1 547 84 ATTENUATED TLR4/MAPK SIGNALING IN MONOCYTES FROM PATIENTS WITH CRMO RESULTS IN IMPAIRED IL-10 EXPRESSION. CHRONIC RECURRENT MULTIFOCAL OSTEOMYELITIS (CRMO) IS AN AUTOINFLAMMATORY BONE DISORDER OF UNKNOWN ORIGIN. WE PREVIOUSLY DEMONSTRATED THAT MONOCYTES FROM CRMO PATIENTS FAIL TO EXPRESS THE IMMUNE-MODULATORY CYTOKINE INTERLEUKIN-10 (IL-10) IN A CHROMATIN DEPENDENT MANNER. HERE, WE DEMONSTRATE THAT ATTENUATED EXTRACELLULAR-SIGNAL REGULATED KINASE (ERK)1 AND 2 SIGNALING IN RESPONSE TO TLR4 ACTIVATION RESULTS IN FAILURE TO INDUCE IL-10 EXPRESSION IN MONOCYTES FROM CRMO PATIENTS. ATTENUATED ERK1/2 ACTIVATION RESULTS IN 1) REDUCED LEVELS OF SP-1, A TRANSCRIPTION FACTOR THAT INDUCES IL-10 EXPRESSION IN MONOCYTES, AND 2) IMPAIRED H3S10 PHOSPHORYLATION OF THE IL10 PROMOTER, AN ACTIVATING EPIGENETIC MARK. THE PRO-INFLAMMATORY CYTOKINES TUMOR NECROSIS FACTOR (TNF)ALPHA AND IL-6 ARE NOT NEGATIVELY AFFECTED, RESULTING IN AN IMBALANCE TOWARDS PRO-INFLAMMATORY CYTOKINES. THUS, IMPAIRED ERK1/2 SIGNALING WITH SUBSEQUENTLY REDUCED SP-1 EXPRESSION AND H3S10 PHOSPHORYLATION OF THE IL10 PROMOTER MAY CENTRALLY CONTRIBUTE TO THE PATHOPHYSIOLOGY OF CRMO. 2012 2 969 36 CHRONIC NON-BACTERIAL OSTEOMYELITIS IS ASSOCIATED WITH IMPAIRED SP1 SIGNALING, REDUCED IL10 PROMOTER PHOSPHORYLATION, AND REDUCED MYELOID IL-10 EXPRESSION. CHRONIC NON-BACTERIAL OSTEOMYELITIS (CNO) IS AN AUTO-INFLAMMATORY DISORDER THAT AFFECTS THE SKELETAL SYSTEM. INTERLEUKIN (IL-)10 IS AN IMMUNE-MODULATORY CYTOKINE THAT CONTROLS INFLAMMATION, AND LIMITS INFLAMMATORY CYTOKINE RESPONSES. DYSREGULATION OF IL-10 EXPRESSION HAS BEEN SHOWN TO RESULT IN AUTOIMMUNE AND INFECTIOUS DISEASES. WE INVESTIGATED IL-10 EXPRESSION BY MONOCYTIC CELLS FROM CNO PATIENTS AND CONTROLS. IN RESPONSE TO STIMULATION WITH LPS, IL-10 EXPRESSION FROM CNO MONOCYTES WAS REDUCED (P<0.001). THIS WAS INDEPENDENT OF IL10 PROMOTER POLYMORPHISMS. THUS, WE INVESTIGATED SP1 RECRUITMENT TO THE IL10 PROMOTER AND SAW MARKEDLY REDUCED BINDING IN CNO MONOCYTES. THIS WAS ACCOMPANIED WITH REDUCED PHOSPHORYLATION OF HISTONE H3 SERINE 10 (H3S10), AN ACTIVATING EPIGENETIC MARK. IMPAIRED RECRUITMENT OF SP1 TO THE IL10 PROMOTER, AND REDUCED H3S10 PHOSPHORYLATION, MAY BE A REFLECTION OF DEFICIENT MAPK SIGNALING IN CNO MONOCYTES IN RESPONSE TO LPS STIMULATION. THUS, WE HAVE DISCOVERED A MECHANISM THAT MAY BE CENTRAL IN THE PATHOPHYSIOLOGY OF CNO. 2011 3 986 22 CHRONIC RECURRENT MULTIFOCAL OSTEOMYELITIS (CRMO) AND JUVENILE SPONDYLOARTHRITIS (JSPA): TO WHAT EXTENT ARE THEY RELATED? CHRONIC RECURRENT MULTIFOCAL OSTEOMYELITIS (CRMO) IS AN AUTOINFLAMMATORY DISEASE OCCURRING MAINLY IN THE PEDIATRIC AGE GROUP (BEFORE 16 YEARS) AND GENERALLY PRESENTS AS A SEPARATE ENTITY. SYNOVITIS, ACNE, PUSTULOSIS, HYPEROSTOSIS AND OSTEITIS (SAPHO) SYNDROME COMBINES OSTEOARTICULAR AND CUTANEOUS INVOLVEMENT, SIMILAR TO CRMO, AND FALLS INTO THE SPECTRUM OF SPONDYLOARTHRITIS (SPA). THE FACT THAT A PATIENT CAN PROGRESS FROM ONE DISEASE TO ANOTHER RAISES THE QUESTION OF WHETHER CRMO, LIKE SAPHO, COULD FALL WITHIN THE SPECTRUM OF SPA, RANGING FROM A PREDOMINANTLY OSTEOARTICULAR FORM TO AN ENTHESITIC FORM WITH MORE OR LESS MARKED SKIN INVOLVEMENT. IN THIS REVIEW, WE SET OUT TO DISCUSS THIS HYPOTHESIS BY HIGHLIGHTING THE DIFFERENCES AND SIMILARITIES BETWEEN CRMO AND JUVENILE SPA IN CLINICAL, RADIOLOGICAL AND PATHOPHYSIOLOGICAL ASPECTS. A COMMON HYPOTHESIS COULD POTENTIALLY CONSIDER INTESTINAL DYSBIOSIS AS THE ORIGIN OF THESE DIFFERENT INFLAMMATORY DISEASES. INTERINDIVIDUAL FACTORS SUCH AS GENDER, ENVIRONMENT, GENETICS AND/OR EPIGENETIC BACKGROUND COULD ACT AS COMBINED DISEASE MODIFIERS. THIS IS WHY WE SUGGEST THAT PATHOPHYSIOLOGY, RATHER THAN CLINICAL PHENOTYPE, BE USED TO RECLASSIFY THESE DISEASES. 