1 6493 161 TRAINED IMMUNITY AND REACTIVITY OF MACROPHAGES AND ENDOTHELIAL CELLS. INNATE IMMUNE CELLS CAN DEVELOP EXACERBATED IMMUNOLOGIC RESPONSE AND LONG-TERM INFLAMMATORY PHENOTYPE FOLLOWING BRIEF EXPOSURE TO ENDOGENOUS OR EXOGENOUS INSULTS, WHICH LEADS TO AN ALTERED RESPONSE TOWARDS A SECOND CHALLENGE AFTER THE RETURN TO A NONACTIVATED STATE. THIS PHENOMENON IS KNOWN AS TRAINED IMMUNITY (TI). TI IS NOT ONLY IMPORTANT FOR HOST DEFENSE AND VACCINE RESPONSE BUT ALSO FOR CHRONIC INFLAMMATIONS SUCH AS CARDIOVASCULAR AND METABOLIC DISEASES SUCH AS ATHEROSCLEROSIS. TI CAN OCCUR IN INNATE IMMUNE CELLS SUCH AS MONOCYTES/MACROPHAGES, NATURAL KILLER CELLS, ENDOTHELIAL CELLS (ECS), AND NONIMMUNE CELLS, SUCH AS FIBROBLAST. IN THIS BRIEF REVIEW, WE ANALYZE THE SIGNIFICANCE OF TI IN ECS, WHICH ARE ALSO CONSIDERED AS INNATE IMMUNE CELLS IN ADDITION TO MACROPHAGES. TI CAN BE INDUCED BY A VARIETY OF STIMULI, INCLUDING LIPOPOLYSACCHARIDES, BCG (BACILLUS CALMETTE-GUERIN), AND OXLDL (OXIDIZED LOW-DENSITY LIPOPROTEIN), WHICH ARE DEFINED AS RISK FACTORS FOR CARDIOVASCULAR AND METABOLIC DISEASES. FURTHERMORE, TI IN ECS IS FUNCTIONAL FOR INFLAMMATION EFFECTIVENESS AND TRANSITION TO CHRONIC INFLAMMATION. REWIRING OF CELLULAR METABOLISM OF THE TRAINED CELLS TAKES PLACE DURING INDUCTION OF TI, INCLUDING INCREASED GLYCOLYSIS, GLUTAMINOLYSIS, INCREASED ACCUMULATION OF TRICARBOXYLIC ACID CYCLE METABOLITES AND ACETYL-COENZYME A PRODUCTION, AS WELL AS INCREASED MEVALONATE SYNTHESIS. SUBSEQUENTLY, THIS LEADS TO EPIGENETIC REMODELING, RESULTING IN IMPORTANT CHANGES IN CHROMATIN ARCHITECTURE THAT ENABLES INCREASED GENE TRANSCRIPTION AND ENHANCED PROINFLAMMATORY IMMUNE RESPONSE. HOWEVER, TI PATHWAYS AND INFLAMMATORY PATHWAYS ARE SEPARATED TO ENSURE MEMORY STAYS WHEN INFLAMMATION UNDERGOES RESOLUTION. ADDITIONALLY, REACTIVE OXYGEN SPECIES PLAY CONTEXT-DEPENDENT ROLES IN TI. THEREFORE, TI PLAYS SIGNIFICANT ROLES IN EC AND MACROPHAGE PATHOLOGY AND CHRONIC INFLAMMATION. HOWEVER, FURTHER CHARACTERIZATION OF TI IN ECS AND MACROPHAGES WOULD PROVIDE NOVEL INSIGHTS INTO CARDIOVASCULAR DISEASE PATHOGENESIS AND NEW THERAPEUTIC TARGETS. GRAPHIC ABSTRACT: A GRAPHIC ABSTRACT IS AVAILABLE FOR THIS ARTICLE. 2021 2 3544 54 IMMUNOMETABOLIC CONTROL OF TRAINED IMMUNITY. INNATE IMMUNE CELLS CAN ADOPT LONG-TERM INFLAMMATORY PHENOTYPES FOLLOWING BRIEF ENCOUNTERS WITH EXOGENOUS (MICROBIAL) OR ENDOGENOUS STIMULI. THIS PHENOMENON IS NAMED TRAINED IMMUNITY AND CAN IMPROVE HOST DEFENSE AGAINST (RECURRENT) INFECTIONS. IN CONTRAST, TRAINED IMMUNITY CAN ALSO BE MALADAPTIVE IN THE CONTEXT OF CHRONIC INFLAMMATORY DISORDERS, SUCH AS ATHEROSCLEROSIS. KEY TO FUTURE THERAPEUTIC EXPLOITATION OF THIS MECHANISM IS THOROUGH KNOWLEDGE OF THE MECHANISMS DRIVING TRAINED IMMUNITY, WHICH CAN BE USED AS PHARMACOLOGICAL TARGETS. THESE MECHANISMS INCLUDE PROFOUND CHANGES IN INTRACELLULAR METABOLISM, WHICH ARE CLOSELY INTERTWINED WITH EPIGENETIC REPROGRAMMING AT THE LEVEL OF HISTONE MODIFICATIONS. GLYCOLYSIS, GLUTAMINE REPLENISHMENT OF THE TRICARBOXYLIC ACID CYCLE WITH ACCUMULATION OF FUMARATE, AND THE MEVALONATE PATHWAY HAVE ALL BEEN IDENTIFIED AS CRITICAL PATHWAYS FOR TRAINED IMMUNITY IN MONOCYTES AND MACROPHAGES. IN THIS REVIEW, WE PROVIDE A STATE-OF-THE-ART OVERVIEW OF HOW THESE METABOLIC PATHWAYS INTERACT WITH EPIGENETIC PROGRAMS TO DEVELOP TRAINED IMMUNITY. 