1 3735 84 INNATE IMMUNE MEMORY: IMPLICATIONS FOR DEVELOPMENT OF PEDIATRIC IMMUNOMODULATORY AGENTS AND ADJUVANTED VACCINES. UNIQUE FEATURES OF IMMUNITY EARLY IN LIFE INCLUDE A DISTINCT IMMUNE SYSTEM PARTICULARLY RELIANT ON INNATE IMMUNITY, WITH WEAK T HELPER (TH)1-POLARIZING IMMUNE RESPONSES, AND IMPAIRED RESPONSES TO CERTAIN VACCINES LEADING TO A HEIGHTENED SUSCEPTIBILITY TO INFECTION. TO THESE IMPORTANT ASPECTS, WE NOW ADD AN INCREASINGLY APPRECIATED CONCEPT THAT THE INNATE IMMUNE SYSTEM DISPLAYS EPIGENETIC MEMORY OF AN EARLIER INFECTION OR VACCINATION, A PHENOMENON THAT HAS BEEN NAMED "TRAINED IMMUNITY." EXPOSURE OF NEONATAL LEUKOCYTES IN VITRO OR NEONATAL ANIMALS OR HUMANS IN VIVO TO SPECIFIC INNATE IMMUNE STIMULI RESULTS IN AN ALTERED INNATE IMMUNE SET POINT. GIVEN THE PARTICULAR IMPORTANCE OF INNATE IMMUNITY EARLY IN LIFE, TRAINED IMMUNITY TO EARLY LIFE INFECTION AND/OR IMMUNIZATION MAY PLAY AN IMPORTANT ROLE IN MODULATING BOTH ACUTE AND CHRONIC DISEASES. 2014 2 6504 33 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 3 6503 23 TRAINED IMMUNITY: REPROGRAMMING INNATE IMMUNITY IN HEALTH AND DISEASE. TRADITIONALLY, THE INNATE AND ADAPTIVE IMMUNE SYSTEMS ARE DIFFERENTIATED BY THEIR SPECIFICITY AND MEMORY CAPACITY. IN RECENT YEARS, HOWEVER, THIS PARADIGM HAS SHIFTED: CELLS OF THE INNATE IMMUNE SYSTEM APPEAR TO BE ABLE TO GAIN MEMORY CHARACTERISTICS AFTER TRANSIENT STIMULATION, RESULTING IN AN ENHANCED RESPONSE UPON SECONDARY CHALLENGE. THIS PHENOMENON HAS BEEN CALLED TRAINED IMMUNITY. TRAINED IMMUNITY IS CHARACTERIZED BY NONSPECIFIC INCREASED RESPONSIVENESS, MEDIATED VIA EXTENSIVE METABOLIC AND EPIGENETIC REPROGRAMMING. TRAINED IMMUNITY EXPLAINS THE HETEROLOGOUS EFFECTS OF VACCINES, WHICH RESULT IN INCREASED PROTECTION AGAINST SECONDARY INFECTIONS. HOWEVER, IN CHRONIC INFLAMMATORY CONDITIONS, TRAINED IMMUNITY CAN INDUCE MALADAPTIVE EFFECTS AND CONTRIBUTE TO HYPERINFLAMMATION AND PROGRESSION OF CARDIOVASCULAR DISEASE, AUTOINFLAMMATORY SYNDROMES, AND NEUROINFLAMMATION. IN THIS REVIEW WE SUMMARIZE THE CURRENT STATE OF THE FIELD OF TRAINED IMMUNITY, ITS MECHANISMS, AND ITS ROLES IN BOTH HEALTH AND DISEASE. 2021 4 1310 23 DEFINING TRAINED IMMUNITY AND ITS ROLE IN HEALTH AND DISEASE. IMMUNE MEMORY IS A DEFINING FEATURE OF THE ACQUIRED IMMUNE SYSTEM, BUT ACTIVATION OF THE INNATE IMMUNE SYSTEM CAN ALSO RESULT IN ENHANCED RESPONSIVENESS TO SUBSEQUENT TRIGGERS. THIS PROCESS HAS BEEN TERMED 'TRAINED IMMUNITY', A DE FACTO INNATE IMMUNE MEMORY. RESEARCH IN THE PAST DECADE HAS POINTED TO THE BROAD BENEFITS OF TRAINED IMMUNITY FOR HOST DEFENCE BUT HAS ALSO SUGGESTED POTENTIALLY DETRIMENTAL OUTCOMES IN IMMUNE-MEDIATED AND CHRONIC INFLAMMATORY DISEASES. HERE WE DEFINE 'TRAINED IMMUNITY' AS A BIOLOGICAL PROCESS AND DISCUSS THE INNATE STIMULI AND THE EPIGENETIC AND METABOLIC REPROGRAMMING EVENTS THAT SHAPE THE INDUCTION OF TRAINED IMMUNITY. 