2023 4 4667 33 NEW INSIGHTS INTO ADULT AND PAEDIATRIC CHRONIC NON-BACTERIAL OSTEOMYELITIS CNO. PURPOSE OF REVIEW: TO DESCRIBE IN DETAIL THE CLINICAL SYNOPSIS AND PATHOPHYSIOLOGY OF CHRONIC NON-BACTERIAL OSTEOMYELITIS AND SAPHO SYNDROME. RECENT FINDINGS: CHRONIC NON-BACTERIAL OSTEOMYELITIS (CNO) HAS BEEN IDENTIFIED AS A DISEASE ENTITY FOR ALMOST 50 YEARS. THIS INFLAMMATORY BONE DISORDER IS CHARACTERIZED BY OSTEOLYTIC AS WELL AS HYPEROSTOTIC/OSTEOSCLEROTIC LESIONS. IT IS CHRONIC IN NATURE, BUT IT CAN PRESENT WITH EPISODIC FLAIRS AND PHASES OF REMISSION, WHICH HAVE LED TO THE DENOMINATION "CHRONIC RECURRENT OSTEOMYELITIS", WITH ITS SEVERE MULTIFOCAL FORM "CHRONIC RECURRENT MULTIFOCAL OSTEOMYELITIS" (CRMO). FOR ALMOST THREE DECADES, AN INFECTIOUS AETIOLOGY HAD BEEN CONSIDERED, SINCE ESPECIALLY PROPIONIBACTERIUM ACNES HAD BEEN ISOLATED FROM BONE LESIONS OF INDIVIDUAL PATIENTS. HOWEVER, THIS CONCEPT HAS BEEN CHALLENGED SINCE LONG-TERM ANTIBIOTIC THERAPY DID NOT ALTER THE COURSE OF DISEASE AND MODERN MICROBIOLOGICAL TECHNIQUES (INCLUDING PCR) FAILED TO CONFIRM BONE INFECTION AS AN UNDERLYING CAUSE. OVER RECENT YEARS, A PROFOUND DYSREGULATION OF CYTOKINE EXPRESSION PROFILES HAS BEEN DEMONSTRATED IN INNATE IMMUNE CELLS OF CNO PATIENTS. A HALLMARK OF MONOCYTES FROM CNO PATIENTS IS THE FAILURE TO PRODUCE IMMUNE REGULATORY CYTOKINES INTERLEUKIN-10 (IL-10) AND IL-19, WHICH HAVE BEEN LINKED WITH GENETIC AND EPIGENETIC ALTERATIONS. SUBSEQUENTLY, A SIGNIFICANT UPREGULATION OF PRO-INFLAMMATORY, NLRP3 INFLAMMASOME-DEPENDENT CYTOKINES (IL-1BETA AND TNF-ALPHA), HAS BEEN DEMONSTRATED. THE CURRENT KNOWLEDGE ON CNO, THE UNDERLYING MOLECULAR PATHOPHYSIOLOGY, AND MODERN IMAGING STRATEGIES ARE SUMMARIZED; DIFFERENTIAL DIAGNOSES, TREATMENT OPTIONS, OUTCOME MEASURES, AS WELL AS QUALITY OF LIFE STUDIES ARE DISCUSSED. 2020 5 2196 23 EPIGENETIC MODIFICATION MEDIATES THE INCREASE OF LAG-3(+) T CELLS IN CHRONIC OSTEOMYELITIS. IMMUNE SUPPRESSION PLAYS CRITICAL ROLES IN THE DEVELOPMENT OF CHRONIC OSTEOMYELITIS, AND THE MECHANISMS UNDERLYING THE DEVELOPMENT OF IMMUNE SUPPRESSION IN CHRONIC OSTEOMYELITIS HAVE ATTRACTED MUCH ATTENTION. LAG-3 IS AN IMPORTANT SUPPRESSOR OF T CELL ACTIVATION, BUT THE ROLE OF LAG-3 IN THE IMMUNE REGULATION OF CHRONIC OSTEOMYELITIS IS CURRENTLY UNKNOWN. WE SOUGHT TO DEMONSTRATE IF LAG-3 PLAYS CRUCIAL ROLES IN CHRONIC OSTEOMYELITIS PROGRESSION AND HAS EFFECTS ON IMMUNE SUPPRESSION AND EXHAUSTING OF T CELLS, AND WHAT IS THE MECHANISM UNDERLYING LAG-3 DEREGULATION IN CHRONIC OSTEOMYELITIS. WE EXAMINED THE EXPRESSION OF LAG-3 IN THE T CELLS OF PERIPHERAL BLOOD OF 50 HEALTHY CONTROLS AND 50 PATIENTS WITH CHRONIC OSTEOMYELITIS BY FLOW CYTOMETRY. CLINICAL DATA WERE ANALYZED TO DETERMINE THE CORRELATION BETWEEN INFLAMMATION INDEX AND LAG-3 EXPRESSION. MOREOVER, WE ISOLATED THE CD4(+) T CELLS FROM HEALTHY CONTROLS AND CHRONIC OSTEOMYELITIS PATIENTS TO COMPARE CELL PROLIFERATION AND IFN-GAMMA PRODUCTION. CHROMATIN IMMUNOPRECIPITATION ASSAYS WERE UTILIZED TO ANALYZE THE EPIGENETIC MODIFICATION ON LAG-3 EXPRESSION IN T CELLS. WE FOUND THAT LAG-3 WAS SIGNIFICANTLY INCREASED IN THE T CELLS OF PERIPHERAL BLOOD FROM CHRONIC OSTEOMYELITIS PATIENTS. SUBSEQUENTLY, CLINICAL DATA ANALYSIS SUGGESTED THAT THE HIGHER EXPRESSION OF LAG-3 WAS ASSOCIATED WITH SEVERER INFLAMMATION SITUATION. CONSISTENTLY, LAG-3(+)CD4(+) T CELLS EXHIBITED IMPAIRED CELL PROLIFERATION AND IFN-GAMMA SECRETION. DEREGULATION OF HISTONE METHYLATION MEDIATED THE INCREASE OF LAG-3(+) T CELLS DURING CHRONIC OSTEOMYELITIS. TAKEN TOGETHER, OUR STUDY DEMONSTRATES THE INCREASE OF LAG-3(+) T CELLS AND ITS IMMUNE REGULATORY ROLES IN CHRONIC OSTEOMYELITIS PROGRESSION, SUGGESTING NEW MECHANISMS AND POTENTIAL THERAPEUTIC TARGETS FOR CHRONIC OSTEOMYELITIS. 