2021 3 6505 42 TRAINED INNATE IMMUNITY AS A NOVEL MECHANISM LINKING INFECTION AND THE DEVELOPMENT OF ATHEROSCLEROSIS. RATIONALE: THERE IS STRONG EPIDEMIOLOGICAL EVIDENCE FOR AN ASSOCIATION BETWEEN ACUTE AND CHRONIC INFECTIONS AND THE OCCURRENCE OF ATHEROSCLEROTIC CARDIOVASCULAR DISEASE. THE UNDERLYING PATHOPHYSIOLOGICAL MECHANISMS REMAIN UNCLEAR. MONOCYTE-DERIVED MACROPHAGES ARE THE MOST ABUNDANT IMMUNE CELLS IN ATHEROSCLEROTIC PLAQUES. IT HAS RECENTLY BEEN ESTABLISHED THAT MONOCYTES/MACROPHAGES CAN DEVELOP A LONG-LASTING PROINFLAMMATORY PHENOTYPE AFTER BRIEF STIMULATION WITH MICRO-ORGANISMS OR MICROBIAL PRODUCTS, WHICH HAS BEEN TERMED TRAINED IMMUNITY. OBJECTIVE: THE AIM OF THIS STUDY IS TO ASSESS WHETHER TRAINED IMMUNITY MEDIATES THE LINK BETWEEN INFECTIONS AND ATHEROSCLEROTIC CARDIOVASCULAR DISEASE. METHODS AND RESULTS: BRIEF EXPOSURE OF MONOCYTES TO VARIOUS MICRO-ORGANISMS RESULTS IN THE DEVELOPMENT OF MACROPHAGES WITH A PERSISTENT PROINFLAMMATORY PHENOTYPE: THIS REPRESENTS A DE FACTO NONSPECIFIC INNATE IMMUNE MEMORY, WHICH HAS BEEN TERMED TRAINED IMMUNITY. THIS IS MEDIATED BY EPIGENETIC REPROGRAMMING AT THE LEVEL OF HISTONE METHYLATION AND A PROFOUND REWIRING OF INTRACELLULAR METABOLISM. ALTHOUGH THIS MECHANISM OFFERS POWERFUL PROTECTION AGAINST REINFECTION, TRAINED MACROPHAGES DISPLAY AN ATHEROGENIC PHENOTYPE IN TERMS OF CYTOKINE PRODUCTION AND FOAM CELL FORMATION. TRAINED MONOCYTES ARE PRESENT UP TO 3 MONTHS AFTER EXPERIMENTAL INFECTION IN HUMANS. MOREOVER, A TRAINED IMMUNITY PHENOTYPE IS PRESENT IN PATIENTS WITH ESTABLISHED ATHEROSCLEROSIS. CONCLUSIONS: WE PROPOSE THAT TRAINED IMMUNITY PROVIDES THE MISSING MECHANISTIC LINK THAT EXPLAINS THE ASSOCIATION BETWEEN INFECTIONS AND ATHEROSCLEROSIS. THEREFORE, PHARMACOLOGICAL MODULATION OF TRAINED IMMUNITY HAS THE POTENTIAL TO PREVENT INFECTION-RELATED ATHEROSCLEROTIC CARDIOVASCULAR DISEASE IN THE FUTURE. 2018 4 3734 57 INNATE IMMUNE MEMORY IN MONOCYTES AND MACROPHAGES: THE POTENTIAL THERAPEUTIC STRATEGIES FOR ATHEROSCLEROSIS. ATHEROSCLEROSIS IS A COMPLEX METABOLIC DISEASE CHARACTERIZED BY THE DYSFUNCTION OF LIPID METABOLISM AND CHRONIC INFLAMMATION IN THE INTIMAL SPACE OF THE VESSEL. AS THE MOST ABUNDANT INNATE IMMUNE CELLS, MONOCYTE-DERIVED MACROPHAGES PLAY A PIVOTAL ROLE IN THE INFLAMMATORY RESPONSE, CHOLESTEROL METABOLISM, AND FOAM CELL FORMATION. IN RECENT DECADES, IT HAS BEEN DEMONSTRATED THAT MONOCYTES AND MACROPHAGES CAN ESTABLISH INNATE IMMUNE MEMORY (ALSO TERMED TRAINED IMMUNITY) VIA ENDOGENOUS AND EXOGENOUS ATHEROGENIC STIMULI AND EXHIBIT A LONG-LASTING PROINFLAMMATORY PHENOTYPE. THE IMPORTANT CELLULAR METABOLISM PROCESSES, INCLUDING GLYCOLYSIS, OXIDATIVE PHOSPHORYLATION (OXPHOS), THE TRICARBOXYLIC ACID (TCA) CYCLE, FATTY ACID SYNTHESIS, AND CHOLESTEROL SYNTHESIS, ARE REPROGRAMMED. TRAINED MONOCYTES/MACROPHAGES WITH INNATE IMMUNE MEMORY CAN BE PERSISTENTLY HYPERACTIVATED AND CAN UNDERGO EXTENSIVE EPIGENETIC REWIRING, WHICH CONTRIBUTES TO THE PATHOPHYSIOLOGICAL DEVELOPMENT OF ATHEROSCLEROSIS VIA INCREASED PROINFLAMMATORY CYTOKINE PRODUCTION AND LIPID ACCUMULATION. HERE, WE PROVIDE AN OVERVIEW OF THE REGULATION OF CELLULAR METABOLIC PROCESSES AND EPIGENETIC MODIFICATIONS OF INNATE IMMUNE MEMORY IN MONOCYTES/MACROPHAGES AS WELL AS THE POTENTIAL ENDOGENOUS AND EXOGENOUS STIMULATIONS INVOLVED IN THE PROGRESSION OF ATHEROSCLEROSIS THAT HAVE BEEN REPORTED RECENTLY. THESE ELUCIDATIONS MIGHT BE BENEFICIAL FOR FURTHER UNDERSTANDING INNATE IMMUNE MEMORY AND THE DEVELOPMENT OF THERAPEUTIC STRATEGIES FOR INFLAMMATORY DISEASES AND ATHEROSCLEROSIS. 