2020 5 2861 35 FROM TRAINED IMMUNITY IN ALLERGY TO TRAINED IMMUNITY-BASED ALLERGEN VACCINES. INNATE IMMUNE CELLS EXPERIENCE LONG LASTING METABOLIC AND EPIGENETIC CHANGES AFTER AN ENCOUNTER WITH SPECIFIC STIMULI. THIS FACILITATES ENHANCED IMMUNE RESPONSES UPON SECONDARY EXPOSITION TO BOTH THE SAME AND UNRELATED PATHOGENS, A PROCESS TERMED TRAINED IMMUNITY. TRAINED IMMUNITY-BASED VACCINES (TIBV) ARE VACCINES ABLE TO INDUCE INNATE IMMUNE MEMORY, THUS CONFERRING HETEROLOGOUS PROTECTION AGAINST A BROAD RANGE OF PATHOGENS. WHILE TRAINED IMMUNITY HAS BEEN WELL DOCUMENTED IN THE CONTEXT OF INFECTIONS AND MULTIPLE IMMUNE-MEDIATED DISEASES, THE ROLE OF INNATE IMMUNE MEMORY AND ITS CONTRIBUTION TO THE INITIATION AND MAINTENANCE OF CHRONIC ALLERGIC DISEASES REMAINS POORLY UNDERSTOOD. OVER THE LAST YEARS, DIFFERENT STUDIES ATTEMPTING TO UNCOVER THE ROLE OF TRAINED IMMUNITY IN ALLERGY HAVE EMERGED. EXPOSITION TO ENVIRONMENTAL FACTORS IMPACTING ALLERGY DEVELOPMENT SUCH AS ALLERGENS OR VIRUSES INDUCES THE REPROGRAMMING OF INNATE IMMUNE CELLS TO ACQUIRE A MORE PRO-INFLAMMATORY PHENOTYPE IN THE CONTEXT OF ASTHMA OR FOOD ALLERGY. SEVERAL STUDIES HAVE CONVINCINGLY DEMONSTRATED THAT PREVENTION OF VIRAL INFECTIONS USING TIBV CONTRIBUTES TO REDUCE WHEEZING ATTACKS IN CHILDREN, WHICH REPRESENT A HIGH-RISK FACTOR FOR ASTHMA DEVELOPMENT LATER IN LIFE. INNATE IMMUNE CELLS TRAINED WITH SPECIFIC STIMULI MIGHT ALSO ACQUIRE ANTI-INFLAMMATORY FEATURES AND PROMOTE TOLERANCE, WHICH MAY HAVE IMPORTANT IMPLICATIONS FOR CHRONIC INFLAMMATORY DISEASES SUCH AS ALLERGIES. RECENT FINDINGS SHOWED THAT ALLERGOID-MANNAN CONJUGATES, WHICH ARE NEXT GENERATION VACCINES FOR ALLERGEN-SPECIFIC IMMUNOTHERAPY (AIT), ARE ABLE TO REPROGRAM MONOCYTES INTO TOLEROGENIC DENDRITIC CELLS BY MECHANISMS DEPENDING ON METABOLIC AND EPIGENETIC REWIRING. A BETTER UNDERSTANDING OF THE UNDERLYING MECHANISMS OF TRAINED IMMUNITY IN ALLERGY WILL PAVE THE WAY FOR THE DESIGN OF NOVEL TRAINED IMMUNITY-BASED ALLERGEN VACCINES AS POTENTIAL ALTERNATIVE STRATEGIES FOR THE PREVENTION AND TREATMENT OF ALLERGIC DISEASES. 