2017 6 1357 23 DEVELOPMENT OF INNATE IMMUNE MEMORY BY NON-IMMUNE CELLS DURING STAPHYLOCOCCUS AUREUS INFECTION DEPENDS ON REACTIVE OXYGEN SPECIES. INTRODUCTION: THE MECHANISMS UNDERLYING INNATE IMMUNE MEMORY (TRAINED IMMUNITY) COMPRISE EPIGENETIC REPROGRAMMING OF TRANSCRIPTIONAL PATHWAYS ASSOCIATED WITH ALTERATIONS OF INTRACELLULAR METABOLISM. WHILE THE MECHANISMS OF INNATE IMMUNE MEMORY CARRIED OUT BY IMMUNE CELLS ARE WELL CHARACTERIZED, SUCH PROCESSES IN NON-IMMUNE CELLS, ARE POORLY UNDERSTOOD. THE OPPORTUNISTIC PATHOGEN, STAPHYLOCOCCUS AUREUS, IS RESPONSIBLE FOR A MULTITUDE OF HUMAN DISEASES, INCLUDING PNEUMONIA, ENDOCARDITIS AND OSTEOMYELITIS, AS WELL AS ANIMAL INFECTIONS, INCLUDING CHRONIC CATTLE MASTITIS THAT ARE EXTREMELY DIFFICULT TO TREAT. AN INDUCTION OF INNATE IMMUNE MEMORY MAY BE CONSIDERED AS A THERAPEUTIC ALTERNATIVE TO FIGHT S. AUREUS INFECTION. METHODS: IN THE CURRENT WORK, WE DEMONSTRATED THE DEVELOPMENT OF INNATE IMMUNE MEMORY IN NON-IMMUNE CELLS DURING S. AUREUS INFECTION EMPLOYING A COMBINATION OF TECHNIQUES INCLUDING ENZYME-LINKED IMMUNOSORBENT ASSAY (ELISA), MICROSCOPIC ANALYSIS, AND CYTOMETRY. RESULTS: WE OBSERVED THAT TRAINING OF HUMAN OSTEOBLAST-LIKE MG-63 CELLS AND LUNG EPITHELIAL A549 CELLS WITH BETA-GLUCAN INCREASED IL-6 AND IL-8 PRODUCTION UPON A STIMULATION WITH S. AUREUS, CONCOMITANT WITH HISTONES MODIFICATIONS. IL-6 AND IL-8 PRODUCTION WAS POSITIVELY CORRELATED WITH AN ACETYLATION OF HISTONE 3 AT LYSINE 27 (H3K27), THUS SUGGESTING EPIGENETIC REPROGRAMMING IN THESE CELLS. AN ADDITION OF THE ROS SCAVENGER N-ACETYLCYSTEINE, NAC, PRIOR TO BETA-GLUCAN PRETREATMENT FOLLOWED BY AN EXPOSURE TO S. AUREUS, RESULTED IN DECREASED IL-6 AND IL-8 PRODUCTION, THEREBY SUPPORTING THE INVOLVEMENT OF ROS IN THE INDUCTION OF INNATE IMMUNE MEMORY. EXPOSURE OF CELLS TO LACTOCOCCUS LACTIS RESULTED IN INCREASED IL-6 AND IL-8 PRODUCTION BY MG-63 AND A549 CELLS UPON A STIMULATION WITH S. AUREUS THAT WAS CORRELATED WITH H3K27 ACETYLATION, SUGGESTING THE ABILITY OF THIS BENEFICIAL BACTERIUM TO INDUCE INNATE IMMUNE MEMORY. DISCUSSION: THIS WORK IMPROVES OUR UNDERSTANDING OF INNATE IMMUNE MEMORY IN NON-IMMUNE CELLS IN THE CONTEXT OF S. AUREUS INFECTION. IN ADDITION TO KNOWN INDUCERS, PROBIOTICS MAY REPRESENT GOOD CANDIDATES FOR THE INDUCTION OF INNATE IMMUNE MEMORY. OUR FINDINGS MAY HELP THE DEVELOPMENT OF ALTERNATIVE THERAPEUTIC APPROACHES FOR THE PREVENTION OF S. AUREUS INFECTION. 2023 7 6542 25 TRANSCRIPTOME ARCHITECTURE OF OSTEOBLASTIC CELLS INFECTED WITH STAPHYLOCOCCUS AUREUS REVEALS STRONG INFLAMMATORY RESPONSES AND SIGNATURES OF METABOLIC AND EPIGENETIC DYSREGULATION. STAPHYLOCOCCUS AUREUS IS AN OPPORTUNISTIC PATHOGEN THAT CAUSES A RANGE OF DEVASTATING DISEASES INCLUDING CHRONIC OSTEOMYELITIS, WHICH PARTIALLY RELIES ON THE INTERNALIZATION AND PERSISTENCE OF S. AUREUS IN OSTEOBLASTS. THE IDENTIFICATION OF THE MECHANISMS OF THE OSTEOBLAST RESPONSE TO INTRACELLULAR S. AUREUS IS THUS CRUCIAL TO IMPROVE THE KNOWLEDGE OF THIS INFECTIOUS PATHOLOGY. SINCE THE SIGNAL FROM SPECIFICALLY INFECTED BACTERIA-BEARING CELLS IS DILUTED AND THE RESULTS ARE CONFOUNDED BY BYSTANDER EFFECTS OF UNINFECTED CELLS, WE DEVELOPED A NOVEL MODEL OF LONG-TERM INFECTION. USING A FLOW CYTOMETRIC APPROACH WE ISOLATED ONLY S. AUREUS-BEARING CELLS FROM MIXED POPULATIONS THAT ALLOWS TO IDENTIFY SIGNALS SPECIFIC TO INTRACELLULAR INFECTION. HERE WE PRESENT AN IN-DEPTH ANALYSIS OF THE EFFECT OF LONG-TERM S. AUREUS INFECTION ON THE TRANSCRIPTIONAL PROGRAM OF HUMAN OSTEOBLAST-LIKE CELLS. AFTER RNA-SEQ AND KEGG AND REACTOME PATHWAY ENRICHMENT ANALYSIS, THE REMODELED TRANSCRIPTOMIC PROFILE OF