2022 5 4570 42 MYELOMONOCYTIC CELLS IN GIANT CELL ARTERITIS ACTIVATE TRAINED IMMUNITY PROGRAMS SUSTAINING INFLAMMATION AND CYTOKINE PRODUCTION. OBJECTIVE: TRAINED IMMUNITY (TI) IS A DE FACTO MEMORY PROGRAM OF INNATE IMMUNE CELLS, CHARACTERIZED BY IMMUNOMETABOLIC AND EPIGENETIC CHANGES SUSTAINING ENHANCED PRODUCTION OF CYTOKINES. TI EVOLVED AS A PROTECTIVE MECHANISM AGAINST INFECTIONS; HOWEVER, INAPPROPRIATE ACTIVATION CAN CAUSE DETRIMENTAL INFLAMMATION AND MIGHT BE IMPLICATED IN THE PATHOGENESIS OF CHRONIC INFLAMMATORY DISEASES. IN THIS STUDY, WE INVESTIGATED THE ROLE OF TI IN THE PATHOGENESIS OF GIANT CELL ARTERITIS (GCA), A LARGE-VESSEL VASCULITIS CHARACTERIZED BY ABERRANT MACROPHAGE ACTIVATION AND EXCESS CYTOKINE PRODUCTION. METHODS: MONOCYTES FROM GCA PATIENTS AND FROM AGE- AND SEX-MATCHED HEALTHY DONORS WERE SUBJECTED TO POLYFUNCTIONAL STUDIES, INCLUDING CYTOKINE PRODUCTION ASSAYS AT BASELINE AND FOLLOWING STIMULATION, INTRACELLULAR METABOLOMICS, CHROMATIN IMMUNOPRECIPITATION-QPCR, AND COMBINED ATAC/RNA SEQUENCING. IMMUNOMETABOLIC ACTIVATION (I.E. GLYCOLYSIS) WAS ASSESSED IN INFLAMED VESSELS OF GCA PATIENTS WITH FDG-PET AND IMMUNOHISTOCHEMISTRY (IHC), AND THE ROLE OF THIS PATHWAY IN SUSTAINING CYTOKINE PRODUCTION WAS CONFIRMED WITH SELECTIVE PHARMACOLOGIC INHIBITION IN GCA MONOCYTES. RESULTS: GCA MONOCYTES EXHIBITED HALLMARK MOLECULAR FEATURES OF TI. SPECIFICALLY, THESE INCLUDED ENHANCED IL-6 PRODUCTION UPON STIMULATION, TYPICAL IMMUNOMETABOLIC CHANGES (E.G. INCREASED GLYCOLYSIS AND GLUTAMINOLYSIS) AND EPIGENETIC CHANGES PROMOTING ENHANCED TRANSCRIPTION OF GENES GOVERNING PRO-INFLAMMATORY ACTIVATION. IMMUNOMETABOLIC CHANGES OF TI (I.E. GLYCOLYSIS) WERE A FEATURE OF MYELOMONOCYTIC CELLS IN GCA LESIONS AND WERE REQUIRED FOR ENHANCED CYTOKINE PRODUCTION. CONCLUSIONS: MYELOMONOCYTIC CELLS IN GCA ACTIVATE TI PROGRAMS SUSTAINING ENHANCED INFLAMMATORY ACTIVATION WITH EXCESS CYTOKINE PRODUCTION. 2023 6 4489 43 MONOCYTE AND MACROPHAGE IMMUNOMETABOLISM IN ATHEROSCLEROSIS. ATHEROSCLEROSIS IS CHARACTERIZED BY CHRONIC LOW GRADE INFLAMMATION OF ARTERIES THAT RESULTS IN THE DEVELOPMENT OF LIPID DENSE PLAQUES. CHRONIC INFLAMMATION INDUCED BY WESTERN-TYPE DIET IS ASSOCIATED WITH THE RISK OF DEVELOPING ATHEROSCLEROSIS, AND NEW INSIGHTS SHED LIGHT ON THE IMPORTANCE OF METABOLIC AND FUNCTIONAL REPROGRAMMING IN MONOCYTES AND MACROPHAGES FOR PROGRESSION OF ATHEROSCLEROSIS. THIS REVIEW AIMS TO PROVIDE AN OVERVIEW OF OUR CURRENT UNDERSTANDING INTO HOW THE METABOLIC REPROGRAMMING OF GLUCOSE, CHOLESTEROL, FATTY ACID, AND AMINO ACID METABOLISM IN MACROPHAGES CONTRIBUTES TO INFLAMMATION DURING ATHEROSCLEROSIS. RECENT INSIGHTS SUGGEST THAT TRANSCRIPTIONAL AND EPIGENETIC ADAPTATION WITHIN INNATE IMMUNE CELLS (TERMED TRAINED IMMUNITY) PLAY AN IMPORTANT ROLE IN THE PATHOGENESIS OF ATHEROSCLEROSIS. WE PROPOSE THAT METABOLIC CHANGES INDUCED BY PRO-ATHEROGENIC LIPOPROTEINS PARTLY MEDIATE THESE CHANGES IN TRAINED MACROPHAGES. FINALLY, WE DISCUSS THE POSSIBILITY OF MANIPULATING CELLULAR METABOLISM OF IMMUNE CELLS FOR TARGETED THERAPEUTIC INTERVENTION AGAINST ATHEROSCLEROSIS. 2018 7 6452 44 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 8 5423 30 REGULATION OF MACROPHAGE ACTIVATION AND DIFFERENTIATION IN ATHEROSCLEROSIS. CHRONIC INFLAMMATION IS A HALLMARK OF ATHEROSCLEROSIS AND MACROPHAGES PLAY A CENTRAL ROLE IN CONTROLLING INFLAMMATION AT ALL STAGES OF ATHEROSCLEROSIS. IN ATHEROSCLEROSIS, MACROPHAGES AND MONOCYTE-DERIVED MACROPHAGES ARE CONTINUOUSLY EXPOSED TO CHOLESTEROL, OXIDIZED LIPIDS, CELL DEBRIS, CYTOKINES, AND CHEMOKINES. NOT ONLY DO THESE STIMULI INDUCE A SPECIFIC MACROPHAGE PHENOTYPE, BUT THEY ALSO INTERACT EXTENSIVELY, LEADING TO MACROPHAGE HETEROGENEITY IN ATHEROSCLEROTIC PLAQUES. HEREIN, WE REVIEW THE DIVERSE PHENOTYPES OF MACROPHAGES, THE MECHANISMS UNDERLYING MACROPHAGE ACTIVATION, AND THE CONTRIBUTIONS OF MACROPHAGES TO ATHEROSCLEROSIS IN THIS CONTEXT. WE ALSO SUMMARIZE RECENT STUDIES ON FOAMY MACROPHAGES AND MONOCYTE-DERIVED MACROPHAGES IN PLAQUE DURING DISEASE PROGRESSION. WE PROVIDE A COMPREHENSIVE OVERVIEW OF TRANSCRIPTIONAL, EPIGENETIC, AND METABOLIC REPROGRAMMING OF MACROPHAGES AND DISCUSS THE EMERGING CONCEPTS OF TARGETING CYTOKINES AND MACROPHAGES TO MODULATE ATHEROSCLEROSIS. 