND MACROPHAGES, EXPRESS RECEPTORS FOR INFLAMMATORY CYTOKINES AND RESPOND TO TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA), INTERLEUKIN-1 BETA (IL-1BETA), IL-6, AND OTHER CYTOKINES. AMONG THE SEVERAL CYTOKINES PRODUCED, TNF-ALPHA AND IL-1BETA ARE THE KEY PRO-INFLAMMATORY MOLECULES THAT PLAY CRITICAL ROLES IN THE DEVELOPMENT OF CRC. THE CURRENT REVIEW IS INTENDED TO CONSOLIDATE THE PUBLISHED FINDINGS TO FOCUS ON THE ROLE OF PRO-INFLAMMATORY CYTOKINES, NAMELY TNF-ALPHA AND IL-1BETA, ON INFLAMMATION (AND THE ALTERED IMMUNE RESPONSE) IN THE GUT, TO BETTER UNDERSTAND THE DEVELOPMENT OF CRC IN IBD, USING VARIOUS EXPERIMENTAL MODEL SYSTEMS, PRECLINICAL AND CLINICAL STUDIES. MOREOVER, THIS REVIEW ALSO HIGHLIGHTS THE CURRENT THERAPEUTIC STRATEGIES AVAILABLE (MONOTHERAPY AND COMBINATION THERAPY) TO ALLEVIATE THE SYMPTOMS OR TREAT INFLAMMATION-ASSOCIATED CRC BY USING MONOCLONAL ANTIBODIES OR APTAMERS TO BLOCK PRO-INFLAMMATORY MOLECULES, INHIBITORS OF TYROSINE KINASES IN THE INFLAMMATORY SIGNALING CASCADE, COMPETITIVE INHIBITORS OF PRO-INFLAMMATORY MOLECULES, AND THE NUCLEIC ACID DRUGS LIKE SMALL ACTIVATING RNAS (SARNAS) OR MICRORNA (MIRNA) MIMICS TO ACTIVATE TUMOR SUPPRESSOR OR REPRESS ONCOGENE/PRO-INFLAMMATORY CYTOKINE GENE EXPRESSION. 2021 18 6624 32 UNDERSTANDING PSORIASIS: ROLE OF MIRNAS. PSORIASIS IS A CHRONIC, IMMUNE-MEDIATED INFLAMMATORY SKIN DISEASE, WITH A MULTIFACTORIAL ETIOLOGY AND IMPORTANT IMMUNOLOGIC, GENETIC AND ENVIRONMENTAL COMPONENTS. PSORIASIS VULGARIS REPRESENTS ITS MOST COMMON FORM, WITH A VARIABLE PREVALENCE ACROSS THE GLOBE. ALTHOUGH ITS PATHOGENESIS REMAINS TO BE FULLY ELUCIDATED, A LACK OF BALANCE IN THE EPIGENETIC NETWORK HAS BEEN SHOWN TO TRIGGER CERTAIN ELEMENTS OF THIS DISEASE, POSSIBLY ALTERING ITS OUTCOME. MICRORNAS ARE SMALL NON-CODING RNA MOLECULES INVOLVED IN RNA-SILENCING AND THE POST-TRANSCRIPTIONAL REGULATION OF GENE EXPRESSION, WHICH ALSO APPEAR TO MEDIATE THE IMMUNE DYSFUNCTION IN PSORIASIS. ALTHOUGH MICRORNA RESEARCH IS A NEW FIELD IN DERMATOLOGY AND PSORIASIS, THERE IS RAPIDLY ACCUMULATING EVIDENCE FOR ITS MAJOR CONTRIBUTION IN THE PATHOGENESIS OF CHRONIC INFLAMMATORY CONDITIONS, INCLUDING PSORIASIS AND OTHER DERMATOLOGICAL DISORDERS. FURTHERMORE, CIRCULATING MIRNAS IDENTIFIED IN PATIENTS' BLOOD SAMPLES HAVE BEEN IDENTIFIED AS PROMISING BIOMARKERS OF DIAGNOSIS, PROGNOSIS OR TREATMENT RESPONSE. EXTENDED INVESTIGATIONS IN THIS FIELD ARE REQUIRED, AS UNTIL NOW, THE EXACT INVOLVEMENT OF MIRNAS IN PSORIASIS HAVE REMAINED TO BE ENTIRELY ELUCIDATED. THIS SHORT REVIEW HIGHLIGHTS A NUMBER OF THE ROLES OF MIRNAS FOUND IN DIFFERENT STAGES OF PSORIASIS. 