1 6110 96 THE EPIGENETIC ALTERATION OF SYNOVIAL CELL GENE EXPRESSION IN RHEUMATOID ARTHRITIS AND THE ROLES OF NUCLEAR FACTOR KAPPAB AND NOTCH SIGNALING PATHWAYS. RHEUMATOID ARTHRITIS (RA) IS A COMPLEX PROCESS OF CHRONIC AND PROGRESSIVE INFLAMMATION ASSOCIATED WITH ACTIVATION OF NUMEROUS SIGNALING MOLECULES AND TRANSCRIPTION FACTORS AND HYPERPROLIFERATION OF SYNOVIOCYTES OF THE AFFECTED JOINTS, ALTHOUGH THE GREATER PART OF ITS PATHOPHYSIOLOGICAL PROCESS IS EXPLAINED BY ACTIVATION OF NUCLEAR FACTOR KAPPAB (NF-KAPPAB). FOR EXAMPLE, THE SELF-PERPETUATING NATURE OF THE RHEUMATOID INFLAMMATION IS ASCRIBABLE TO OVEREXPRESSION OF THE PROINFLAMMATORY CYTOKINES TUMOR NECROSIS FACTOR ALPHA AND INTERLEUKIN-1BETA, KNOWN TO ELICIT THE ACTIVATION CASCADE FOR NF-KAPPAB AND ACTIVATOR PROTEIN-1 THAT ARE RESPONSIBLE FOR TRANSCRIPTIONAL INDUCTION OF THESE CYTOKINES AMONG OTHER TARGET GENES, WHICH CONFORM A POSITIVE FEEDBACK LOOP FOR CONTINUATION AND EXPANSION OF THE INFLAMMATORY RESPONSES. IN ADDITION, COMPARATIVE GENE EXPRESSION PROFILE ANALYSES HAVE REVEALED ACTIVATION OF A NUMBER OF GENES THAT EXPLAIN THE "TRANSFORMED-LIKE" PHENOTYPE OF SYNOVIOCYTES. AMONG THE GENES EXPRESSED IN RHEUMATOID SYNOVIOCYTES UPON INFLAMMATORY STIMULI, INDUCTION OF GENE EXPRESSION OF NOTCH PROTEINS AND ITS LIGAND HAVE BEEN FOUND. POSSIBLE ROLES OF NOTCH SIGNALING IN RA SYNOVIOCYTES ARE DISCUSSED. 2005 2 911 32 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 3 3699 24 INFLAMMATORY MEMORIES: IS EPIGENETICS THE MISSING LINK TO PERSISTENT STROMAL CELL ACTIVATION IN RHEUMATOID ARTHRITIS? RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY DISEASE LEADING TO JOINT DESTRUCTION. SYNOVIAL FIBROBLASTS ARE RECOGNIZED AS KEY CELLS IN THE PATHOGENESIS OF RA SINCE THEY ATTRACT AND ACTIVATE IMMUNE CELLS AND PRODUCE MATRIX DEGRADING ENZYMES. MOST NOTABLY SYNOVIAL FIBROBLASTS FROM PATIENTS WITH RA ARE STABLY ACTIVATED AND PRODUCE HIGH LEVELS OF DISEASE-PROMOTING MOLECULES WITHOUT FURTHER STIMULATION BY IMMUNE CELLS. ACCUMULATING DATA SUGGEST THAT EPIGENETIC CHANGES IN STROMAL CELL POPULATIONS MIGHT BE CRUCIALLY INVOLVED IN THE PATHOLOGY OF RA AND OTHER CHRONIC INFLAMMATORY DISEASES. IN THE CURRENT REVIEW, WE DISCUSS THE MECHANISMS BY WHICH EPIGENETIC CHANGES MIGHT CAUSE THE STABLE ACTIVATION OF SYNOVIAL FIBROBLASTS IN RA AND HOW CHANGES IN THE EPIGENOME MIGHT ALTER IMMUNE FUNCTION AND INFLAMMATORY RESPONSE AND THEREBY PROMOTE THE DEVELOPMENT OF CHRONIC DISEASES. 2011 4 783 23 CELL-SPECIFIC EPIGENETIC DRIVERS OF PATHOGENESIS IN RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS IS A COMPLEX, INFLAMMATORY AUTOIMMUNE DISEASE, WHICH IS CHARACTERIZED BY PAIN, SWELLING AND JOINT DAMAGE DRIVEN BY THE ALTERED BEHAVIOR OF A NUMBER OF DIFFERENT CELL TYPES SUCH AS SYNOVIAL FIBROBLASTS MACROPHAGES AND LYMPHOCYTES. THE MECHANISM UNDERLYING PATHOGENESIS IS UNCLEAR BUT INCREASING EVIDENCE POINTS TO ALTERED EPIGENETIC REGULATION WITHIN THESE CELL TYPES WHICH PROMOTES THE ACTIVATED DESTRUCTIVE BEHAVIOR THAT UNDERLIES DISEASE PATHOGENESIS. THIS REVIEW SUMMARIZES THE KEY EPIGENETIC MODIFICATIONS IN THE MOST IMPORTANT CELLS TYPES IN RHEUMATOID ARTHRITIS, WHICH ARE ASSOCIATED WITH DISEASE ACTIVITY. WE ALSO DISCUSS EMERGING AVENUES OF RESEARCH FOCUSING ON READERS OF EPIGENETIC MARKERS WHICH MAY SERVE TO BE POTENTIAL THERAPEUTIC TARGETS. 