1 6495 108 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 2 4041 53 MACROPHAGE PLASTICITY IN DUCHENNE MUSCULAR DYSTROPHY: A NEXUS OF PATHOLOGICAL REMODELLING WITH THERAPEUTIC IMPLICATIONS. DUCHENNE MUSCULAR DYSTROPHY (DMD) IS CHARACTERIZED BY CHRONIC SKELETAL MUSCLE NECROSIS, LEADING TO MUSCLE REGENERATION FAILURE AND FIBROSIS. ALTHOUGH MACROPHAGES (MPS) ARE NORMALLY ESSENTIAL FOR MUSCLE REGENERATION, DYSREGULATED MP FUNCTION PROMOTES PATHOLOGICAL MUSCLE REMODELLING. INFILTRATING MPS CAN BE PREDOMINANTLY PRO-INFLAMMATORY (M1 BIASED), ANTI-INFLAMMATORY (M2 BIASED) OR OF A MIXED PHENOTYPE AND CAN ORIGINATE FROM THE ADULT BONE MARROW (MONOCYTE DEPENDENT) OR EMBRYONIC PRECURSORS (MONOCYTE INDEPENDENT). IN MDX MICE (GENETIC MODEL OF DMD) LACKING EITHER TOLL-LIKE RECEPTOR (TLR) 2 OR TLR4, IT IS FOUND THAT MP INFILTRATION OF DYSTROPHIC MUSCLE IS SIGNIFICANTLY REDUCED AND THAT THE MP PHENOTYPE IS SHIFTED TOWARD A MORE ANTI-INFLAMMATORY PROFILE. THIS IS ACCOMPANIED BY SIGNIFICANT IMPROVEMENTS IN MUSCLE HISTOLOGY AND FORCE PRODUCTION. LACK OF THE CHEMOKINE RECEPTOR CCR2, WHICH IMPEDES MONOCYTE RELEASE FROM THE BONE MARROW, LEADS TO SIMILAR BENEFICIAL EFFECTS IN MDX MICE. EVIDENCE WAS ALSO FOUND FOR TLR4-REGULATED INDUCTION OF TRAINED INNATE IMMUNITY IN MPS CULTURED FROM THE BONE MARROW OF MDX MICE BEFORE THEIR ENTRY INTO THE MUSCLE. THESE MPS EXHIBIT EPIGENETIC AND METABOLIC ALTERATIONS, ACCOMPANIED BY NON-SPECIFIC HYPER-RESPONSIVENESS TO MULTIPLE STIMULI, WHICH IS MANIFESTED BY POTENTIATED UPREGULATION OF BOTH PRO- AND ANTI-INFLAMMATORY GENES. IN SUMMARY, EXAGGERATED RECRUITMENT OF MONOCYTE-DERIVED MPS AND SIGNS OF TRAINED INNATE IMMUNITY AT THE LEVEL OF THE BONE MARROW ARE FEATURES OF THE IMMUNOPHENOTYPE ASSOCIATED WITH DYSTROPHIC MUSCLE DISEASE. THESE PHENOMENA ARE REGULATED BY TOLL-LIKE RECEPTORS THAT BIND ENDOGENOUS DAMAGE-ASSOCIATED MOLECULAR PATTERN (DAMP) MOLECULES, SUGGESTING THAT DAMP RELEASE FROM DYSTROPHIC MUSCLES MODULATES MP PLASTICITY AT THE BONE MARROW LEVEL THROUGH TOLL-LIKE RECEPTOR-DRIVEN MECHANISMS. 2022 3 3732 29 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 4 6452 32 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 5 6376 30 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 6 3436 33 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 7 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 8 6500 35 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 9 6502 35 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 10 6504 36 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 11 6498 33 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 6494 28 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 13 6503 30 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 14 1482 28 DIVERSITY, MECHANISMS, AND SIGNIFICANCE OF MACROPHAGE PLASTICITY. MACROPHAGES ARE A DIVERSE SET OF CELLS PRESENT IN ALL BODY COMPARTMENTS. THIS DIVERSITY IS IMPRINTED BY THEIR ONTOGENETIC ORIGIN (EMBRYONAL VERSUS ADULT BONE MARROW-DERIVED CELLS); THE ORGAN CONTEXT; BY THEIR ACTIVATION OR DEACTIVATION BY VARIOUS SIGNALS IN THE CONTEXTS OF MICROBIAL INVASION, TISSUE DAMAGE, AND METABOLIC DERANGEMENT; AND BY POLARIZATION OF ADAPTIVE T CELL RESPONSES. CLASSIC ADAPTIVE RESPONSES OF MACROPHAGES INCLUDE TOLERANCE, PRIMING, AND A WIDE SPECTRUM OF ACTIVATION STATES, INCLUDING M1, M2, OR