2023 6 6501 25 TRAINED IMMUNITY: LINKING OBESITY AND CARDIOVASCULAR DISEASE ACROSS THE LIFE-COURSE? OBESITY, A CHRONIC INFLAMMATORY DISEASE, IS THE MOST PREVALENT MODIFIABLE RISK FACTOR FOR CARDIOVASCULAR DISEASE. THE MECHANISMS UNDERLYING INFLAMMATION IN OBESITY ARE INCOMPLETELY UNDERSTOOD. RECENT DEVELOPMENTS HAVE CHALLENGED THE DOGMA OF IMMUNOLOGICAL MEMORY OCCURRING EXCLUSIVELY IN THE ADAPTIVE IMMUNE SYSTEM AND SHOW THAT THE INNATE IMMUNE SYSTEM HAS POTENTIAL TO BE REPROGRAMMED. THIS INNATE IMMUNE MEMORY (TRAINED IMMUNITY) IS CHARACTERIZED BY EPIGENETIC AND METABOLIC REPROGRAMMING OF MYELOID CELLS FOLLOWING ENDOGENOUS OR EXOGENOUS STIMULATION, RESULTING IN ENHANCED INFLAMMATION TO SUBSEQUENT STIMULI. TRAINED IMMUNITY PHENOTYPES HAVE NOW BEEN REPORTED FOR OTHER IMMUNE AND NON-IMMUNE CELLS. HERE, WE PROVIDE A NOVEL PERSPECTIVE ON THE PUTATIVE ROLE OF TRAINED IMMUNITY IN MEDIATING THE ADVERSE CARDIOVASCULAR EFFECTS OF OBESITY AND HIGHLIGHT POTENTIAL TRANSLATIONAL PATHWAYS. 2020 7 3732 28 INNATE IMMUNE MEMORY AND THE HOST RESPONSE TO INFECTION. UNLIKE THE ADAPTIVE IMMUNE SYSTEM, THE INNATE IMMUNE SYSTEM HAS CLASSICALLY BEEN CHARACTERIZED AS BEING DEVOID OF MEMORY FUNCTIONS. HOWEVER, RECENT RESEARCH SHOWS THAT INNATE MYELOID AND LYMPHOID CELLS HAVE THE ABILITY TO RETAIN MEMORY OF PRIOR PATHOGEN EXPOSURE AND BECOME PRIMED TO ELICIT A ROBUST, BROAD-SPECTRUM RESPONSE TO SUBSEQUENT INFECTION. THIS PHENOMENON HAS BEEN TERMED INNATE IMMUNE MEMORY OR TRAINED IMMUNITY. INNATE IMMUNE MEMORY IS INDUCED VIA ACTIVATION OF PATTERN RECOGNITION RECEPTORS AND THE ACTIONS OF CYTOKINES ON HEMATOPOIETIC PROGENITORS AND STEM CELLS IN BONE MARROW AND INNATE LEUKOCYTES IN THE PERIPHERY. THE TRAINED PHENOTYPE IS INDUCED AND SUSTAINED VIA EPIGENETIC MODIFICATIONS THAT REPROGRAM TRANSCRIPTIONAL PATTERNS AND METABOLISM. THESE MODIFICATIONS AUGMENT ANTIMICROBIAL FUNCTIONS, SUCH AS LEUKOCYTE EXPANSION, CHEMOTAXIS, PHAGOCYTOSIS, AND MICROBIAL KILLING, TO FACILITATE AN AUGMENTED HOST RESPONSE TO INFECTION. ALTERNATIVELY, INNATE IMMUNE MEMORY MAY CONTRIBUTE TO THE PATHOGENESIS OF CHRONIC DISEASES, SUCH AS ATHEROSCLEROSIS AND ALZHEIMER'S DISEASE. 2022 8 6496 35 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 9 3661 27 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 10 1876 20 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 11 6452 22 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 12 6502 26 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 13 2525 25 EPIGENETICS AND TRAINED IMMUNITY. SIGNIFICANCE: A GROWING BODY OF CLINICAL AND EXPERIMENTAL EVIDENCE HAS CHALLENGED THE TRADITIONAL UNDERSTANDING THAT ONLY THE ADAPTIVE IMMUNE SYSTEM CAN MOUNT IMMUNOLOGICAL MEMORY. RECENT FINDINGS DESCRIBE THE ADAPTIVE CHARACTERISTICS