2021 5 3789 30 INTERLEUKIN 17 CONTRIBUTES TO THE CHRONICITY OF INFLAMMATORY DISEASES SUCH AS RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY DISEASE LEADING TO JOINT DESTRUCTION AND BONE RESORPTION. THE PROINFLAMMATORY CYTOKINE INTERLEUKIN 17 (IL-17), PRIMARILY PRODUCED BY TH17 CELLS, HAS BEEN SHOWN TO BE INVOLVED IN ALL STAGES OF THE DISEASE AND TO BE AN IMPORTANT CONTRIBUTOR OF RA CHRONICITY. THREE MAJOR PROCESSES DRIVE THE IL-17-MEDIATED CHRONICITY. SEVERAL EPIGENETIC EVENTS, ENHANCED IN RA PATIENTS, LEAD TO THE INCREASED PRODUCTION OF IL-17 BY TH17 CELLS. IL-17 THEN INDUCES THE PRODUCTION OF SEVERAL INFLAMMATORY MEDIATORS IN THE DISEASED SYNOVIUM, WHICH ARE FURTHER SYNERGISTICALLY ENHANCED VIA COMBINATIONS OF IL-17 WITH OTHER CYTOKINES. IL-17 ALSO PROMOTES THE SURVIVAL OF BOTH THE SYNOVIOCYTES AND INFLAMMATORY CELLS AND PROMOTES THE MATURATION OF THESE IMMUNE CELLS. THIS LEADS TO AN INCREASED NUMBER OF SYNOVIOCYTES AND INFLAMMATORY CELLS IN THE SYNOVIAL FLUID AND IN THE SYNOVIUM LEADING TO THE HYPERPLASIA AND EXACERBATED INFLAMMATION OBSERVED IN JOINTS OF RA PATIENTS. FURTHERMORE, THESE IL-17-DRIVEN EVENTS INITIATE SEVERAL FEEDBACK-LOOP MECHANISMS LEADING TO INCREASED EXPANSION OF TH17 CELLS AND THEREBY INCREASED PRODUCTION OF IL-17. IN THIS REVIEW, WE AIM TO DEPICT A COMPLETE PICTURE OF THE IL-17-DRIVEN VICIOUS CIRCLE LEADING TO RA CHRONICITY AND TO PINPOINT THE KEY ASPECTS THAT REQUIRE FURTHER EXPLORATION. 2014 6 4298 31 MICRORNA-146A GOVERNS FIBROBLAST ACTIVATION AND JOINT PATHOLOGY IN ARTHRITIS. SYNOVIAL FIBROBLASTS ARE KEY CELLS ORCHESTRATING THE INFLAMMATORY RESPONSE IN ARTHRITIS. HERE WE DEMONSTRATE THAT LOSS OF MIR-146A, A KEY EPIGENETIC REGULATOR OF THE INNATE IMMUNE RESPONSE, LEADS TO INCREASED JOINT DESTRUCTION IN A TNF-DRIVEN MODEL OF ARTHRITIS BY SPECIFICALLY REGULATING THE BEHAVIOR OF SYNOVIAL FIBROBLASTS. ABSENCE OF MIR-146A IN SYNOVIAL FIBROBLASTS DISPLAY A HIGHLY DEREGULATED GENE EXPRESSION PATTERN AND ENHANCED PROLIFERATION IN VITRO AND IN VIVO. DEFICIENCY OF MIR-146A INDUCES DEREGULATION OF TUMOR NECROSIS FACTOR (TNF) RECEPTOR ASSOCIATED FACTOR 6 (TRAF6) IN SYNOVIAL FIBROBLASTS, LEADING TO INCREASED PROLIFERATION. IN ADDITION, LOSS OF MIR-146A SHIFTS THE METABOLIC STATE OF FIBROBLASTS TOWARDS GLYCOLYSIS AND AUGMENTS THE ABILITY OF SYNOVIAL FIBROBLASTS TO SUPPORT THE GENERATION OF OSTEOCLASTS BY CONTROLLING THE BALANCE OF OSTEOCLASTOGENIC REGULATORY FACTORS RECEPTOR ACTIVATOR OF NF-KAPPAB LIGAND (RANKL) AND OSTEOPROTEGERIN (OPG). BONE MARROW TRANSPLANTATION EXPERIMENTS CONFIRMED THE IMPORTANCE OF MIR-146A IN THE RADIORESISTANT MESENCHYMAL COMPARTMENT FOR THE CONTROL OF ARTHRITIS SEVERITY, IN PARTICULAR FOR INFLAMMATORY JOINT DESTRUCTION. THIS STUDY THEREFORE IDENTIFIES MICRORNA-146A AS AN IMPORTANT LOCAL EPIGENETIC REGULATOR OF THE INFLAMMATORY RESPONSE IN ARTHRITIS. IT IS A CENTRAL ELEMENT OF AN ANTI-INFLAMMATORY FEEDBACK LOOP IN RESIDENT SYNOVIAL FIBROBLASTS, WHO ARE ORCHESTRATING THE INFLAMMATORY RESPONSE IN CHRONIC ARTHRITIS. MIR-146A RESTRICTS THEIR ACTIVATION, THEREBY PREVENTING EXCESSIVE TISSUE DAMAGE DURING ARTHRITIS. 2017 7 4412 27 MOLECULAR AND CELLULAR BASIS OF RHEUMATOID JOINT DESTRUCTION. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY DISEASE ASSOCIATED WITH JOINT DESTRUCTION. SYNOVIAL FIBROBLASTS ARE KEY PLAYERS IN THIS PATHOLOGICAL PROCESS. THEY FAVORISE A PRO-INFLAMMATORY ENVIRONMENT IN THE SYNOVIAL TISSUE, INTERACT WITH THE IMMUNE SYSTEM AND REGULATE THE DIFFERENTIATION OF MONOCYTES INTO OSTEOCLASTS. SYNOVIAL HYPERPLASIA IS ANOTHER CHARACTERISTIC OF RA, REFLECTING NOT ONLY AN IMBALANCE BETWEEN PROLIFERATION AND APOPTOSIS, BUT ALSO THE MIGRATION OF CELLS INTO THE SYNOVIAL TISSUE. GENE TRANSFER EXPERIMENTS HAVE BEEN USED AS IMPORTANT TOOLS FOR THE UNDERSTANDING OF MOLECULAR AND CELLULAR CHANGES THAT CHARACTERIZE THE ACTIVATED RA SYNOVIAL FIBROBLASTS. ACTIVATED SYNOVIAL FIBROBLASTS CAN INVADE CARTILAGE AND BONE. SYNOVIAL ACTIVATION IS DRIVEN BY CYTOKINES, SUCH AS TNFALPHA AND IL-1, AS WELL AS IL-15, 16, 17, 18, 22, 23, BUT ALSO BY CYTOKINE-INDEPENDENT MECHANISMS THAT INVOLVE THE INNATE IMMUNE SYSTEM (I.E. TLRS), A UNIQUE COMMUNICATION NETWORK OF MICROPARTICLES AND EPIGENETIC CHANGES (E.G. L1 RETROELEMENTS). 2006 8 4657 24 NEW ADVANCES OF DNA METHYLATION AND HISTONE MODIFICATIONS IN RHEUMATOID ARTHRITIS, WITH SPECIAL EMPHASIS ON MECP2. EPIGENETICS IS A STEADILY GROWING RESEARCH AREA IN MANY HUMAN DISEASES, ESPECIALLY IN AUTOIMMUNE DISEASES SUCH AS RHEUMATOID ARTHRITIS (RA). RA IS AN AUTOIMMUNE DISEASE WITH UNCLEAR ETIOLOGY CHARACTERIZED BY CHRONIC INFLAMMATION AND JOINT DESTRUCTION AND FIBROBLAST-LIKE SYNOVIOCYTES (FLS) DISPLAY A CRUCIAL ROLE IN THE PATHOGENESIS OF RA. EVEN THOUGH THE ETIOLOGY IS NOT YET FULLY UNDERSTOOD, RA IS GENERALLY CONSIDERED TO BE CAUSED BY A COMBINATION OF EPIGENETIC MODIFICATION, DEREGULATED IMMUNOMODULATION, AND ENVIRONMENTAL FACTORS. EPIGENETIC MODIFICATIONS, INCLUDING DNA METHYLATION AND POST-TRANSLATIONAL HISTONE MODIFICATIONS, SUCH AS HISTONE METHYLATION AND HISTONE (DE)ACETYLATION ARE IDENTIFIED AS REGULATORY MECHANISMS IN CONTROLLING AGGRESSIVE FLS ACTIVATION IN PATIENTS AND ANIMAL MODELS. IN THE LAST 3YEARS, THE FIELD OF EPIGENETICS IN RA HAS IMPRESSIVELY INCREASED. METHYL-CPG-BINDING PROTEIN 2 (MECP2) IS FIRST IDENTIFIED AS A TRANSCRIPTIONAL REPRESSOR THAT INHIBITS GENE EXPRESSION THROUGH THE INTERPRETATION OF TWO EPIGENETIC MARKERS, DNA METHYLATION AND HISTONE MODIFICATION. THE COOPERATIVE ACTION AMONG MECP2, DNA METHYLATION AND HISTONE MODIFICATIONS INDICATES THAT MECP2 SHOULD PARTICIPATE IN THE PATHOGENESIS OF RA THROUGH SILENCE OF CERTAIN GENE TRANSCRIPTION. IN THIS REVIEW, WE CONSIDER THE ROLE OF DNA METHYLATION AND HISTONE MODIFICATIONS IN THE DEVELOPMENT OF RA, WITH A SPECIAL FOCUS ON INCREASED MECP2 EXPRESSION IN RA ANIMAL MODELS. 2013 9 6597 26 TUNING MONOCYTES AND MACROPHAGES FOR PERSONALIZED THERAPY AND DIAGNOSTIC CHALLENGE IN RHEUMATOID ARTHRITIS. MONOCYTES/MACROPHAGES PLAY A CENTRAL ROLE IN CHRONIC INFLAMMATORY DISORDERS, INCLUDING RHEUMATOID ARTHRITIS (RA). ACTIVATION OF THESE CELLS RESULTS IN THE PRODUCTION OF VARIOUS MEDIATORS RESPONSIBLE FOR INFLAMMATION AND RA PATHOGENESIS. ON THE OTHER HAND, THE DEPLETION OF MACROPHAGES USING SPECIFIC ANTIBODIES OR CHEMICAL AGENTS CAN PREVENT THEIR SYNOVIAL TISSUE INFILTRATION AND SUBSEQUENTLY ATTENUATES INFLAMMATION. THEIR PLASTICITY IS A MAJOR FEATURE THAT HELPS THE SWITCH FROM A PRO-INFLAMMATORY PHENOTYPE (M1) TO AN ANTI-INFLAMMATORY STATE (M2). THEREFORE, UNDERSTANDING THE PRECISE STRATEGY TARGETING PRO-INFLAMMATORY MONOCYTES/MACROPHAGES SHOULD BE A POWERFUL WAY OF INHIBITING