1 6504 134 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 2 6503 36 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 3 6501 37 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 4 1310 32 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 6452 34 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 6 6497 38 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 7 2525 41 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 8 6502 44 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 9 6494 40 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 10 2861 49 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 11 3735 33 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 12 6505 36 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 13 3544 35 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 14 3732 36 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 15 4488 39 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 16 6498 42 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 17 1876 31 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 18 2344 27 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 6376 43 THE ROLE OF NEUTROPHILS IN TRAINED IMMUNITY. THE PRINCIPLE OF TRAINED IMMUNITY REPRESENTS INNATE IMMUNE MEMORY DUE TO SUSTAINED, MAINLY EPIGENETIC, CHANGES TRIGGERED BY ENDOGENOUS OR EXOGENOUS STIMULI IN BONE MARROW (BM) PROGENITORS (CENTRAL TRAINED IMMUNITY) AND THEIR INNATE IMMUNE CELL PROGENY, THEREBY TRIGGERING ELEVATED RESPONSIVENESS AGAINST SECONDARY STIMULI. BM PROGENITORS CAN RESPOND TO MICROBIAL AND STERILE SIGNALS, THEREBY POSSIBLY ACQUIRING TRAINED IMMUNITY-MEDIATED LONG-LASTING ALTERATIONS THAT MAY SHAPE THE FATE AND FUNCTION OF THEIR PROGENY, FOR EXAMPLE, NEUTROPHILS. NEUTROPHILS, THE MOST ABUNDANT INNATE IMMUNE CELL POPULATION, ARE PRODUCED IN THE BM FROM COMMITTED PROGENITOR CELLS IN A PROCESS DESIGNATED GRANULOPOIESIS. NEUTROPHILS ARE THE FIRST RESPONDERS AGAINST INFECTIOUS OR INFLAMMATORY CHALLENGES AND HAVE VERSATILE FUNCTIONS IN IMMUNITY. TOGETHER WITH OTHER INNATE IMMUNE CELLS, NEUTROPHILS ARE EFFECTORS OF PERIPHERAL TRAINED IMMUNITY. HOWEVER, GIVEN THE SHORT LIFETIME OF NEUTROPHILS, THEIR ABILITY TO ACQUIRE IMMUNOLOGICAL MEMORY MAY LIE IN THE CENTRAL TRAINING OF THEIR BM PROGENITORS RESULTING IN GENERATION OF REPROGRAMMED, THAT IS, "TRAINED", NEUTROPHILS. ALTHOUGH TRAINED IMMUNITY MAY HAVE BENEFICIAL EFFECTS IN INFECTION OR CANCER, IT MAY ALSO MEDIATE DETRIMENTAL OUTCOMES IN CHRONIC INFLAMMATION. HERE, WE REVIEW THE EMERGING RESEARCH AREA OF TRAINED IMMUNITY WITH A PARTICULAR EMPHASIS ON THE ROLE OF NEUTROPHILS AND GRANULOPOIESIS. 2023 20 9 48 'TRAINED IMMUNITY': CONSEQUENCES FOR LYMPHOID MALIGNANCIES. IN HEMATOLOGICAL MALIGNANCIES COMPLEX INTERACTIONS EXIST BETWEEN THE IMMUNE SYSTEM, MICROORGANISMS AND MALIGNANT CELLS. ON ONE HAND, MICROORGANISMS CAN INDUCE CANCER, AS ILLUSTRATED BY SPECIFIC INFECTION-INDUCED LYMPHOPROLIFERATIVE DISEASES SUCH AS HELICOBACTER PYLORI-ASSOCIATED GASTRIC MUCOSA-ASSOCIATED LYMPHOID TISSUE LYMPHOMA. ON THE OTHER HAND, MALIGNANT CELLS CREATE AN IMMUNOSUPPRESSIVE ENVIRONMENT FOR THEIR OWN BENEFIT, BUT THIS ALSO RESULTS IN AN INCREASED RISK OF INFECTIONS. DISRUPTED INNATE IMMUNITY CONTRIBUTES TO THE NEOPLASTIC TRANSFORMATION OF BLOOD CELLS BY SEVERAL MECHANISMS, INCLUDING THE UNCONTROLLED CLEARANCE OF MICROBIAL AND AUTOANTIGENS RESULTING IN CHRONIC IMMUNE STIMULATION AND PROLIFERATION, CHRONIC INFLAMMATION, AND DEFECTIVE IMMUNE SURVEILLANCE AND ANTI-CANCER IMMUNITY. RESTORING DYSFUNCTION OR ENHANCING RESPONSIVENESS OF THE INNATE IMMUNE SYSTEM MIGHT THEREFORE REPRESENT A NEW ANGLE FOR THE PREVENTION AND TREATMENT OF HEMATOLOGICAL MALIGNANCIES, IN PARTICULAR LYMPHOID MALIGNANCIES AND ASSOCIATED INFECTIONS. RECENTLY, IT HAS BEEN SHOWN THAT CELLS OF THE INNATE IMMUNE SYSTEM, SUCH AS MONOCYTES/MACROPHAGES AND NATURAL KILLER CELLS, HARBOR FEATURES OF IMMUNOLOGICAL MEMORY AND DISPLAY ENHANCED FUNCTIONALITY LONG-TERM AFTER STIMULATION WITH CERTAIN MICROORGANISMS AND VACCINES. THESE FUNCTIONAL CHANGES RELY ON EPIGENETIC REPROGRAMMING AND HAVE BEEN TERMED 'TRAINED IMMUNITY'. IN THIS REVIEW THE CONCEPT OF 'TRAINED IMMUNITY' IS DISCUSSED IN THE SETTING OF LYMPHOID MALIGNANCIES. AMELIORATION OF INFECTIOUS COMPLICATIONS AND HEMATOLOGICAL DISEASE PROGRESSION CAN BE ENVISIONED TO RESULT FROM THE INDUCTION OF TRAINED IMMUNITY, BUT FUTURE STUDIES ARE REQUIRED TO PROVE THIS EXCITING NEW HYPOTHESIS. 2016