OF THE INNATE IMMUNE SYSTEM, UNDERSCORED BY ITS ABILITY TO REMEMBER ANTECEDENT FOREIGN ENCOUNTERS AND RESPOND IN A NONSPECIFIC SENSITIZED MANNER TO REINFECTION. THIS HAS BEEN TERMED TRAINED INNATE IMMUNITY. ALTHOUGH BENEFICIAL IN THE CONTEXT OF RECURRENT INFECTIONS, THIS MIGHT ACTUALLY CONTRIBUTE TO CHRONIC IMMUNE-MEDIATED DISEASES, SUCH AS ATHEROSCLEROSIS. RECENT ADVANCES: IN LINE WITH ITS PROPOSED ROLE IN SUSTAINING CELLULAR MEMORIES, EPIGENETIC REPROGRAMMING HAS EMERGED AS A CRITICAL DETERMINANT OF TRAINED IMMUNITY. RECENT TECHNOLOGICAL AND COMPUTATIONAL ADVANCES THAT IMPROVE UNBIASED ACQUISITION OF EPIGENOMIC PROFILES HAVE SIGNIFICANTLY ENHANCED OUR APPRECIATION FOR THE COMPLEXITIES OF CHROMATIN ARCHITECTURE IN THE CONTEXTS OF DIVERSE IMMUNOLOGICAL CHALLENGES. CRITICAL ISSUES: KEY TO RESOLVING THE DISTINCT CHROMATIN SIGNATURES OF INNATE IMMUNE MEMORY IS A COMPREHENSIVE UNDERSTANDING OF THE PRECISE PHYSIOLOGICAL TARGETS OF REGULATORY PROTEINS THAT RECOGNIZE, DEPOSIT, AND REMOVE CHEMICAL MODIFICATIONS FROM CHROMATIN AS WELL AS OTHER GENE-REGULATING FACTORS. DRAWING FROM A RAPIDLY EXPANDING COMPENDIUM OF EXPERIMENTAL AND CLINICAL STUDIES, THIS REVIEW DETAILS A CURRENT PERSPECTIVE OF THE EPIGENETIC PATHWAYS THAT SUPPORT THE ADAPTED PHENOTYPES OF MONOCYTES AND MACROPHAGES. FUTURE DIRECTIONS: WE EXPLORE FUTURE STRATEGIES THAT ARE AIMED AT EXPLOITING THE MECHANISM OF TRAINED IMMUNITY TO IMPROVE THE PREVENTION AND TREATMENT OF INFECTIONS AND IMMUNE-MEDIATED CHRONIC DISORDERS. 2018 14 4488 21 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 15 6497 23 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 16 6505 28 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 17 6101 20 THE EMERGING ROLE OF EPIGENETICS IN THE IMMUNE RESPONSE TO VACCINATION AND INFECTION: A SYSTEMATIC REVIEW. EXTENSIVE RESEARCH HAS HIGHLIGHTED THE ROLE OF INFECTION-INDUCED EPIGENETIC EVENTS IN THE DEVELOPMENT OF CANCER. MORE RECENTLY, ATTENTION HAS FOCUSED ON THE ABILITY OF NON-CARCINOGENIC INFECTIONS, AS WELL AS VACCINES, TO MODIFY THE HUMAN EPIGENOME AND MODULATE THE IMMUNE RESPONSE. THIS REVIEW EXPLORES THIS RAPIDLY EVOLVING AREA OF INVESTIGATION AND OUTLINES THE MANY AND VARIED WAYS IN WHICH VACCINATION AND NATURAL INFECTION CAN INFLUENCE THE HUMAN EPIGENOME FROM MODULATION OF THE INNATE AND ADAPTIVE IMMUNE RESPONSE, TO BIOLOGICAL AGEING AND MODIFICATION OF DISEASE RISK. THE IMPLICATIONS OF THESE EPIGENETIC CHANGES ON IMMUNE REGULATION AND THEIR POTENTIAL APPLICATION TO THE DIAGNOSIS AND TREATMENT OF CHRONIC INFECTION AND VACCINE DEVELOPMENT ARE ALSO DISCUSSED. 