INFECTED CELLS REVEALED EXACERBATED IMMUNE AND INFLAMMATORY RESPONSES, AS WELL AS METABOLIC DYSREGULATIONS THAT LIKELY INFLUENCE THE INTRACELLULAR LIFE OF BACTERIA. NUMEROUS GENES ENCODING EPIGENETIC REGULATORS WERE DOWNREGULATED. THE LATER INCLUDED GENES CODING FOR COMPONENTS OF CHROMATIN-REPRESSIVE COMPLEXES (E.G., NURD, BAHD1 AND PRC1) AND EPIFACTORS INVOLVED IN DNA METHYLATION. SETS OF GENES ENCODING PROTEINS OF CELL ADHESION OR NEUROTRANSMISSION WERE ALSO DEREGULATED. OUR RESULTS SUGGEST THAT INTRACELLULAR S. AUREUS INFECTION HAS A LONG-TERM IMPACT ON THE GENOME AND EPIGENOME OF HOST CELLS, WHICH MAY EXERT PATHO-PHYSIOLOGICAL DYSFUNCTIONS ADDITIONALLY TO THE DEFENSE RESPONSE DURING THE INFECTION PROCESS. OVERALL, THESE RESULTS NOT ONLY IMPROVE OUR CONCEPTUAL UNDERSTANDING OF BIOLOGICAL PROCESSES INVOLVED IN THE LONG-TERM S. AUREUS INFECTIONS OF OSTEOBLAST-LIKE CELLS, BUT ALSO PROVIDE AN ATLAS OF DEREGULATED HOST GENES AND BIOLOGICAL PATHWAYS AND IDENTIFY NOVEL MARKERS AND POTENTIAL CANDIDATES FOR PROPHYLACTIC AND THERAPEUTIC APPROACHES. 2022 8 3666 22 INFECTION, STEM CELLS AND CANCER SIGNALS. THE ASSOCIATION OF CANCER WITH PRECEDING PARASITIC INFECTIONS HAS BEEN OBSERVED FOR OVER 200 YEARS. SOME SUCH CANCERS ARISE FROM INFECTION OF TISSUE STEM CELLS BY VIRUSES WITH INSERTION OF VIRAL ONCOGENES INTO THE HOST DNA (MOUSE POLYOMA VIRUS, MOUSE MAMMARY TUMOR VIRUS). IN OTHER CASES THE VIRUS DOES NOT INSERT ITS DNA INTO THE HOST CELLS, BUT RATHER COMMANDEERS THE METABOLISM OF THE INFECTED CELLS, SO THAT THE CELLS CONTINUE TO PROLIFERATE AND DO NOT DIFFERENTIATE (HUMAN PAPILLOMA VIRUS AND CERVICAL CANCER). CYTOPLASMIC EPSTEIN BARR VIRUS INFECTION IS ASSOCIATED WITH A SPECIFIC GENE TRANSLOCATION (IG/C-MYC) THAT ACTIVATES PROLIFERATION OF AFFECTED CELLS (BURKITT LYMPHOMA). IN CHRONIC OSTEOMYELITIS AN INFLAMMATORY REACTION TO THE INFECTION APPEARS TO ACT THROUGH PRODUCTION OF INFLAMMATORY CYTOKINES AND OXYGEN RADICAL FORMATION TO INDUCE EPITHELIAL CANCERS. INFECTION WITH HELICOBACTER PYLORI LEADS TO EPIGENETIC CHANGES IN METHYLATION AND INFECTION BY A PARASITE. CLONORCHIS SINENSIS ALSO ACTS AS A PROMOTER OF CANCER OF THE BILE DUCTS OF THE LIVER (CHOLANIOCARCINOMA). THE COMMON THREAD AMONG THESE DIVERSE PATHWAYS IS THAT THE INFECTIONS ACT TO ALTER TISSUE STEM CELL SIGNALING WITH CONTINUED PROLIFERATION OF TUMOR TRANSIT AMPLIFYING CELLS. 2011 9 6345 25 THE ROLE OF EPIGENETICS IN AUTOIMMUNE/INFLAMMATORY DISEASE. HISTORICALLY, SYSTEMIC SELF-INFLAMMATORY CONDITIONS WERE CLASSIFIED AS EITHER AUTOINFLAMMATORY AND CAUSED BY THE INNATE IMMUNE SYSTEM OR AUTOIMMUNE AND DRIVEN BY ADAPTIVE IMMUNE RESPONSES. HOWEVER, IT BECAME CLEAR THAT REALITY IS MUCH MORE COMPLEX AND THAT AUTOIMMUNE/INFLAMMATORY CONDITIONS RANGE ALONG AN "INFLAMMATORY SPECTRUM" WITH PRIMARILY AUTOINFLAMMATORY VS. AUTOIMMUNE CONDITIONS RESEMBLING EXTREMES AT EITHER END. EPIGENETIC MODIFICATIONS INFLUENCE GENE EXPRESSION AND ALTER CELLULAR FUNCTIONS WITHOUT MODIFYING THE GENOMIC SEQUENCE. METHYLATION OF CPG DNA DINUCLEOTIDES AND/OR THEIR HYDROXYMETHYLATION, POST-TRANSLATIONAL MODIFICATIONS TO AMINO TERMINI OF HISTONE PROTEINS, AND NON-CODING RNA EXPRESSION ARE MAIN EPIGENETIC EVENTS. THE PATHOPHYSIOLOGY OF AUTOIMMUNE/INFLAMMATORY DISEASES HAS BEEN CLOSELY LINKED WITH DISEASE CAUSING GENE MUTATIONS (RARE) OR A COMBINATION OF GENETIC SUSCEPTIBILITY AND EPIGENETIC MODIFICATIONS ARISING FROM EXPOSURE TO THE ENVIRONMENT (MORE COMMON). OVER RECENT YEARS, PROGRESS HAS BEEN MADE IN UNDERSTANDING MOLECULAR MECHANISMS INVOLVED IN SYSTEMIC INFLAMMATION AND THE CONTRIBUTION OF INNATE AND ADAPTIVE IMMUNE RESPONSES. EPIGENETIC EVENTS HAVE BEEN IDENTIFIED AS (I) CENTRAL PATHOPHYSIOLOGICAL FACTORS IN