CHRONIC INFLAMMATION AND BONE EROSION. IN THIS REVIEW, WE DEMONSTRATE POTENTIAL CONSEQUENCES OF DIFFERENT EPIGENETIC REGULATIONS ON INFLAMMATORY CYTOKINES PRODUCTION BY MONOCYTES. IN ADDITION, WE PRESENT UNIQUE PROFILES OF MONOCYTES/MACROPHAGES CONTRIBUTING TO IDENTIFICATION OF NEW BIOMARKERS OF DISEASE ACTIVITY OR PREDICTING TREATMENT RESPONSE IN RA. WE ALSO OUTLINE NOVEL APPROACHES OF TUNING MONOCYTES/MACROPHAGES BY BIOLOGIC DRUGS, SMALL MOLECULES OR BY OTHER THERAPEUTIC MODALITIES TO REDUCE ARTHRITIS. FINALLY, THE IMPORTANCE OF CELLULAR HETEROGENEITY OF MONOCYTES/MACROPHAGES IS HIGHLIGHTED BY SINGLE-CELL TECHNOLOGIES, WHICH LEADS TO THE DESIGN OF CELL-SPECIFIC THERAPEUTIC PROTOCOLS FOR PERSONALIZED MEDICINE IN RA IN THE FUTURE. 2021 10 5937 32 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 11 1608 35 DNA METHYLATION-GOVERNED GENE EXPRESSION IN AUTOIMMUNE ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE HALLMARKED BY PROGRESSIVE AND IRREVERSIBLE JOINT DESTRUCTION. RA PATHOGENESIS IS A T CELL-REGULATED AND B CELL-MEDIATED PROCESS IN WHICH ACTIVATED LYMPHOCYTE-PRODUCED CHEMOKINES AND CYTOKINES PROMOTE LEUKOCYTE INFILTRATION THAT ULTIMATELY LEADS TO DESTRUCTION OF THE JOINTS. THERE IS AN OBVIOUS NEED TO DISCOVER NEW DRUGS FOR RA TREATMENT THAT HAVE DIFFERENT BIOLOGICAL TARGETS OR MODES OF ACTION THAN THE CURRENTLY EMPLOYED THERAPEUTICS. ENVIRONMENTAL FACTORS SUCH AS CIGARETTE SMOKE, CERTAIN DIET COMPONENTS, AND ORAL PATHOGENS CAN SIGNIFICANTLY AFFECT GENE REGULATION VIA EPIGENETIC FACTORS. EPIGENETICS OPENED A NEW FIELD FOR PHARMACOLOGY, AND DNA METHYLATION AND HISTONE MODIFICATION-IMPLICATED FACTORS ARE FEASIBLE TARGETS FOR RA THERAPY. EXPLORING RA PATHOGENESIS INVOLVED EPIGENETIC FACTORS AND MECHANISMS IS CRUCIAL FOR DEVELOPING MORE EFFICIENT RA THERAPIES. HERE WE REVIEW EPIGENETIC ALTERATIONS ASSOCIATED WITH RA PATHOGENESIS INCLUDING DNA METHYLATION AND INTERACTING FACTORS. ADDITIONALLY, WE WILL SUMMARIZE THE LITERATURE REVEALING THE INVOLVED MOLECULAR STRUCTURES AND INTERACTIONS. FINALLY, POTENTIAL EPIGENETIC FACTOR-BASED THERAPIES WILL BE DISCUSSED THAT MAY HELP IN BETTER MANAGEMENT OF RA IN THE FUTURE. 2019 12 4738 32 NOVEL FIBROBLAST PHENOTYPES IN HOMEOSTASIS AND CHRONIC INFLAMMATION: FROM FUNCTIONS TO POTENTIAL REGULATORS. FIBROBLASTS ARE ESSENTIAL COMPONENTS OF THE STROMA, SUSTAINING A VARIETY OF TISSUES AND BEING KEY TO THE PROCESS OF TISSUE REPAIR AFTER INJURY. THEIR ROLE IN TISSUE REPAIR HAS BEEN ATTRIBUTED TO THEIR ABILITY TO ACQUIRE A CONTRACTILE, EXTRACELLULAR MATRIX-PRODUCING PHENOTYPE KNOWN AS MYOFIBROBLASTS. THIS PROPERTY IS PRIMARILY DEPENDENT ON THEIR RESPONSE TO THE PLEIOTROPIC CYTOKINE TRANSFORMING GROWTH FACTOR-BETA1. UNTIL RECENTLY, THE POTENTIAL ROLE OF FIBROBLASTS IN OTHER HOMEOSTATIC AND DISEASE-RELATED PROCESSES WAS LESS WELL UNDERSTOOD. ALTHOUGH IN VITRO STUDIES INDICATED THAT FIBROBLASTS ARE ABLE TO RESPOND TO AND SECRETE INFLAMMATORY MEDIATORS, DEFINITIVE EVIDENCE OF THEIR CONTRIBUTION TO CHRONIC INFLAMMATION WAS LIMITED. HOWEVER, THE EMERGENCE OF TECHNIQUES THAT ALLOW EXPLORATION OF TISSUES AT THE SINGLE CELL LEVEL HAS CHALLENGED THE PREVIOUS PARADIGMS ON FIBROBLAST IDENTITY AND FUNCTIONS, AND HAS LED TO THE DISCOVERY OF SIGNIFICANT DIVERSITY, SHOWING THE PRESENCE OF FIBROBLASTS WITH ALTERNATE TRANSCRIPTIONAL PROFILES