2020 18 2344 20 EPIGENETIC REGULATION OF MACROPHAGES: FROM HOMEOSTASIS MAINTENANCE TO HOST DEFENSE. MACROPHAGES ARE CRUCIAL MEMBERS OF THE INNATE IMMUNE RESPONSE AND IMPORTANT REGULATORS. THE DIFFERENTIATION AND ACTIVATION OF MACROPHAGES REQUIRE THE TIMELY REGULATION OF GENE EXPRESSION, WHICH DEPENDS ON THE INTERACTION OF A VARIETY OF FACTORS, INCLUDING TRANSCRIPTION FACTORS AND EPIGENETIC MODIFICATIONS. EPIGENETIC CHANGES ALSO GIVE MACROPHAGES THE ABILITY TO SWITCH RAPIDLY BETWEEN CELLULAR PROGRAMS, INDICATING THE ABILITY OF EPIGENETIC MECHANISMS TO AFFECT PHENOTYPE PLASTICITY. IN THIS REVIEW, WE FOCUS ON KEY EPIGENETIC EVENTS ASSOCIATED WITH MACROPHAGE FATE, HIGHLIGHTING EVENTS RELATED TO THE MAINTENANCE OF TISSUE HOMEOSTASIS, RESPONSES TO DIFFERENT STIMULI AND THE FORMATION OF INNATE IMMUNE MEMORY. FURTHER UNDERSTANDING OF THE EPIGENETIC REGULATION OF MACROPHAGES WILL BE HELPFUL FOR MAINTAINING TISSUE INTEGRITY, PREVENTING CHRONIC INFLAMMATORY DISEASES AND DEVELOPING THERAPIES TO ENHANCE HOST DEFENSE. 2020 19 3539 22 IMMUNE SENESCENCE, EPIGENETICS AND AUTOIMMUNITY. AGING OF THE IMMUNE SYSTEM IN HUMANS AND ANIMALS IS CHARACTERIZED BY A DECLINE IN BOTH ADAPTIVE AND INNATE IMMUNE RESPONSES. PARADOXICALLY, AGING IS ALSO ASSOCIATED WITH A STATE OF CHRONIC INFLAMMATION ("INFLAMMAGING") AND AN INCREASED LIKELIHOOD OF DEVELOPING AUTOIMMUNE DISEASES. EPIGENETIC CHANGES IN NON-DIVIDING AND DIVIDING CELLS, INCLUDING IMMUNE CELLS, DUE TO ENVIRONMENTAL FACTORS CONTRIBUTE TO THE INFLAMMATION AND AUTOIMMUNITY THAT CHARACTERIZE BOTH THE STATE AND DISEASES OF AGING. HERE, WE REVIEW THE EPIGENETIC MECHANISMS INVOLVED IN THE DEVELOPMENT OF IMMUNE SENESCENCE AND AUTOIMMUNITY IN OLD AGE. 2018 20 6506 23 TRAINED INNATE IMMUNITY NOT ALWAYS AMICABLE. THE CONCEPT OF „TRAINED INNATE IMMUNITY" IS UNDERSTOOD AS THE ABILITY OF INNATE IMMUNE CELLS TO REMEMBER INVADING AGENTS AND TO RESPOND NONSPECIFICALLY TO REINFECTION WITH INCREASED STRENGTH. TRAINED IMMUNITY IS ORCHESTRATED BY EPIGENETIC MODIFICATIONS LEADING TO CHANGES IN GENE EXPRESSION AND CELL PHYSIOLOGY. ALTHOUGH THIS PHENOMENON WAS ORIGINALLY SEEN MAINLY AS A BENEFICIAL EFFECT, SINCE IT CONFERS BROAD IMMUNOLOGICAL PROTECTION, ENHANCED IMMUNE RESPONSE OF REPROGRAMMED INNATE IMMUNE CELLS MIGHT RESULT IN THE DEVELOPMENT OR PERSISTENCE OF CHRONIC METABOLIC, AUTOIMMUNE OR NEUROINFALMMATORY DISORDERS. THIS PAPER OVERVIEWS SEVERAL EXAMPLES WHERE THE INDUCTION OF TRAINED IMMUNITY MAY BE ESSENTIAL IN THE DEVELOPMENT OF DISEASES CHARACTERIZED BY FLAWED INNATE IMMUNE RESPONSE. 2019