2021 9 3436 36 HYPERGLYCEMIC MEMORY OF INNATE IMMUNE CELLS PROMOTES IN VITRO PROINFLAMMATORY RESPONSES OF HUMAN MONOCYTES AND MURINE MACROPHAGES. IT HAS BEEN WELL ESTABLISHED THAT THE PRESENCE OF DIABETES IS ACCOMPANIED BY A CHRONIC INFLAMMATORY STATE PROMOTING VARIOUS DIABETES-ASSOCIATED COMPLICATIONS. ONE POTENTIAL DRIVER OF THIS ENHANCED INFLAMMATORY STATE IN PATIENTS WITH DIABETES IS HYPERGLYCEMIA. EVEN AFTER BLOOD GLUCOSE CONTROL IS ACHIEVED, DIABETES-ASSOCIATED COMPLICATIONS PERSIST, SUGGESTING THE PRESENCE OF A "HYPERGLYCEMIC MEMORY." INNATE IMMUNE CELLS, CRITICALLY INVOLVED IN VARIOUS COMPLICATIONS ASSOCIATED WITH DIABETES, CAN BUILD NONSPECIFIC, IMMUNOLOGICAL MEMORY (TRAINED IMMUNITY) VIA EPIGENETIC REGULATION. WE EXAMINE THE POTENTIAL INVOLVEMENT OF HYPERGLYCEMIA-INDUCED TRAINED IMMUNITY IN PROMOTING INFLAMMATION. OUR RESULTS SHOW THAT HYPERGLYCEMIA INDUCES A TRAINED PHENOTYPE IN VIVO IN MICE AND IN VITRO IN HUMAN MONOCYTES, REPRESENTATIVE BY AN INCREASED TNF-ALPHA SECRETION AFTER EX VIVO STIMULATION WITH LPS. THESE EFFECTS WERE LARGELY MEDIATED BY EPIGENETIC CHANGES CONTROLLED BY THE MIXED LINEAGE LEUKEMIA (MLL) FAMILY BECAUSE TREATMENT WITH THE MLL INHIBITOR MENIN-MLL DURING THE PROCESS OF TRAINED IMMUNITY ACQUISITION REPRESSED THE PROINFLAMMATORY PHENOTYPE. COLLECTIVELY, OUR RESULTS IDENTIFY A NOVEL LINK BETWEEN HYPERGLYCEMIA AND INFLAMMATION IN INNATE IMMUNE CELLS THAT MIGHT EXPLAIN THE INCREASED PROINFLAMMATORY STATE DURING DIABETES POTENTIALLY CONTRIBUTING TO THE DEVELOPMENT OF VARIOUS DIABETES-ASSOCIATED COMPLICATIONS. 2021 10 6502 52 TRAINED IMMUNITY: LONG-TERM ADAPTATION IN INNATE IMMUNE RESPONSES. ADAPTIVE IMMUNE RESPONSES ARE CHARACTERIZED BY ANTIGEN SPECIFICITY AND INDUCTION OF LIFELONG IMMUNOLOGIC MEMORY. RECENTLY, IT HAS BEEN REPORTED THAT INNATE IMMUNE CELLS CAN ALSO BUILD IMMUNE MEMORY CHARACTERISTICS-A PROCESS TERMED TRAINED IMMUNITY. TRAINED IMMUNITY DESCRIBES THE PERSISTENT HYPERRESPONSIVE PHENOTYPE THAT INNATE IMMUNE CELLS CAN DEVELOP AFTER BRIEF STIMULATION. PATHOGENIC STIMULI SUCH AS MICROORGANISMS, AND ALSO ENDOGENOUS MOLECULES INCLUDING URIC ACID, OXIDIZED LDL (LOW-DENSITY LIPOPROTEIN), AND CATECHOLAMINES, ARE CAPABLE OF INDUCING MEMORY IN MONOCYTES AND MACROPHAGES. WHILE TRAINED IMMUNITY PROVIDES FAVORABLE CROSS-PROTECTION IN THE CONTEXT OF INFECTIOUS DISEASES, THE HEIGHTENED IMMUNE RESPONSE CAN BE MALADAPTIVE IN DISEASES DRIVEN BY CHRONIC SYSTEMIC INFLAMMATION, SUCH AS ATHEROSCLEROSIS. TRAINED IMMUNITY IS MAINTAINED BY DISTINCT EPIGENETIC AND METABOLIC MECHANISMS AND PERSISTS FOR AT LEAST SEVERAL MONTHS IN VIVO DUE TO REPROGRAMMING OF MYELOID PROGENITOR CELLS. ADDITIONALLY, CERTAIN NONIMMUNE CELLS ARE ALSO FOUND TO EXHIBIT TRAINED IMMUNITY CHARACTERISTICS. THUS, TRAINED IMMUNITY PRESENTS AN EXCITING FRAMEWORK TO DEVELOP NEW APPROACHES TO VACCINATION AND ALSO NOVEL PHARMACOLOGICAL TARGETS IN THE TREATMENT OF INFLAMMATORY DISEASES. 2021 11 6498 47 TRAINED IMMUNITY IN MONOCYTE/MACROPHAGE: NOVEL MECHANISM OF PHYTOCHEMICALS IN THE TREATMENT OF ATHEROSCLEROTIC CARDIOVASCULAR DISEASE. ATHEROSCLEROSIS (AS) IS THE PATHOLOGY OF ATHEROSCLEROTIC CARDIOVASCULAR DISEASES (ASCVD), CHARACTERIZED BY PERSISTENT CHRONIC INFLAMMATION IN THE VESSEL WALL, IN WHICH MONOCYTES/MACROPHAGES PLAY A KEY ROLE. IT HAS BEEN REPORTED THAT INNATE IMMUNE SYSTEM CELLS CAN ASSUME A PERSISTENT PROINFLAMMATORY STATE AFTER SHORT STIMULATION WITH ENDOGENOUS ATHEROGENIC STIMULI. THE PATHOGENESIS OF AS CAN BE INFLUENCED BY THIS PERSISTENT HYPERACTIVATION OF THE INNATE IMMUNE