ADDITION TO GENETIC DISEASE PREDISPOSITION AND (II) AS CO-FACTORS DETERMINING CLINICAL PICTURES AND OUTCOMES IN INDIVIDUALS WITH MONOGENIC DISEASE. THUS, A COMPLETE UNDERSTANDING OF EPIGENETIC CONTRIBUTORS TO AUTOIMMUNE/INFLAMMATORY DISEASE WILL RESULT IN APPROACHES TO PREDICT INDIVIDUAL DISEASE OUTCOMES AND THE INTRODUCTION OF EFFECTIVE, TARGET-DIRECTED, AND TOLERABLE THERAPIES. HERE, WE SUMMARIZE RECENT FINDINGS THAT SIGNIFY THE IMPORTANCE OF EPIGENETIC MODIFICATIONS IN AUTOIMMUNE/INFLAMMATORY DISORDERS ALONG THE INFLAMMATORY SPECTRUM CHOOSING THREE EXAMPLES: THE AUTOINFLAMMATORY BONE CONDITION CHRONIC NONBACTERIAL OSTEOMYELITIS (CNO), THE "MIXED PATTERN" DISORDER PSORIASIS, AND THE AUTOIMMUNE DISEASE SYSTEMIC LUPUS ERYTHEMATOSUS (SLE). 2019 10 6535 24 TRANSCRIPTIONAL REGULATION OF THE ANTI-INFLAMMATORY CYTOKINE IL-10 IN ACQUIRED IMMUNE CELLS. ALTHOUGH THE MAJOR ROLE OF THE IMMUNE RESPONSE IS HOST DEFENSE FROM A WIDE RANGE OF POTENTIALLY PATHOGENIC MICROORGANISMS, EXCESS IMMUNE RESPONSES CAN RESULT IN SEVERE HOST DAMAGE. THE HOST THUS REQUIRES ANTI-INFLAMMATORY MECHANISMS TO PREVENT REACTIVITY TO SELF. INTERLEUKIN-10 (IL-10) IS A CYTOKINE WITH BROAD ANTI-INFLAMMATORY PROPERTIES INVOLVED IN THE PATHOGENESIS OF VARIOUS DISEASES. IL-10 WAS ORIGINALLY DESCRIBED AS A T HELPER (T(H)2) DERIVED CYTOKINE, BUT FURTHER STUDIES INDICATED THAT IL-10 IS EXPRESSED NOT ONLY BY MANY CELLS OF THE ADAPTIVE IMMUNE SYSTEM, INCLUDING T AND B CELLS, BUT ALSO BY THE INNATE IMMUNE CELLS, INCLUDING DENDRITIC CELLS (DCS), MACROPHAGES, MAST CELLS, AND NATURAL KILLER (NK) CELLS. IN ADDITION, IL-10 CAN BE INDUCED IN T(H)1 AND T(H)17 CELLS BY CHRONIC INFLAMMATION AS A SYSTEM OF FEEDBACK REGULATION. IN THIS REVIEW, WE FOCUS ON THE MOLECULAR MECHANISMS UNDERLYING IL10 GENE EXPRESSION IN ADAPTIVE IMMUNE CELLS AND SUMMARIZE THE RECENT PROGRESSES IN EPIGENETIC AND TRANSCRIPTIONAL REGULATION OF THE IL10 GENE. UNDERSTANDING THE TRANSCRIPTIONAL REGULATORY EVENTS MAY HELP IN THE DEVELOPMENT OF NEW STRATEGIES TO CONTROL INFLAMMATORY DISEASES. 2012 11 2405 26 EPIGENETIC RESPONSE IN MICE MASTITIS: ROLE OF HISTONE H3 ACETYLATION AND MICRORNA(S) IN THE REGULATION OF HOST INFLAMMATORY GENE EXPRESSION DURING STAPHYLOCOCCUS AUREUS INFECTION. BACKGROUND: THERE IS RENEWED INTEREST TOWARDS UNDERSTANDING THE HOST-PATHOGEN INTERACTION IN THE LIGHT OF EPIGENETIC MODIFICATIONS. ALTHOUGH EPITHELIAL TISSUE IS THE MAJOR SITE FOR HOST-PATHOGEN INTERACTIONS, THERE IS HANDFUL OF STUDIES TO SHOW HOW EPITHELIAL CELLS RESPOND TO PATHOGENS. BACTERIAL INFECTION IN THE MAMMARY GLAND PARENCHYMA INDUCES LOCAL AND SUBSEQUENTLY SYSTEMIC INFLAMMATION THAT RESULTS IN A COMPLEX DISEASE CALLED MASTITIS. GLOBALLY STAPHYLOCOCCUS AUREUS IS THE SINGLE LARGEST MASTITIS PATHOGEN AND THE INFECTION CAN ULTIMATELY RESULT IN EITHER SUBCLINICAL OR CHRONIC AND SOMETIMES LIFELONG INFECTION. RESULTS: IN THE PRESENT REPORT WE HAVE ADDRESSED THE DIFFERENTIAL INFLAMMATORY RESPONSE IN MICE MAMMARY TISSUE DURING INTRAMAMMARY INFECTION AND THE ALTERED EPIGENETIC CONTEXT INDUCED BY TWO CLOSELY RELATED STRAINS OF S. AUREUS, ISOLATED FROM FIELD SAMPLES. IMMUNOHISTOCHEMICAL AND IMMUNOBLOTTING ANALYSIS SHOWED STRAIN SPECIFIC HYPERACETYLATION AT HISTONE H3K9 AND H3K14 RESIDUES. GLOBAL GENE EXPRESSION ANALYSIS IN S. AUREUS INFECTED MICE MAMMARY TISSUE REVEALED A SELECTIVE SET OF UPREGULATED GENES THAT SIGNIFICANTLY CORRELATED WITH THE PROMOTER SPECIFIC, HISTONE H3K14 ACETYLATION. FURTHERMORE, WE HAVE IDENTIFIED SEVERAL DIFFERENTIALLY EXPRESSED KNOWN MIRNAS AND 3 NOVEL MIRNAS IN S. AUREUS INFECTED MICE MAMMARY TISSUE BY SMALL RNA SEQUENCING. BY EMPLOYING THESE GENE EXPRESSION DATA, AN ATTEMPT HAS BEEN MADE TO DELINEATE THE GENE REGULATORY