IN A VARIETY OF TISSUES. THESE STUDIES HAVE ALSO SUGGESTED POTENTIAL ROLES OF NOVEL FIBROBLAST SUBTYPES AS REGULATORS OF EPITHELIAL HOMEOSTASIS AND RENEWAL, INFLAMMATORY CELL INFILTRATION AND ACTIVATION, AND ANTIGEN PRESENTATION. HERE, WE PROVIDE A COMPREHENSIVE REVIEW OF THE RECENT LITERATURE ON FIBROBLAST DIVERSITY IN THE DIGESTIVE TRACT, SKIN, LUNGS AND JOINTS. WE ALSO REVIEW EVIDENCE OF THEIR CONTRIBUTION TO THE REGULATION OF HOMEOSTASIS AND CHRONIC INFLAMMATION, AS WELL AS THEIR INTERACTIONS WITH OTHER CELLS IN VARIOUS TISSUE COMPARTMENTS. WE DISCUSS EVIDENCE OF DIFFERENT FACTORS INVOLVED IN THE CONTROL OF FIBROBLAST FUNCTION, ADDRESSING THE ROLE OF VARIOUS CYTOKINES, TRANSCRIPTION FACTORS AND EPIGENETIC CHANGES, AS WELL AS MICROENVIRONMENTAL FACTORS, INCLUDING EXTRACELLULAR MATRIX STIFFNESS, HYPOXIA, AND METABOLIC SHIFTS. 2023 13 2036 23 EPIGENETIC CHANGES OF THE IMMUNE SYSTEM WITH ROLE IN TUMOR DEVELOPMENT. TUMOR DEVELOPMENT IS CLOSELY RELATED TO CHRONIC INFLAMMATION AND TO EVASION OF IMMUNE DEFENSE MECHANISMS BY NEOPLASTIC CELLS. THE MEDIATORS OF THE INFLAMMATORY PROCESS AS WELL AS PROTEINS INVOLVED IN IMMUNE RESPONSE OR IMMUNE RESPONSE EVASION CAN BE SUBJECT TO VARIOUS EPIGENETIC CHANGES SUCH AS METHYLATION, ACETYLATION, OR PHOSPHORYLATION. SOME OF THESE, SUCH AS CYTOKINE SUPPRESSORS, ARE UNDERGOING REPRESSION THROUGH EPIGENETIC CHANGES, AND OTHERS SUCH AS CYTOKINES OR CHEMOKINES ARE UNDERGOING ACTIVATION THROUGH EPIGENETIC CHANGES, BOTH MODIFICATIONS HAVING AS A RESULT TUMOR PROGRESSION. THE ACTIVATING CHANGES CAN AFFECT THE RECEPTOR MOLECULES INVOLVED IN IMMUNE RESPONSE AND THESE PROMOTE INFLAMMATION AND SUBSEQUENTLY TUMOR DEVELOPMENT WHILE THE INACTIVATING CHANGES SEEM TO BE RELATED TO THE TUMOR REGRESSION PROCESS. THE PROTEINS INVOLVED IN ANTIGEN PRESENTATION, AND, THEREFORE IN IMMUNE RESPONSE ESCAPE, SUCH AS CLASSICAL HLA PROTEINS AND RELATED APM (ANTIGEN PRESENTATION MACHINERY) WITH THEIR EPIGENETIC CHANGES CONTRIBUTE TO THE TUMOR DEVELOPMENT PROCESS, EITHER TO TUMOR PROGRESSION OR REGRESSION, DEPENDING ON THE IMMUNE EFFECTOR CELLS THAT ARE IN PLAY. 2018 14 1232 31 CROSSTALK BETWEEN INFLAMMATORY SIGNALING AND METHYLATION IN CANCER. INFLAMMATION IS AN INTRICATE IMMUNE RESPONSE AGAINST INFECTION AND TISSUE DAMAGE. WHILE THE INITIAL IMMUNE RESPONSE IS IMPORTANT FOR PREVENTING TUMORIGENESIS, CHRONIC INFLAMMATION IS IMPLICATED IN CANCER PATHOGENESIS. IT HAS BEEN LINKED TO VARIOUS STAGES OF TUMOR DEVELOPMENT INCLUDING TRANSFORMATION, PROLIFERATION, ANGIOGENESIS, AND METASTASIS. IMMUNE CELLS, THROUGH THE PRODUCTION OF INFLAMMATORY MEDIATORS SUCH AS CYTOKINES, CHEMOKINES, TRANSFORMING GROWTH FACTORS, AND ADHESION MOLECULES CONTRIBUTE TO THE SURVIVAL, GROWTH, AND PROGRESSION OF THE TUMOR IN ITS MICROENVIRONMENT. THE ABERRANT EXPRESSION AND SECRETION OF PRO-INFLAMMATORY AND GROWTH FACTORS BY THE TUMOR CELLS RESULT IN THE RECRUITMENT OF IMMUNE CELLS, THUS CREATING A MUTUAL CROSSTALK. THE RECIPROCAL SIGNALING BETWEEN THE TUMOR CELLS AND THE IMMUNE CELLS CREATES AND MAINTAINS A SUCCESSFUL TUMOR NICHE. MANY INFLAMMATORY FACTORS ARE REGULATED BY EPIGENETIC MECHANISMS INCLUDING DNA METHYLATION AND HISTONE MODIFICATIONS. IN PARTICULAR, DNA AND HISTONE METHYLATION ARE CRUCIAL FORMS OF TRANSCRIPTIONAL REGULATION AND ABERRANT METHYLATION HAS BEEN ASSOCIATED WITH