SYSTEM, WHICH IS TERMED TRAINED IMMUNITY. TRAINED IMMUNITY HAS ALSO BEEN IMPLICATED AS A KEY PATHOLOGICAL MECHANISM, LEADING TO PERSISTENT CHRONIC INFLAMMATION IN AS. TRAINED IMMUNITY IS MEDIATED VIA EPIGENETIC AND METABOLIC REPROGRAMMING AND OCCURS IN MATURE INNATE IMMUNE CELLS AND THEIR BONE MARROW PROGENITORS. NATURAL PRODUCTS ARE PROMISING CANDIDATES FOR NOVEL PHARMACOLOGICAL AGENTS THAT CAN BE USED TO PREVENT OR TREAT CARDIOVASCULAR DISEASES (CVD). A VARIETY OF NATURAL PRODUCTS AND AGENTS EXHIBITING ANTIATHEROSCLEROTIC ABILITIES HAVE BEEN REPORTED TO POTENTIALLY INTERFERE WITH THE PHARMACOLOGICAL TARGETS OF TRAINED IMMUNITY. THIS REVIEW DESCRIBES IN AS MUCH DETAIL AS POSSIBLE THE MECHANISMS INVOLVED IN TRAINED IMMUNITY AND HOW PHYTOCHEMICALS OF THIS PROCESS INHIBIT AS BY AFFECTING TRAINED MONOCYTES/MACROPHAGES. 2023 12 6497 47 TRAINED IMMUNITY IN ATHEROSCLEROTIC CARDIOVASCULAR DISEASE. TRAINED IMMUNITY, ALSO KNOWN AS INNATE IMMUNE MEMORY, IS A PERSISTENT HYPER-RESPONSIVE FUNCTIONAL STATE OF INNATE IMMUNE CELLS. ACCUMULATING EVIDENCE IMPLICATES TRAINED IMMUNITY AS AN UNDERLYING MECHANISM OF CHRONIC INFLAMMATION IN ATHEROSCLEROTIC CARDIOVASCULAR DISEASE. IN THIS CONTEXT, TRAINED IMMUNITY IS INDUCED BY ENDOGENOUS ATHEROSCLEROSIS-PROMOTING FACTORS, SUCH AS MODIFIED LIPOPROTEINS OR HYPERGLYCAEMIA, CAUSING BROAD METABOLIC AND EPIGENETIC REPROGRAMMING OF THE MYELOID CELL COMPARTMENT. IN ADDITION TO TRADITIONAL CARDIOVASCULAR RISK FACTORS, LIFESTYLE FACTORS, INCLUDING UNHEALTHY DIETS, SEDENTARY LIFESTYLE, SLEEP DEPRIVATION AND PSYCHOSOCIAL STRESS, AS WELL AS INFLAMMATORY COMORBIDITIES, HAVE BEEN SHOWN TO ACTIVATE TRAINED IMMUNITY-LIKE MECHANISMS IN BONE MARROW HAEMATOPOIETIC STEM CELLS. IN THIS REVIEW, WE DISCUSS THE MOLECULAR AND CELLULAR MECHANISMS OF TRAINED IMMUNITY, ITS SYSTEMIC REGULATION THROUGH HAEMATOPOIETIC PROGENITOR CELLS IN THE BONE MARROW, AND THE ACTIVATION OF THESE MECHANISMS BY CARDIOVASCULAR DISEASE RISK FACTORS. WE ALSO HIGHLIGHT OTHER TRAINED IMMUNITY FEATURES THAT ARE RELEVANT FOR ATHEROSCLEROTIC CARDIOVASCULAR DISEASE, INCLUDING THE DIVERSE CELL TYPES THAT SHOW MEMORY CHARACTERISTICS AND TRANSGENERATIONAL INHERITANCE OF TRAINED IMMUNITY TRAITS. FINALLY, WE PROPOSE POTENTIAL STRATEGIES FOR THE THERAPEUTIC MODULATION OF TRAINED IMMUNITY TO MANAGE ATHEROSCLEROTIC CARDIOVASCULAR DISEASE. 2023 13 6496 59 TRAINED IMMUNITY CONTRIBUTION TO AUTOIMMUNE AND INFLAMMATORY DISORDERS. A DYSREGULATED IMMUNE RESPONSE TOWARD SELF-ANTIGENS CHARACTERIZES AUTOIMMUNE AND AUTOINFLAMMATORY (AIF) DISORDERS. AUTOANTIBODIES OR AUTOREACTIVE T CELLS CONTRIBUTE TO AUTOIMMUNE DISEASES, WHILE AUTOINFLAMMATION RESULTS FROM A HYPER-FUNCTIONAL INNATE IMMUNE SYSTEM. ASIDE FROM THEIR DIFFERENCES, MANY STUDIES SUGGEST THAT MONOCYTES AND MACROPHAGES (MO/MA) SIGNIFICANTLY CONTRIBUTE TO THE DEVELOPMENT OF BOTH TYPES OF DISEASE. MO/MA ARE INNATE IMMUNE CELLS THAT PROMOTE AN IMMUNE-MODULATORY, PRO-INFLAMMATORY, OR REPAIR RESPONSE DEPENDING ON THE MICROENVIRONMENT. HOWEVER, UNDERSTANDING THE CONTRIBUTION OF THESE CELLS TO DIFFERENT IMMUNE DISORDERS HAS BEEN DIFFICULT DUE TO THEIR HIGH FUNCTIONAL AND PHENOTYPIC PLASTICITY. SEVERAL FACTORS CAN INFLUENCE THE FUNCTION OF MO/MA UNDER THE LANDSCAPE OF AUTOIMMUNE/AUTOINFLAMMATORY DISEASES, SUCH AS GENETIC PREDISPOSITION, EPIGENETIC CHANGES, OR INFECTIONS. FOR INSTANCE, SOME VACCINES AND MICROORGANISMS CAN INDUCE EPIGENETIC CHANGES IN MO/MA, MODIFYING THEIR FUNCTIONAL RESPONSES. THIS PHENOMENON IS KNOWN AS TRAINED IMMUNITY. TRAINED IMMUNITY CAN BE MEDIATED BY MO/MA AND NK CELLS INDEPENDENTLY OF T AND B CELL FUNCTION. IT IS DEFINED AS THE ALTERED INNATE IMMUNE RESPONSE TO THE SAME OR