NETWORKS IN THE STRAIN SPECIFIC INFLAMMATORY RESPONSE. APPARENTLY, ONE OF THE ISOLATES OF S. AUREUS ACTIVATED THE NF-KAPPAB SIGNALING LEADING TO DRASTIC INFLAMMATORY RESPONSE AND INDUCTION OF IMMUNE SURVEILLANCE, WHICH COULD POSSIBLY LEAD TO RAPID CLEARANCE OF THE PATHOGEN. THE OTHER STRAIN REPRESSED MOST OF THE INFLAMMATORY RESPONSE, WHICH MIGHT HELP IN ITS SUSTENANCE IN THE HOST TISSUE. CONCLUSION: TAKEN TOGETHER, OUR STUDIES SHED SUBSTANTIAL LIGHTS TO UNDERSTAND THE MECHANISMS OF STRAIN SPECIFIC DIFFERENTIAL INFLAMMATORY RESPONSE TO S. AUREUS INFECTION DURING MASTITIS. IN A BROADER PERSPECTIVE THIS STUDY ALSO PAVES THE WAY TO UNDERSTAND HOW CERTAIN BACTERIA CAN EVADE THE IMMUNE SURVEILLANCE AND CAUSE SUSTAINED INFECTION WHILE OTHERS ARE RAPIDLY CLEARED FROM THE HOST BODY. 2014 12 1033 23 CITRULLINATION OF AUTOANTIGENS IMPLICATES NETOSIS IN THE INDUCTION OF AUTOIMMUNITY. TOLERANCE BLOCKS THE EXPRESSION OF AUTOANTIBODIES, WHEREAS AUTOIMMUNITY PROMOTES IT. HOW TOLERANCE BREAKS AND AUTOANTIBODY PRODUCTION BEGINS THUS ARE CRUCIAL QUESTIONS FOR UNDERSTANDING AND TREATMENT OF AUTOIMMUNE DISEASES. EVIDENCE IMPLICATES CELL DEATH AND AUTOANTIGEN MODIFICATIONS IN THE INITIATION OF AUTOIMMUNE REACTIONS. ONE FORM OF NEUTROPHIL CELL DEATH CALLED NETOSIS DESERVES ATTENTION BECAUSE IT REQUIRES THE POST-TRANSLATIONAL MODIFICATION OF HISTONES AND RESULTS IN THE EXTRACELLULAR RELEASE OF CHROMATIN. NETOSIS RECEIVED ITS NAME FROM NET, THE ACRONYM GIVEN TO NEUTROPHIL EXTRACELLULAR TRAP. THE EXTRACELLULAR CHROMATIN INCORPORATES HISTONES IN WHICH ARGININES HAVE BEEN CONVERTED TO CITRULLINES BY PEPTIDYLARGININE DEIMINASE IV (PAD4). THE DEIMINATED CHROMATIN MAY FUNCTION TO CAPTURE OR 'TRAP' BACTERIAL PATHOGENS, THUS GENERATING AN EXTRACELLULAR COMPLEX OF DEIMINATED HISTONES AND BACTERIAL CELL ADJUVANTS. THE COMPLEX OF BACTERIAL ANTIGENS AND DEIMINATED CHROMATIN MAY BE INTERNALISED BY HOST PHAGOCYTES DURING ACUTE INFLAMMATORY CONDITIONS, AS ARISE DURING BACTERIAL INFECTIONS OR CHRONIC AUTOINFLAMMATORY DISORDERS. THE UPTAKE AND PROCESSING OF DEIMINATED CHROMATIN TOGETHER WITH BACTERIAL ADJUVANTS BY PHAGOCYTES MAY INDUCE THE PRESENTATION OF MODIFIED HISTONE EPITOPES AND CO-STIMULATION, THUS YIELDING A POWERFUL STIMULUS TO BREAK TOLERANCE. AUTOANTIBODIES TO DEIMINATED HISTONES ARE PREVALENT IN FELTY'S SYNDROME PATIENTS AND ARE PRESENT IN SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) AND PATIENTS WITH RHEUMATOID ARTHRITIS (RA). THESE OBSERVATIONS CLEARLY IMPLICATE HISTONE DEIMINATION AS AN EPIGENETIC MARK THAT CAN ACT AS AN AUTOANTIBODY STIMULANT. 2014 13 4412 21 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 14 1323 22 DENDRITIC CELLS IN SYSTEMIC LUPUS ERYTHEMATOSUS: FROM PATHOGENESIS TO THERAPEUTIC APPLICATIONS. SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) IS A SEVERE CHRONIC SYSTEMIC AUTOIMMUNE DISEASE CAUSED BY COMPLICATED INTERACTIONS AMONG GENETIC, EPIGENETIC, AND IMMUNOLOGICAL FACTORS. DENDRITIC CELLS (DCS), AS THE MOST IMPORTANT ANTIGEN-PRESENTING CELLS, PLAY PIVOTAL ROLES IN BOTH TRIGGERING PATHOGENIC AUTOIMMUNE RESPONSES, AND ALSO MAINTAINING IMMUNE TOLERANCE. DISTINCT DC SUBSETS ARE ENDOWED WITH DIVERSIFIED PHENOTYPIC AND FUNCTIONAL CHARACTERISTICS, AND PLAY VARIABLE ROLES IN SHAPING IMMUNITY AND TOLERANCE DURING THE DEVELOPMENT OF SLE. ABNORMAL ACTIVATION OR DISABLED TOLERANCE OF DCS NOT ONLY TRIGGERS ABERRANT PRODUCTION OF INFLAMMATORY MEDIATORS AND TYPE I INTERFERONS LEADING TO PATHOGENIC INNATE IMMUNITY AND AUTOINFLAMMATION, BUT ALSO CAUSES AN IMBALANCE OF EFFECTOR VERSUS REGULATORY T CELL RESPONSES AND SUSTAINED PRODUCTION OF AUTO-ANTIBODIES FROM B CELLS, LEADING TO CONTINUOUSLY AMPLIFIED AUTOIMMUNE PATHOGENESIS IN