DEREGULATED GENE EXPRESSION IN ONCOGENESIS. SUCH DEREGULATIONS HAVE BEEN REPORTED IN BOTH SOLID TUMORS AND HEMATOLOGICAL MALIGNANCIES. WITH TECHNOLOGICAL ADVANCEMENTS TO STUDY GENOME-WIDE EPIGENETIC LANDSCAPES, IT IS NOW POSSIBLE TO IDENTIFY MOLECULAR MECHANISMS UNDERLYING ALTERED INFLAMMATORY PROFILES IN CANCER. IN THIS REVIEW, WE DISCUSS THE ROLE OF DNA AND HISTONE METHYLATION IN REGULATION OF INFLAMMATORY PATHWAYS IN HUMAN CANCERS AND REVIEW THE MERITS AND CHALLENGES OF TARGETING INFLAMMATORY MEDIATORS AS WELL AS EPIGENETIC REGULATORS IN CANCER. 2021 15 1150 35 CONNECTION BETWEEN INFLAMMATION AND CARCINOGENESIS IN GASTROINTESTINAL TRACT: FOCUS ON TGF-BETA SIGNALING. INFLAMMATION IS A PRIMARY DEFENSE PROCESS AGAINST VARIOUS EXTRACELLULAR STIMULI, SUCH AS VIRUSES, PATHOGENS, FOODS, AND ENVIRONMENTAL POLLUTANTS. WHEN CELLS RESPOND TO STIMULI FOR SHORT PERIODS OF TIME, IT RESULTS IN ACUTE OR PHYSIOLOGICAL INFLAMMATION. HOWEVER, IF THE STIMULATION IS SUSTAINED FOR LONGER TIME OR A PATHOLOGICAL STATE OCCURS, IT IS KNOWN AS CHRONIC OR PATHOLOGICAL INFLAMMATION. SEVERAL STUDIES HAVE SHOWN THAT TUMORIGENESIS IN THE GASTROINTESTINAL (GI) TRACT IS CLOSELY ASSOCIATED WITH CHRONIC INFLAMMATION, FOR WHICH ABNORMAL CELLULAR ALTERATIONS THAT ACCOMPANY CHRONIC INFLAMMATION SUCH AS OXIDATIVE STRESSES, GENE MUTATIONS, EPIGENETIC CHANGES, AND INFLAMMATORY CYTOKINES, ARE SHARED WITH CARCINOGENIC PROCESSES, WHICH FORMS A CRITICAL CROSS-LINK BETWEEN CHRONIC INFLAMMATION AND CARCINOGENESIS. TRANSFORMING GROWTH FACTOR (TGF)-BETA IS A MULTI-POTENT CYTOKINE THAT PLAYS AN IMPORTANT ROLE IN REGULATION OF CELL GROWTH, APOPTOSIS AND DIFFERENTIATION. MOST IMPORTANTLY, TGF-BETA IS A STRONG ANTI-INFLAMMATORY CYTOKINE THAT REGULATES THE DEVELOPMENT OF EFFECTOR CELLS. TGF-BETA HAS A SUPPRESSIVE EFFECT ON CARCINOGENESIS UNDER NORMAL CONDITIONS BY INHIBITING ABNORMAL CELL GROWTH, BUT ON THE OTHER HAND, MANY GI CANCERS ORIGINATE FROM UNCONTROLLED CELL GROWTH AND DIFFERENTIATION BY GENETIC LOSS OF TGF-BETA SIGNALING MOLECULES OR PERTURBATION OF TGF-BETA ADAPTORS. ONCE A TUMOR HAS DEVELOPED, TGF-BETA EXERTS A PROMOTING EFFECT ON THE TUMOR ITSELF AND STROMAL CELLS TO ENHANCE CELL GROWTH, ALTER THE RESPONSIVENESS OF TUMOR CELLS TO STIMULATE INVASION AND METASTASIS, AND INHIBITED IMMUNE SURVEILLANCE. THEREFORE, NOVEL DEVELOPMENT OF THERAPEUTIC AGENTS TO INHIBIT TGF-BETA-INDUCED PROGRESSION OF TUMOR AND TO RETAIN ITS GROWTH INHIBITORY ACTIVITIES, IN ADDITION TO ANTI-INFLAMMATORY ACTIONS, COULD BE USEFUL IN ONCOLOGY. IN THIS REVIEW, WE DISCUSS THE ROLE OF TGF-BETA IN INFLAMMATION AND CARCINOGENESIS OF THE GI TRACT RELATED TO ABNORMAL TGF-BETA SIGNALING. 2010 16 1864 32 EMERGING AVENUES LINKING INFLAMMATION AND CANCER. THE ROLE OF INFLAMMATION IN CARCINOGENESIS HAS BEEN EXTENSIVELY INVESTIGATED AND WELL DOCUMENTED. MANY BIOCHEMICAL PROCESSES THAT ARE ALTERED DURING CHRONIC INFLAMMATION HAVE BEEN IMPLICATED IN TUMORIGENESIS. THESE INCLUDE SHIFTING CELLULAR REDOX BALANCE TOWARD OXIDATIVE STRESS; INDUCTION OF GENOMIC INSTABILITY; INCREASED DNA DAMAGE; STIMULATION OF CELL PROLIFERATION, METASTASIS, AND ANGIOGENESIS; DEREGULATION OF CELLULAR EPIGENETIC CONTROL OF GENE EXPRESSION; AND INAPPROPRIATE EPITHELIAL-TO-MESENCHYMAL TRANSITION. A WIDE ARRAY OF PROINFLAMMATORY CYTOKINES, PROSTAGLANDINS, NITRIC OXIDE, AND