DIFFERENT MICROORGANISMS DURING A SECOND ENCOUNTER. THE IMPROVEMENT IN CELL FUNCTION IS RELATED TO EPIGENETIC AND METABOLIC CHANGES THAT MODIFY GENE EXPRESSION. ALTHOUGH THE BENEFITS OF IMMUNE TRAINING HAVE BEEN HIGHLIGHTED IN A VACCINATION CONTEXT, THE EFFECTS OF THIS TYPE OF IMMUNE RESPONSE ON AUTOIMMUNITY AND CHRONIC INFLAMMATION STILL REMAIN CONTROVERSIAL. INDUCTION OF TRAINED IMMUNITY REPROGRAMS CELLULAR METABOLISM IN HEMATOPOIETIC STEM CELLS (HSCS), TRANSMITTING A MEMORY-LIKE PHENOTYPE TO THE CELLS. THUS, TRAINED MO/MA DERIVED FROM HSCS TYPICALLY PRESENT A METABOLIC SHIFT TOWARD GLYCOLYSIS, WHICH LEADS TO THE MODIFICATION OF THE CHROMATIN ARCHITECTURE. DURING TRAINED IMMUNITY, THE EPIGENETIC CHANGES FACILITATE THE SPECIFIC GENE EXPRESSION AFTER SECONDARY CHALLENGE WITH OTHER STIMULI. CONSEQUENTLY, THE ENHANCED PRO-INFLAMMATORY RESPONSE COULD CONTRIBUTE TO DEVELOPING OR MAINTAINING AUTOIMMUNE/AUTOINFLAMMATORY DISEASES. HOWEVER, THE PREDICTION OF THE OUTCOME IS NOT SIMPLE, AND OTHER STUDIES PROPOSE THAT TRAINED IMMUNITY CAN INDUCE A BENEFICIAL RESPONSE BOTH IN AIF AND AUTOIMMUNE CONDITIONS BY INDUCING ANTI-INFLAMMATORY RESPONSES. THIS ARTICLE DESCRIBES THE METABOLIC AND EPIGENETIC MECHANISMS INVOLVED IN TRAINED IMMUNITY THAT AFFECT MO/MA, CONTRAPOSING THE CONTROVERSIAL EVIDENCE ON HOW IT MAY IMPACT AUTOIMMUNE/AUTOINFLAMMATION CONDITIONS. 2022 14 1876 38 EMERGING ROLES FOR EPIGENETIC PROGRAMMING IN THE CONTROL OF INFLAMMATORY SIGNALING INTEGRATION IN HEATH AND DISEASE. MACROPHAGES AND DENDRITIC CELLS INITIATE THE INNATE IMMUNE RESPONSE TO INFECTION AND INJURY AND CONTRIBUTE TO INFLAMMATORY SIGNALING TO MAINTAIN THE HOMEOSTASIS OF VARIOUS TISSUES, WHICH INCLUDES RESIDENT MACROPHAGES FOR THE ELIMINATION OF INVADING MICROORGANISMS AND TISSUE DAMAGE. INAPPROPRIATE INFLAMMATORY SIGNALING CAN LEAD TO PERSISTENT INFLAMMATION AND FURTHER DEVELOP INTO AUTOIMMUNE AND INFLAMMATION-ASSOCIATED DISEASES. INFLAMMATORY SIGNALING PATHWAYS HAVE BEEN WELL CHARACTERIZED, BUT HOW THESE SIGNALING PATHWAYS ARE CONVERTED INTO SUSTAINED AND DIVERSE PATTERNS OF EXPRESSION OF CYTOKINES, CHEMOKINES, AND OTHER GENES IN RESPONSE TO ENVIRONMENTAL CHALLENGES IS UNCLEAR. EMERGING EVIDENCE SUGGESTS THE IMPORTANT ROLE OF EPIGENETIC MECHANISMS IN FINELY TUNING THE OUTCOME OF THE HOST INNATE IMMUNE RESPONSE. AN UNDERSTANDING OF EPIGENETIC REGULATION OF INNATE IMMUNE CELL IDENTITY AND FUNCTION WILL ENABLE THE IDENTIFICATION OF THE MECHANISM BETWEEN GENE-SPECIFIC HOST DEFENSES AND INFLAMMATORY DISEASE AND WILL ALSO ALLOW FOR EXPLORATION OF THE PROGRAM OF INNATE IMMUNE MEMORY IN HEALTH AND DISEASE. THIS INFORMATION COULD BE USED TO DEVELOP THERAPEUTIC AGENTS TO ENHANCE THE HOST RESPONSE, PREVENTING CHRONIC INFLAMMATION THROUGH PRESERVING TISSUES AND SIGNALING INTEGRITY. 2017 15 4510 62 MTOR-DEPENDENT OXIDATIVE STRESS REGULATES OXLDL-INDUCED TRAINED INNATE IMMUNITY IN HUMAN MONOCYTES. INTRODUCTION: CELLS OF THE INNATE IMMUNE SYSTEM PARTICULARLY MONOCYTES AND MACROPHAGES HAVE BEEN RECOGNIZED AS PIVOTAL PLAYERS BOTH DURING THE INITIAL INSULT AS WELL AS THE CHRONIC PHASE OF ATHEROSCLEROSIS. IT HAS RECENTLY BEEN SHOWN THAT OXIDIZED LOW-DENSITY LIPOPROTEIN (OXLDL) INDUCES A LONG-TERM PRO-INFLAMMATORY RESPONSE IN MONOCYTES DUE TO EPIGENETIC AND METABOLIC REPROGRAMMING, AN EMERGING NEW CONCEPT CALLED TRAINED INNATE IMMUNITY. CHANGES IN THE CELLULAR REDOX STATE ARE CRUCIAL EVENTS IN THE REGULATION OF MANY PHYSIOLOGIC FUNCTIONS IN MACROPHAGES INCLUDING TRANSCRIPTION, DIFFERENTIATION AND INFLAMMATORY RESPONSE. HERE WE HAVE ANALYZED THE ROLE OF REACTIVE OXYGEN SPECIES (ROS) IN REGULATING THIS PROINFLAMMATORY MONOCYTE PRIMING IN RESPONSE TO OXLDL-TREATMENT. METHODS