SLE. OVER THE PAST DECADE, SIGNIFICANT PROGRESS HAS BEEN MADE IN REVEALING THE CHANGES OF DC ACCUMULATION OR FUNCTION IN SLE, AND HOW THE FUNCTIONAL DYSREGULATIONS OF DCS CONTRIBUTE TO THE PATHOLOGICAL INFLAMMATION OF SLE, LEADING TO BREAKTHROUGHS IN DC-BASED THERAPEUTICS IN THE TREATMENT OF SLE. IN THIS REVIEW, WE REVIEW THE RECENT ADVANCES IN THE ACTIVATION AND FUNCTION OF THE MAJOR DC SUBSETS IN THE PATHOGENESIS OF SLE AS WELL AS THE THERAPEUTIC POTENTIAL OF TARGETING DC SUBSET OR STATUS AGAINST SLE. 2022 15 6500 20 TRAINED IMMUNITY IN TYPE 2 IMMUNE RESPONSES. IMMUNOLOGICAL MEMORY OF INNATE IMMUNE CELLS, ALSO TERMED "TRAINED IMMUNITY", ALLOWS FOR CROSS-PROTECTION AGAINST DISTINCT PATHOGENS, BUT MAY ALSO DRIVE CHRONIC INFLAMMATION. RECENT STUDIES HAVE SHOWN THAT MEMORY RESPONSES ASSOCIATED WITH TYPE 2 IMMUNITY DO NOT SOLELY RELY ON ADAPTIVE IMMUNE CELLS, SUCH AS T- AND B CELLS, BUT ALSO INVOLVE THE INNATE IMMUNE SYSTEM AND EPITHELIAL CELLS. MEMORY RESPONSES HAVE BEEN DESCRIBED FOR MONOCYTES, MACROPHAGES AND AIRWAY EPITHELIAL CELLS OF ASTHMATIC PATIENTS AS WELL AS FOR MACROPHAGES AND GROUP 2 INNATE LYMPHOID CELLS (ILC2) FROM ALLERGEN-SENSITIZED OR HELMINTH-INFECTED MICE. THE METABOLIC AND EPIGENETIC MECHANISMS THAT MEDIATE ALLERGEN- OR HELMINTH-INDUCED REPROGRAMMING OF INNATE IMMUNE CELLS ARE ONLY BEGINNING TO BE UNCOVERED. TRAINED IMMUNITY HAS BEEN IMPLICATED IN HELMINTH-DRIVEN IMMUNE REGULATION AND ALLERGEN-SPECIFIC IMMUNOTHERAPY, SUGGESTING ITS EXPLOITATION IN FUTURE THERAPIES. HERE, WE DISCUSS RECENT ADVANCES AND KEY REMAINING QUESTIONS REGARDING THE MECHANISMS AND FUNCTIONS OF TRAINED TYPE 2 IMMUNITY IN INFECTION AND INFLAMMATION. 2022 16 6495 16 TRAINED IMMUNITY AS A POTENTIAL TARGET FOR THERAPEUTIC IMMUNOMODULATION IN DUCHENNE MUSCULAR DYSTROPHY. DYSREGULATED INFLAMMATION INVOLVING INNATE IMMUNE CELLS, PARTICULARLY OF THE MONOCYTE/MACROPHAGE LINEAGE, IS A KEY CONTRIBUTOR TO THE PATHOGENESIS OF DUCHENNE MUSCULAR DYSTROPHY (DMD). TRAINED IMMUNITY IS AN EVOLUTIONARILY ANCIENT PROTECTIVE MECHANISM AGAINST INFECTION, IN WHICH EPIGENETIC AND METABOLIC ALTERATIONS CONFER NON-SPECIFIC HYPERRESPONSIVENESS OF INNATE IMMUNE CELLS TO VARIOUS STIMULI. RECENT WORK IN AN ANIMAL MODEL OF DMD (MDX MICE) HAS SHOWN THAT MACROPHAGES EXHIBIT CARDINAL FEATURES OF TRAINED IMMUNITY, INCLUDING THE PRESENCE OF INNATE IMMUNE SYSTEM "MEMORY". THE LATTER IS REFLECTED BY EPIGENETIC CHANGES AND DURABLE TRANSMISSIBILITY OF THE TRAINED PHENOTYPE TO HEALTHY NON-DYSTROPHIC MICE BY BONE MARROW TRANSPLANTATION. MECHANISTICALLY, IT IS SUGGESTED THAT A TOLL-LIKE RECEPTOR (TLR) 4-REGULATED, MEMORY-LIKE CAPACITY OF INNATE IMMUNITY IS INDUCED AT THE LEVEL OF THE BONE MARROW BY FACTORS RELEASED FROM THE DAMAGED MUSCLES, LEADING TO EXAGGERATED UPREGULATION OF BOTH PRO- AND ANTI-INFLAMMATORY GENES. HERE WE PROPOSE A CONCEPTUAL FRAMEWORK FOR THE INVOLVEMENT OF TRAINED IMMUNITY IN DMD PATHOGENESIS AND ITS POTENTIAL TO SERVE AS A NEW THERAPEUTIC TARGET. 2023 17 855 24 CHROMATIN ACCESSIBILITY LANDSCAPES OF IMMUNE CELLS IN RHEUMATOID ARTHRITIS NOMINATE MONOCYTES IN DISEASE PATHOGENESIS. BACKGROUND: RHEUMATOID ARTHRITIS (RA) IS A CHRONIC, SYSTEMIC AUTOIMMUNE DISEASE THAT INVOLVES A VARIETY OF CELL TYPES. HOWEVER, HOW THE EPIGENETIC DYSREGULATIONS OF PERIPHERAL IMMUNE CELLS CONTRIBUTE TO THE PATHOGENESIS OF RA STILL REMAINS LARGELY UNCLEAR. RESULTS: HERE, WE ANALYSED THE GENOME-WIDE ACTIVE DNA REGULATORY ELEMENTS OF FOUR MAJOR IMMUNE CELLS, NAMELY MONOCYTES, B CELLS, CD4(+) T CELLS AND CD8(+) T CELLS, IN PERIPHERAL BLOOD OF RA PATIENTS, OSTEOARTHRITIS (OA) PATIENTS AND HEALTHY DONORS USING ASSAY OF TRANSPOSASE ACCESSIBLE CHROMATIN WITH SEQUENCING (ATAC-SEQ). WE FOUND A STRONG