MATRICELLULAR PROTEINS ARE CLOSELY INVOLVED IN PREMALIGNANT AND MALIGNANT CONVERSION OF CELLS IN A BACKGROUND OF CHRONIC INFLAMMATION. INAPPROPRIATE TRANSCRIPTION OF GENES ENCODING INFLAMMATORY MEDIATORS, SURVIVAL FACTORS, AND ANGIOGENIC AND METASTATIC PROTEINS IS THE KEY MOLECULAR EVENT IN LINKING INFLAMMATION AND CANCER. ABERRANT CELL SIGNALING PATHWAYS COMPRISING VARIOUS KINASES AND THEIR DOWNSTREAM TRANSCRIPTION FACTORS HAVE BEEN IDENTIFIED AS THE MAJOR CONTRIBUTORS IN ABNORMAL GENE EXPRESSION ASSOCIATED WITH INFLAMMATION-DRIVEN CARCINOGENESIS. THE POSTTRANSCRIPTIONAL REGULATION OF GENE EXPRESSION BY MICRORNAS ALSO PROVIDES THE MOLECULAR BASIS FOR LINKING INFLAMMATION TO CANCER. THIS REVIEW HIGHLIGHTS THE MULTIFACETED ROLE OF INFLAMMATION IN CARCINOGENESIS IN THE CONTEXT OF ALTERED CELLULAR REDOX SIGNALING. 2012 17 2054 31 EPIGENETIC CONTRIBUTIONS IN THE DEVELOPMENT OF RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS AN AUTOIMMUNE DISEASE, CHARACTERIZED BY CHRONIC INFLAMMATION OF THE JOINTS WITH SEVERE PAIN AND SWELLING, JOINT DAMAGE AND DISABILITY, WHICH LEADS TO JOINT DESTRUCTION AND LOSS OF FUNCTION. DESPITE EXTENSIVE RESEARCH EFFORTS, THE UNDERLYING CAUSE FOR RA IS STILL UNKNOWN AND CURRENT THERAPIES ARE MORE OR LESS EFFECTIVE IN CONTROLLING SYMPTOMS BUT STILL FAIL TO CURE THE DISEASE. IN RECENT YEARS, EPIGENETIC MODIFICATIONS WERE FOUND TO STRONGLY CONTRIBUTE TO THE DEVELOPMENT OF RA BY AFFECTING DIVERSE ASPECTS OF THE DISEASE AND MODIFYING GENE EXPRESSION LEVELS AND BEHAVIOR OF SEVERAL CELL TYPES, FIRST AND FOREMOST JOINT RESIDENT SYNOVIAL FIBROBLASTS (SF). RASF ARE THE MOST COMMON CELL TYPE AT THE SITE OF INVASION. OWING TO THEIR AGGRESSIVE, INTRINSICALLY ACTIVATED PHENOTYPE, RASF ARE ACTIVE CONTRIBUTORS IN JOINT DAMAGE. RASF ARE CHARACTERIZED BY THEIR ABILITY TO SECRETE CYTOKINES, CHEMOKINES AND JOINT-DAMAGING ENZYMES. FURTHERMORE, THESE CELLS ARE RESISTANT TO APOPTOSIS, LEADING TO HYPERPLASIA OF THE SYNOVIUM. IN ADDITION, RASF HAVE INVASIVE AND MIGRATORY PROPERTIES THAT COULD LEAD TO SPREADING OF THE DISEASE TO UNAFFECTED JOINTS. EPIGENETIC MODIFICATIONS, INCLUDING DNA METHYLATION AND POST-TRANSLATIONAL HISTONE MODIFICATIONS, SUCH AS HISTONE (DE)ACETYLATION, HISTONE METHYLATION AND HISTONE SUMOYLATION WERE IDENTIFIED AS REGULATORY MECHANISMS IN CONTROLLING AGGRESSIVE CELL ACTIVATION IN VITRO AND IN DISEASE OUTCOME IN ANIMAL MODELS IN VIVO. IN THE LAST 5 YEARS, THE FIELD OF EPIGENETICS IN RA HAS IMPRESSIVELY INCREASED. IN THIS REVIEW WE CONSIDER THE ROLE OF DIVERSE EPIGENETIC MODIFICATIONS IN THE DEVELOPMENT OF RA, WITH A SPECIAL FOCUS ON EPIGENETIC MODIFICATIONS IN RASF. 2012 18 4842 24 ONE YEAR IN REVIEW 2017: PATHOGENESIS OF RHEUMATOID ARTHRITIS. RHEUMATOID ARTHRITIS (RA) IS A CHRONIC INFLAMMATORY AUTOIMMUNE DISEASE INFLUENCED BY BOTH GENETIC AND ENVIRONMENTAL FACTORS. IT HAS BEEN POSTULATED THAT A HIGH-RISK GENETIC BACKGROUND, IN COMBINATION WITH EPIGENETIC MARKS AND ENVIRONMENTAL EXPOSURES, LEADS TO A CASCADE OF EVENTS INDUCING SYNOVITIS AND CONSEQUENT DESTRUCTIVE ARTHRITIS. THE CLINICAL PICTURE OF JOINT INVOLVEMENT IN RA IS THE RESULT OF CHRONIC INFLAMMATION OF THE SYNOVIUM, CHARACTERISED BY INTERACTIONS OF RESIDENT CELLS SUCH AS FIBROBLAST-LIKE SYNOVIOCYTES (FLS) WITH CELLS OF THE INNATE (E.G. MACROPHAGES, DENDRITIC CELLS, MAST CELLS AND NK