AND RESULTS: HUMAN MONOCYTES WERE ISOLATED AND INCUBATED WITH OXLDL FOR 24 H. AFTER 5 DAYS OF RESTING, OXLDL TREATED CELLS PRODUCED SIGNIFICANTLY MORE INFLAMMATORY CYTOKINES UPON RESTIMULATION WITH THE TLR2-AGONIST PAM3CYS. FURTHERMORE, OXLDL INCUBATION INDUCED PERSISTENT MTOR ACTIVATION, ROS FORMATION, HIF1ALPHA ACCUMULATION AND HIF1ALPHA TARGET GENE EXPRESSION, WHILE PHARMACOLOGIC MTOR INHIBITION OR SIRNA MEDIATED INHIBITION OF THE MTORC1 SUBUNIT RAPTOR PREVENTED ROS FORMATION AND PROINFLAMMATORY PRIMING. MTOR DEPENDENT ROS FORMATION WAS ASSOCIATED WITH INCREASED EXPRESSION OF NAPDH OXIDASES AND NECESSARY FOR THE EMERGENCE OF THE PRIMED PHENOTYPE AS ANTIOXIDANT TREATMENT BLOCKED OXLDL PRIMING. INHIBITION OF CYTOSOLIC ROS FORMATION COULD ALSO BLOCK MTOR ACTIVATION AND HIF1ALPHA ACCUMULATION SUGGESTING A POSITIVE FEEDBACK LOOP BETWEEN MTOR AND CYTOSOLIC ROS. ALTHOUGH MITOCHONDRIAL ROS SCAVENGING DID NOT BLOCK HIF1ALPHA-ACCUMULATION AT AN EARLY TIME POINT (24 H), IT WAS PERSISTENTLY REDUCED ON DAY 6. THEREFORE, MITOCHONDRIAL ROS FORMATION APPEARS TO OCCUR INITIALLY DOWNSTREAM OF THE MTOR-CYTOROS-HIF1ALPHA FEEDBACK LOOP BUT SEEMS TO BE A CRUCIAL FACTOR THAT CONTROLS THE LONG-TERM ACTIVATION OF THE MTOR-HIF1ALPHA-AXIS. CONCLUSION: IN SUMMARY, OUR DATA DEMONSTRATE THAT MTOR DEPENDENT ROS PRODUCTION CONTROLS THE OXLDL-INDUCED TRAINED INNATE IMMUNITY PHENOTYPE IN HUMAN MONOCYTE DERIVED MACROPHAGES. PHARMACOLOGIC MODULATION OF THESE PATHWAYS MIGHT PROVIDE A POTENTIAL APPROACH TO MODULATE INFLAMMATION, ASSOCIATED WITH ABERRANT MONOCYTE ACTIVATION, DURING ATHEROSCLEROSIS DEVELOPMENT. 2018 16 3661 45 INDUCTION OF INNATE IMMUNE MEMORY BY ENGINEERED NANOPARTICLES IN MONOCYTES/MACROPHAGES: FROM HYPOTHESIS TO REALITY. THE CAPACITY OF ENGINEERED NANOPARTICLES TO ACTIVATE CELLS OF THE INNATE IMMUNE SYSTEM, IN PARTICULAR MONOCYTES AND MACROPHAGES, IS CONSIDERED AT THE BASIS OF THEIR TOXIC/INFLAMMATORY EFFECTS. IT IS, HOWEVER, EVIDENT THAT EVEN NANOPARTICLES THAT DO NOT DIRECTLY INDUCE INFLAMMATORY ACTIVATION, AND ARE THEREFORE CONSIDERED AS SAFE, CAN NEVERTHELESS INDUCE EPIGENETIC MODIFICATIONS AND AFFECT METABOLIC PATHWAYS IN MONOCYTES AND MACROPHAGES. SINCE EPIGENETIC AND METABOLIC CHANGES ARE THE MAIN MECHANISMS OF INNATE MEMORY, WE HAD PREVIOUSLY PROPOSED THAT NANOPARTICLES CAN INDUCE/MODULATE INNATE MEMORY, THAT IS, HAVE THE ABILITY OF SHAPING THE SECONDARY RESPONSE TO INFLAMMATORY CHALLENGES. IN LIGHT OF NEW DATA, IT IS NOW POSSIBLE TO SUPPORT THE ORIGINAL HYPOTHESIS AND SHOW THAT DIFFERENT TYPES OF NANOPARTICLES CAN BOTH DIRECTLY INDUCE INNATE MEMORY, PRIMING MACROPHAGES FOR A MORE POTENT RESPONSE TO SUBSEQUENT STIMULI, AND MODULATE BACTERIA-INDUCED MEMORY BY ATTENUATING THE PRIMING-INDUCED ENHANCEMENT. THIS EVIDENCE RAISES TWO IMPORTANT ISSUES. FIRST, IN ADDITION TO OVERT TOXIC/INFLAMMATORY EFFECTS, WE SHOULD CONSIDER EVALUATING THE CAPACITY TO INDUCE INNATE MEMORY AND THE RELATED EPIGENETIC AND METABOLIC CHANGES IN THE IMMUNOSAFETY ASSESSMENT OF NANOMATERIALS, SINCE MODULATION OF INNATE MEMORY MAY BE AT THE BASIS OF LONG-TERM UNWANTED IMMUNOLOGICAL EFFECTS. THE OTHER IMPORTANT CONSIDERATION IS THAT THIS CAPACITY OF NANOMATERIALS COULD OPEN A NEW AVENUE IN IMMUNOMODULATION AND THE POSSIBILITY OF USING ENGINEERED NANOMATERIALS FOR IMPROVING IMMUNE RESPONSES TO VACCINES AND RESISTANCE TO INFECTIONS, AND MODULATE ANOMALOUS IMMUNE/INFLAMMATORY REACTIONS IN CHRONIC INFLAMMATORY DISEASES, AUTOIMMUNITY, AND A RANGE OF OTHER IMMUNE-RELATED PATHOLOGIES. 