2018 19 1275 27 DAMAGE-ASSOCIATED MOLECULAR PATTERNS IN INFLAMMATORY BOWEL DISEASE: FROM BIOMARKERS TO THERAPEUTIC TARGETS. THE CHRONIC INFLAMMATORY PROCESS UNDERLYING INFLAMMATORY BOWEL DISEASE (IBD), COMPRISING CROHN'S DISEASE AND ULCERATIVE COLITIS, DERIVES FROM THE INTERPLAY OF SEVERAL COMPONENTS IN A GENETICALLY SUSCEPTIBLE HOST. THESE COMPONENTS INCLUDE ENVIRONMENTAL ELEMENTS AND GUT MICROBIOTA A DYSBIOSIS. FOR DECADES, IMMUNE ABNORMALITIES HAVE BEEN INVESTIGATED AS CRITICALLY IMPORTANT IN IBD PATHOGENESIS, AND ATTEMPTS TO DEVELOP EFFECTIVE THERAPIES HAVE PREDOMINANTLY TARGETED THE IMMUNE SYSTEM. NEVERTHELESS, IMMUNE EVENTS REPRESENT ONLY ONE OF THE CONSTITUENTS CONTRIBUTING TO IBD PATHOGENESIS WITHIN THE CONTEXT OF THE COMPLEX CELLULAR AND MOLECULAR NETWORK UNDERLYING CHRONIC INTESTINAL INFLAMMATION. THESE FACTORS NEED TO BE APPRECIATED WITHIN THE MILIEU OF NON-IMMUNE COMPONENTS. DAMAGE-ASSOCIATED MOLECULAR PATTERNS (DAMPS), WHICH ARE ESSENTIALLY ENDOGENOUS STRESS PROTEINS EXPRESSED OR RELEASED AS A RESULT OF CELL OR TISSUE DAMAGE, HAVE BEEN SHOWN TO ACT AS DIRECT PRO-INFLAMMATORY MEDIATORS. EXCESSIVE OR PERSISTENT SIGNALLING MEDIATED BY SUCH MOLECULES CAN UNDERLIE SEVERAL CHRONIC INFLAMMATORY DISORDERS, INCLUDING IBD. THE RELEASE OF ENDOGENOUS DAMPS AMPLIFIES THE INFLAMMATORY RESPONSE DRIVEN BY IMMUNE AND NON-IMMUNE CELLS AND PROMOTES EPIGENETIC REPROGRAMMING IN IBD. THE EFFECTS DETERMINE PATHOLOGIC CHANGES, WHICH MAY SUSTAIN CHRONIC INTESTINAL INFLAMMATION AND ALSO UNDERLIE SPECIFIC DISEASE PHENOTYPES. IN ADDITION TO HIGHLIGHTING THE POTENTIAL USE OF DAMPS SUCH AS CALPROTECTIN AS BIOMARKERS, RESEARCH ON DAMPS MAY REVEAL NOVEL MECHANISTIC ASSOCIATIONS IN IBD PATHOGENESIS AND IS EXPECTED TO UNCOVER PUTATIVE THERAPEUTIC TARGETS. 2018 20 2553 29 EPIGENETICS IN PSORIASIS: PERSPECTIVE OF DNA METHYLATION. PSORIASIS IS A CHRONIC INFLAMMATORY SKIN DISEASE CHARACTERIZED BY EXCESSIVE PROLIFERATION OF KERATINOCYTES (KCS). ONSET OF PSORIASIS IS RELATED TO GENETIC, IMMUNE AND ENVIRONMENTAL FACTORS. THE ENVIRONMENT CAN INTERACT WITH THE GENOME THROUGH EPIGENETIC MODIFICATIONS, INCLUDING DNA METHYLATION, AND THIS MODIFICATION IS INVOLVED IN THE PATHOGENESIS OF PSORIASIS. IN ADDITION TO A SKIN DISEASE, PSORIASIS IS ALSO CONSIDERED A SYSTEMIC DISEASE. WE REVIEWED THE CURRENT LITERATURE OF PSORIATIC DNA METHYLATION FOR STUDIES FROM SEVERAL ASPECTS ON THE DNA METHYLATION DISTRIBUTION PATTERNS IN DIFFERENT TISSUES/CELLS, SINGLE-NUCLEOTIDE POLYMORPHISMS, AND CANDIDATE DISEASE GENES AND IDENTIFIED TARGET GENES REGULATED BY DNA METHYLATION THAT HAVE BEEN DIRECTLY/INDIRECTLY VALIDATED. THIS REVIEW CONTRIBUTES TO A COMPREHENSIVE UNDERSTANDING OF THE IMPORTANT A ROLE THAT DNA METHYLATION PLAYS IN PSORIASIS FROM A HOLISTIC PERSPECTIVE AND WILL PROMOTE THE IMPLEMENTATION OF DNA METHYLATION IN DIAGNOSTIC AND THERAPEUTIC STRATEGIES FOR PSORIATIC PATIENTS. 2021