CELLS, NEUTROPHILS) AND ADAPTIVE IMMUNE SYSTEM (E.G. B AND T LYMPHOCYTES). CURRENTLY, OUR UNDERSTANDING OF THE ROLE OF INNATE AND ADAPTIVE IMMUNITY IN THE PATHOGENESIS OF RA IS EXPANDING. THE CONCEPT OF HOW IMMUNE RESPONSES CONTRIBUTE TO THE DISEASE HAS DRAMATICALLY EVOLVED OVER THE LAST 50 YEARS. SHEDDING SOME LIGHT ON THE DIFFERENT ASPECTS OF RA PATHOGENESIS WILL HELP TO IDENTIFY NEW TARGETS FOR THE DEVELOPMENT OF DISEASE-MODIFYING THERAPIES. THUS, IN THIS REVIEW WE REPORT NEW INSIGHTS IN RA PATHOGENESIS, RESULTING FROM A LITERATURE RESEARCH DATE PUBLISHED IN THE LAST YEAR. 2017 19 6395 37 THE ROLE OF THE MEDIATORS OF INFLAMMATION IN CANCER DEVELOPMENT. EPIGENETIC DISORDERS SUCH AS POINT MUTATIONS IN CELLULAR TUMOR SUPPRESSOR GENES, DNA METHYLATION AND POST-TRANSLATIONAL MODIFICATIONS ARE NEEDED TO TRANSFORMATION OF NORMAL CELLS INTO CANCER CELLS. THESE EVENTS RESULT IN ALTERATIONS IN CRITICAL PATHWAYS RESPONSIBLE FOR MAINTAINING THE NORMAL CELLULAR HOMEOSTASIS, TRIGGERING TO AN INFLAMMATORY RESPONSE WHICH CAN LEAD THE DEVELOPMENT OF CANCER. THE INFLAMMATORY RESPONSE IS A UNIVERSAL DEFENSE MECHANISM ACTIVATED IN RESPONSE TO AN INJURY TISSUE, OF ANY NATURE, THAT INVOLVES BOTH INNATE AND ADAPTIVE IMMUNE RESPONSES, THROUGH THE COLLECTIVE ACTION OF A VARIETY OF SOLUBLE MEDIATORS. MANY INFLAMMATORY SIGNALING PATHWAYS ARE ACTIVATED IN SEVERAL TYPES OF CANCER, LINKING CHRONIC INFLAMMATION TO TUMORIGENESIS PROCESS. THUS, INFLAMMATORY RESPONSES PLAY DECISIVE ROLES AT DIFFERENT STAGES OF TUMOR DEVELOPMENT, INCLUDING INITIATION, PROMOTION, GROWTH, INVASION, AND METASTASIS, AFFECTING ALSO THE IMMUNE SURVEILLANCE. IMMUNE CELLS THAT INFILTRATE TUMORS ENGAGE IN AN EXTENSIVE AND DYNAMIC CROSSTALK WITH CANCER CELLS, AND SOME OF THE MOLECULAR EVENTS THAT MEDIATE THIS DIALOG HAVE BEEN REVEALED. A RANGE OF INFLAMMATION MEDIATORS, INCLUDING CYTOKINES, CHEMOKINES, FREE RADICALS, PROSTAGLANDINS, GROWTH AND TRANSCRIPTION FACTORS, MICRORNAS, AND ENZYMES AS, CYCLOOXYGENASE AND MATRIX METALLOPROTEINASE, COLLECTIVELY ACTS TO CREATE A FAVORABLE MICROENVIRONMENT FOR THE DEVELOPMENT OF TUMORS. IN THIS REVIEW ARE PRESENTED THE MAIN MEDIATORS OF THE INFLAMMATORY RESPONSE AND DISCUSSED THE LIKELY MECHANISMS THROUGH WHICH, THEY INTERACT WITH EACH OTHER TO CREATE A CONDITION FAVORABLE TO DEVELOPMENT OF CANCER. 2015 20 6309 25 THE REGULATION OF MIRNAS IN INFLAMMATION-RELATED CARCINOGENESIS. CHRONIC INFLAMMATION PLAYS IMPORTANT ROLES IN THE INITIATION AND DEVELOPMENT OF VARIOUS CANCERS, PARTICULARLY GASTROINTESTINAL CANCER. CANCER IS CHARACTERIZED BY STEPWISE ACCUMULATION OF GENETIC AND EPIGENETIC ALTERATIONS OF GENES. AS A HIGH RISK FACTOR FOR CANCER, CHRONIC INFLAMMATORY RESPONSE PRODUCES GREAT AMOUNT OF MEDIATORS, INCLUDING CYTOKINES, REACTIVE OXYGEN AND NITROGEN SPECIES, PROTEINASES, WHICH CAN INDUCE GENETIC AND EPIGENETIC CHANGES OF CANCER-ASSOCIATED GENES AND PATHWAYS. FURTHERMORE, INFLAMMATION ALSO MODULATES THE EXPRESSION OF MIRNAS THAT NOT ONLY REGULATE THE EXPRESSION OF TUMOR-RELATED PROTEINS BUT ALSO ENHANCE THE TUMOR-PROMOTING INFLAMMATORY PROCESS. IN THE CURRENT REVIEW, WE SUMMARIZE THE MECHANISMS BY WHICH INFLAMMATORY MEDIATORS AND SIGNALING REGULATE THE BIOSYNTHESIS OF MIRNAS, AS WELL AS THE INVOLVEMENT OF MIRNAS IN THE FEEDBACK LOOPS PROMOTING INFLAMMATION-ASSOCIATED CARCINOGENESIS. 2015