2020 17 4488 41 MONOCYTE AND HAEMATOPOIETIC PROGENITOR REPROGRAMMING AS COMMON MECHANISM UNDERLYING CHRONIC INFLAMMATORY AND CARDIOVASCULAR DISEASES. A LARGE NUMBER OF CARDIOVASCULAR EVENTS ARE NOT PREVENTED BY CURRENT THERAPEUTIC REGIMENS. IN SEARCH FOR ADDITIONAL, INNOVATIVE STRATEGIES, IMMUNE CELLS HAVE BEEN RECOGNIZED AS KEY PLAYERS CONTRIBUTING TO ATHEROSCLEROTIC PLAQUE PROGRESSION AND DESTABILIZATION. PARTICULARLY THE ROLE OF INNATE IMMUNE CELLS IS OF MAJOR INTEREST, FOLLOWING THE RECENT PARADIGM SHIFT THAT INNATE IMMUNITY, LONG CONSIDERED TO BE INCAPABLE OF LEARNING, DOES EXHIBIT IMMUNOLOGICAL MEMORY MEDIATED VIA EPIGENETIC REPROGRAMMING. COMPELLING EVIDENCE SHOWS THAT ATHEROSCLEROTIC RISK FACTORS PROMOTE IMMUNE CELL MIGRATION BY PRE-ACTIVATION OF CIRCULATING INNATE IMMUNE CELLS. INNATE IMMUNE CELL ACTIVATION VIA METABOLIC AND EPIGENETIC REPROGRAMMING PERPETUATES A SYSTEMIC LOW-GRADE INFLAMMATORY STATE IN CARDIOVASCULAR DISEASE (CVD) THAT IS ALSO COMMON IN OTHER CHRONIC INFLAMMATORY DISORDERS. THIS OPENS A NEW THERAPEUTIC AREA IN WHICH METABOLIC OR EPIGENETIC MODULATION OF INNATE IMMUNE CELLS MAY RESULT IN DECREASED SYSTEMIC CHRONIC INFLAMMATION, ALLEVIATING CVD, AND ITS CO-MORBIDITIES. 2018 18 6494 32 TRAINED IMMUNITY AS A NOVEL THERAPEUTIC STRATEGY. RECENT STUDIES HAVE SHOWN THAT UPON CERTAIN VACCINATIONS OR INFECTIONS HUMAN INNATE IMMUNE CELLS CAN UNDERGO EXTENSIVE METABOLIC AND EPIGENETIC REPROGRAMMING, WHICH RESULTS IN ENHANCED IMMUNE RESPONSES UPON HETEROLOGOUS RE-INFECTION, A PROCESS TERMED TRAINED IMMUNITY. TRAINED IMMUNITY HAS ALSO BEEN SHOWN TO BE INAPPROPRIATELY ACTIVATED IN INFLAMMATORY DISEASES. THIS PROVIDES THE POTENTIAL FOR IDENTIFYING NOVEL THERAPEUTIC TARGETS: POTENTIATION OF TRAINED IMMUNITY COULD PROTECT FROM SECONDARY INFECTIONS AND REVERSE IMMUNOTOLERANT STATES, WHILE INHIBITION OF TRAINED IMMUNITY MIGHT REDUCE EXCESSIVE IMMUNE ACTIVATION IN CHRONIC INFLAMMATORY CONDITIONS. BY TARGETING SPECIFIC MECHANISMS OF TRAINED IMMUNITY ON EITHER IMMUNOLOGIC, METABOLIC OR EPIGENETIC LEVEL, NOVEL THERAPEUTIC APPROACHES COULD BE DEVELOPED. 2018 19 6504 45 TRAINED INNATE IMMUNITY AND ITS IMPLICATIONS FOR MUCOSAL IMMUNITY AND INFLAMMATION. THE LONG-STANDING DOGMA THAT IMMUNOLOGICAL MEMORY IS THE EXCLUSIVE PREROGATIVE OF THE ADAPTIVE IMMUNE SYSTEM HAS BEEN CHALLENGED BY EMERGING EVIDENCE THAT INNATE IMMUNITY CAN ALSO MAINTAIN MEMORY OF PAST EVENTS. SUCH IMMUNOLOGICAL IMPRINTING TAKES TWO FORMS, TRAINED INNATE IMMUNITY AND TOLERANCE. TRAINED IMMUNITY INVOLVES METABOLIC AND EPIGENETIC ADAPTATIONS IN INNATE IMMUNE CELLS AND THEIR PROGENITORS IN THE BONE MARROW UPON EXPOSURE TO CERTAIN MICROBIAL AND/OR INFLAMMATORY STIMULI SO THAT THE "TRAINED" CELLS WOULD BE POISED TO RESPOND MUCH FASTER AND STRONGER TO A SUBSEQUENT CHALLENGE (E.G., A NEW INFECTION THAT IS NOT NECESSARILY THE SAME AS THE EARLIER ONE). CONVERSELY, TOLERANCE LEADS TO ATTENUATED IMMUNE RESPONSES TO SECONDARY STIMULI. THIS REVIEW FOCUSES ON TRAINED IMMUNITY AND DISCUSSES EVIDENCE FOR ITS EXISTENCE FROM LOWER ORGANISMS TO HUMANS, ITS MECHANISTIC UNDERPINNINGS, AND ITS TRANSLATIONAL RAMIFICATIONS. ALTHOUGH TRAINED IMMUNITY CAN BE CONSIDERED AS AN EVOLUTIONARILY CONSERVED BENEFICIAL RESPONSE AGAINST REINFECTIONS, IN THE SETTING OF MODERN SOCIETIES WITH HIGH PREVALENCE OF CHRONIC MUCOSAL AND SYSTEMIC INFLAMMATORY DISEASES, TRAINED IMMUNITY COULD ALSO PROMOTE MALADAPTIVE IMMUNE RESPONSES THAT AGGRAVATE PATHOLOGY. THUS, DEPENDING ON CONTEXT, INNATE IMMUNE MEMORY COULD BE THERAPEUTICALLY MANIPULATED USING DEFINED AGONISTS TO EITHER PROMOTE INNATE IMMUNE RESPONSES (PARTICULARLY USEFUL FOR THE TREATMENT OF INFECTIONS OR CHEMOTHERAPY-INDUCED MYELOSUPPRESSION) OR SUPPRESS EXCESSIVE INFLAMMATION IN INFLAMMATORY AND AUTOIMMUNE DISEASES. 2019 20 6535 41 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