M2-LIKE. MOREOVER, MACROPHAGES CAN RETAIN LONG-TERM IMPRINTING OF MICROBIAL ENCOUNTERS (TRAINED INNATE IMMUNITY). SINGLE-CELL ANALYSIS OF MONONUCLEAR PHAGOCYTES IN HEALTH AND DISEASE HAS ADDED A NEW DIMENSION TO OUR UNDERSTANDING OF THE DIVERSITY OF MACROPHAGE DIFFERENTIATION AND ACTIVATION. EPIGENETIC LANDSCAPES, TRANSCRIPTION FACTORS, AND MICRORNA NETWORKS UNDERLIE THE ADAPTABILITY OF MACROPHAGES TO DIFFERENT ENVIRONMENTAL CUES. MACROPHAGE PLASTICITY, AN ESSENTIAL COMPONENT OF CHRONIC INFLAMMATION, AND ITS INVOLVEMENT IN DIVERSE HUMAN DISEASES, MOST NOTABLY CANCER, IS DISCUSSED HERE AS A PARADIGM. 2020 15 6535 29 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 16 6497 34 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 17 1310 26 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 18 3733 31 INNATE IMMUNE MEMORY IN INFLAMMATORY ARTHRITIS. THE CONCEPT OF IMMUNOLOGICAL MEMORY WAS DEMONSTRATED IN ANTIQUITY WHEN PROTECTION AGAINST RE-EXPOSURE TO PATHOGENS WAS OBSERVED DURING THE PLAGUE OF ATHENS. IMMUNOLOGICAL MEMORY HAS BEEN LINKED WITH THE ADAPTIVE FEATURES OF T AND B CELLS; HOWEVER, IN THE PAST DECADE, EVIDENCE HAS DEMONSTRATED THAT INNATE IMMUNE CELLS CAN EXHIBIT MEMORY, A PHENOMENON CALLED 'INNATE IMMUNE MEMORY' OR 'TRAINED IMMUNITY'. INNATE IMMUNE MEMORY IS CURRENTLY BEING DEFINED AND IS TRANSFORMING OUR UNDERSTANDING OF CHRONIC INFLAMMATION AND AUTOIMMUNITY. IN THIS REVIEW, WE PROVIDE AN UP-TO-DATE OVERVIEW OF THE MEMORY-LIKE FEATURES OF INNATE IMMUNE CELLS IN INFLAMMATORY ARTHRITIS AND THE CROSSTALK BETWEEN CHRONIC INFLAMMATORY MILIEU AND CELL REPROGRAMMING. ABERRANT PRO-INFLAMMATORY SIGNALLING, INCLUDING CYTOKINES, REGULATES THE METABOLIC AND EPIGENETIC REPROGRAMMING OF HAEMATOPOIETIC PROGENITORS, LEADING TO EXACERBATED INFLAMMATORY RESPONSES AND OSTEOCLAST DIFFERENTIATION, IN TURN LEADING TO BONE DESTRUCTION. MOREOVER, IMPRINTED MEMORY ON MATURE CELLS INCLUDING TERMINALLY DIFFERENTIATED OSTEOCLASTS ALTERS RESPONSIVENESS TO THERAPIES AND MODIFIES DISEASE OUTCOMES, COMMONLY MANIFESTED BY PERSISTENT INFLAMMATORY FLARES AND RELAPSE FOLLOWING MEDICATION WITHDRAWAL. 2023 19 3734 37 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 20 4040 23 MACROPHAGE PLASTICITY AND POLARIZATION: IN VIVO VERITAS. DIVERSITY AND PLASTICITY ARE HALLMARKS OF CELLS OF THE MONOCYTE-MACROPHAGE LINEAGE. IN RESPONSE TO IFNS, TOLL-LIKE RECEPTOR ENGAGEMENT, OR IL-4/IL-13 SIGNALING, MACROPHAGES UNDERGO M1 (CLASSICAL) OR M2 (ALTERNATIVE) ACTIVATION, WHICH REPRESENT EXTREMES OF A CONTINUUM IN A UNIVERSE OF ACTIVATION STATES. PROGRESS HAS NOW BEEN MADE IN DEFINING THE SIGNALING PATHWAYS, TRANSCRIPTIONAL NETWORKS, AND EPIGENETIC MECHANISMS UNDERLYING M1-M2 OR M2-LIKE POLARIZED ACTIVATION. FUNCTIONAL SKEWING OF MONONUCLEAR PHAGOCYTES OCCURS IN VIVO UNDER PHYSIOLOGICAL CONDITIONS (E.G., ONTOGENESIS AND PREGNANCY) AND IN PATHOLOGY (ALLERGIC AND CHRONIC INFLAMMATION, TISSUE REPAIR, INFECTION, AND CANCER). HOWEVER, IN SELECTED PRECLINICAL AND CLINICAL CONDITIONS, COEXISTENCE OF CELLS IN DIFFERENT ACTIVATION STATES AND UNIQUE OR MIXED PHENOTYPES HAVE BEEN OBSERVED, A REFLECTION OF DYNAMIC CHANGES AND COMPLEX TISSUE-DERIVED SIGNALS. THE IDENTIFICATION OF MECHANISMS AND MOLECULES ASSOCIATED WITH MACROPHAGE PLASTICITY AND POLARIZED ACTIVATION PROVIDES A BASIS FOR MACROPHAGE-CENTERED DIAGNOSTIC AND THERAPEUTIC STRATEGIES. 2012