RA-ASSOCIATED CHROMATIN DYSREGULATION SIGNATURE IN MONOCYTES, BUT NO OTHER EXAMINED CELL TYPES. MOREOVER, WE FOUND THAT SERUM C-REACTIVE PROTEIN (CRP) CAN INDUCE THE RA-ASSOCIATED CHROMATIN DYSREGULATION IN MONOCYTES VIA IN VITRO EXPERIMENTS. AND THE EXTENT OF THIS DYSREGULATION WAS REGULATED THROUGH THE TRANSCRIPTION FACTOR FRA2. CONCLUSIONS: TOGETHER, OUR STUDY REVEALED A CRP-INDUCED PATHOGENIC CHROMATIN DYSREGULATION SIGNATURE IN MONOCYTES FROM RA PATIENTS AND PREDICTED THE RESPONSIBLE SIGNALLING PATHWAY AS POTENTIAL THERAPEUTIC TARGETS FOR THE DISEASE. 2021 18 4298 25 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 19 6452 15 THERAPIES TARGETING TRAINED IMMUNE CELLS IN INFLAMMATORY AND AUTOIMMUNE DISEASES. THE CONCEPT OF TRAINED IMMUNITY HAS RECENTLY EMERGED AS A MECHANISM CONTRIBUTING TO SEVERAL IMMUNE MEDIATED INFLAMMATORY CONDITIONS. TRAINED IMMUNITY IS DEFINED BY THE IMMUNOLOGICAL MEMORY DEVELOPED IN INNATE IMMUNE CELLS AFTER A PRIMARY NON-SPECIFIC STIMULUS THAT, IN TURN, PROMOTES A HEIGHTENED INFLAMMATORY RESPONSE UPON A SECONDARY CHALLENGE. THE MOST CHARACTERISTIC CHANGES ASSOCIATED TO THIS PROCESS INVOLVE THE REWIRING OF CELL METABOLISM AND EPIGENETIC REPROGRAMMING. UNDER PHYSIOLOGICAL CONDITIONS, THE ROLE OF TRAINED IMMUNE CELLS ENSURES A PROMPT RESPONSE. THIS ACTION IS LIMITED BY EFFECTIVE RESOLUTION OF INFLAMMATION AND TISSUE REPAIR IN ORDER TO RESTORE HOMEOSTASIS. HOWEVER, UNRESTRAINED ACTIVATION OF INNATE IMMUNE CELLS CONTRIBUTES TO THE DEVELOPMENT OF CHRONIC INFLAMMATION AND TISSUE DESTRUCTION THROUGH THE SECRETION OF INFLAMMATORY CYTOKINES, PROTEASES AND GROWTH FACTORS. THEREFORE, INTERVENTIONS AIMED AT REVERSING THE CHANGES INDUCED BY TRAINED IMMUNITY PROVIDE POTENTIAL THERAPEUTIC APPROACHES TO TREAT INFLAMMATORY AND AUTOIMMUNE DISEASES LIKE RHEUMATOID ARTHRITIS (RA). WE REVIEW CELLULAR APPROACHES THAT TARGET METABOLISM AND THE EPIGENETIC REPROGRAMMING OF DENDRITIC CELLS, MACROPHAGES, NATURAL KILLER CELLS, AND OTHER TRAINED CELLS IN THE CONTEXT OF AUTOIMMUNE INFLAMMATORY DISEASES. 2020 20 5049 26 PHARMACOLOGICAL INHIBITION OF RORC2 ENHANCES HUMAN TH17-TREG STABILITY AND FUNCTION. INFLAMMATORY BOWEL DISEASES (IBD) ARE CHRONIC CONDITIONS THAT RESULT FROM UNCONTROLLED INTESTINAL INFLAMMATION. PATHOGENIC TH17 CELLS, CHARACTERIZED BY PRODUCTION OF IL-17A IN THE ABSENCE OF IL-10, ARE THOUGHT TO CONTRIBUTE TO THIS INFLAMMATION, BUT IN HUMANS, ANTIBODY-MEDIATED BLOCKADE OF IL-17A IS AN INEFFECTIVE IBD THERAPY WHEREAS IL-23 BLOCKADE IS EFFECTIVE. HERE, WE INVESTIGATED THE EFFECTS OF PHARMACOLOGICAL INHIBITION OF RORC2, THE TH17 CELL LINEAGE-DEFINING TRANSCRIPTION FACTOR, ON IN VIVO-DIFFERENTIATED HUMAN TH17 CELLS AND TH17-LIKE TREGS (TH17-TREGS). BMS-336, A SMALL MOLECULE RORC2 INVERSE AGONIST, INHIBITED EXPRESSION OF RORC2-REGULATED GENES IN PERIPHERAL TH17 CELLS (CD4(+) CD25(-) CD127(+) CXCR3(-) CCR4(+) CCR6(+) ) IN A DOSE-DEPENDENT MANNER, WITH SIMILAR INHIBITORY EFFECTS ON LAMINAR PROPRIA MONONUCLEAR CELLS FROM IBD AND NON-IBD SUBJECTS. EXPOSURE OF PERIPHERAL TH17-TREGS (CD4(+) CD25(HI) CD127(LO) CXCR3(-) CCR4(+) CCR6(+) ) TO BMS-336 ALSO INHIBITED IL-17A PRODUCTION AND PREVENTED INFLAMMATORY CYTOKINE-INDUCED DESTABILIZATION, AS EVIDENCED BY PRESERVED FOXP3 EXPRESSION AND EPIGENETIC STATUS OF THE TREG-SPECIFIC DEMETHYLATION REGION. IN PARALLEL, RORC2 INHIBITION INCREASED THE PRODUCTION OF IL-10 IN TH17-TREGS, RESULTING IN ENHANCED SUPPRESSION OF INFLAMMATORY CYTOKINES FROM MYELOID CELLS. THUS, VIA ITS ABILITY TO SIMULTANEOUSLY INHIBIT TH17 CELLS AND ENHANCE THE STABILITY AND FUNCTION OF TH17-TREGS, PHARMACOLOGICAL INHIBITION OF RORC2 IS A PROMISING APPROACH TO SUPPRESS INFLAMMATION AND PROMOTE IMMUNE REGULATION IN IBD. 2020