1 5425 106 REGULATION OF MYELOPOIESIS BY THE TRANSCRIPTION FACTOR IRF8. INTERFERON REGULATORY FACTOR-8 (IRF8) IS A TRANSCRIPTION FACTOR EXPRESSED IN HEMATOPOIETIC CELLS, PARTICULARLY IN MONONUCLEAR PHAGOCYTES [MONOCYTES/MACROPHAGES AND DENDRITIC CELLS (DCS)] AND THEIR PROGENITORS. VARIOUS STUDIES HAVE DEMONSTRATED THAT IRF8 IS ESSENTIAL FOR THE DEVELOPMENT OF MONOCYTES, DCS, EOSINOPHILS, AND BASOPHILS. CONVERSELY, IRF8 SUPPRESSES THE GENERATION OF NEUTROPHILS. ACCORDINGLY, IRF8 (-/-) MICE DEVELOP IMMUNODEFICIENCY AND A CHRONIC MYELOID LEUKEMIA (CML)-LIKE DISEASE. MUTATIONS AND LOSS OF EXPRESSION OF THE HUMAN IRF8 GENE ARE ALSO ASSOCIATED WITH IMMUNODEFICIENCY AND CML, RESPECTIVELY. RECENT FINDINGS HAVE BEGUN TO REVEAL THE TRANSCRIPTION FACTOR NETWORK AND EPIGENETIC CHANGES GOVERNED BY IRF8. FOR EXAMPLE, IN MONONUCLEAR PHAGOCYTE PROGENITORS, IRF8 COOPERATES WITH PU.1 TO PROMOTE THE FORMATION OF PROMOTER-DISTAL ENHANCERS TO INDUCE MONOCYTE-RELATED GENES INCLUDING THE CRITICAL DOWNSTREAM TRANSCRIPTION FACTOR GENE KLF4. ON THE OTHER HAND, IRF8 BLOCKS C/EBPALPHA ACTIVITY TO SUPPRESS THE NEUTROPHIL DIFFERENTIATION PROGRAM. INDEED, IRF8 (-/-) MONONUCLEAR PHAGOCYTE PROGENITORS FAIL TO EFFICIENTLY GENERATE MONOCYTES AND DCS AND, INSTEAD, ABERRANTLY GIVE RISE TO NEUTROPHILS. THIS ARTICLE PROVIDES AN OVERVIEW OF RECENT ADVANCES IN OUR UNDERSTANDING OF THE ROLE OF IRF8 IN MYELOPOIESIS AND RELATED DISEASES. 2015 2 3701 24 INFLAMMATORY RESPONSE TO REGULATED CELL DEATH IN GOUT AND ITS FUNCTIONAL IMPLICATIONS. GOUT, A CHRONIC INFLAMMATORY ARTHRITIS DISEASE, IS CHARACTERIZED BY HYPERURICEMIA AND CAUSED BY INTERACTIONS BETWEEN GENETIC, EPIGENETIC, AND METABOLIC FACTORS. ACUTE GOUT SYMPTOMS ARE TRIGGERED BY THE INFLAMMATORY RESPONSE TO MONOSODIUM URATE CRYSTALS, WHICH IS MEDIATED BY THE INNATE IMMUNE SYSTEM AND IMMUNE CELLS (E.G., MACROPHAGES AND NEUTROPHILS), THE NACHT, LRR, AND PYD DOMAINS-CONTAINING PROTEIN 3 (NLRP3) INFLAMMASOME ACTIVATION, AND PRO-INFLAMMATORY CYTOKINE (E.G., IL-1BETA) RELEASE. RECENT STUDIES HAVE INDICATED THAT THE MULTIPLE PROGRAMMED CELL DEATH PATHWAYS INVOLVED IN THE INFLAMMATORY RESPONSE INCLUDE PYROPTOSIS, NETOSIS, NECROPTOSIS, AND APOPTOSIS, WHICH INITIATE INFLAMMATORY REACTIONS. IN THIS REVIEW, WE EXPLORE THE CORRELATION AND INTERACTIONS AMONG THESE FACTORS AND THEIR ROLES IN THE PATHOGENESIS OF GOUT TO PROVIDE FUTURE RESEARCH DIRECTIONS AND POSSIBILITIES FOR IDENTIFYING POTENTIAL NOVEL THERAPEUTIC TARGETS AND ENHANCING OUR UNDERSTANDING OF GOUT PATHOGENESIS. 2022 3 1482 27 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 4 4040 21 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 5 6591 25 TUMOR-ASSOCIATED MACROPHAGES AS A PARADIGM OF MACROPHAGE PLASTICITY, DIVERSITY, AND POLARIZATION: LESSONS AND OPEN QUESTIONS. MACROPHAGES ARE PRESENT IN ALL BODY COMPARTMENTS, INCLUDING CANCEROUS TISSUES, AND THEIR FUNCTIONS ARE PROFOUNDLY AFFECTED BY SIGNALS FROM THE MICROENVIRONMENT UNDER HOMEOSTATIC AND PATHOLOGICAL CONDITIONS. TUMOR-ASSOCIATED MACROPHAGES ARE A MAJOR CELLULAR COMPONENT OF CANCER-RELATED INFLAMMATION AND HAVE SERVED AS A PARADIGM FOR THE PLASTICITY AND FUNCTIONAL POLARIZATION OF MONONUCLEAR PHAGOCYTES. TUMOR-ASSOCIATED MACROPHAGES CAN EXERT DUAL INFLUENCE OF CANCER DEPENDING ON THE ACTIVATION STATE, WITH CLASSICALLY ACTIVATED (M1) AND ALTERNATIVELY ACTIVATED (M2) CELLS GENERALLY EXERTING ANTITUMORAL AND PROTUMORAL FUNCTIONS, RESPECTIVELY. THESE ARE EXTREMES IN A CONTINUUM OF POLARIZATION STATES IN A UNIVERSE OF DIVERSITY. TUMOR-ASSOCIATED MACROPHAGES AFFECT VIRTUALLY ALL ASPECTS OF TUMOR TISSUES, INCLUDING STEM CELLS, METABOLISM, ANGIOGENESIS, INVASION, AND METASTASIS. PROGRESS HAS BEEN MADE IN DEFINING SIGNALING MOLECULES, TRANSCRIPTION FACTORS, EPIGENETIC CHANGES, AND REPERTOIRE OF MICRORNAS UNDERLYING MACROPHAGE POLARIZATION. PRECLINICAL AND EARLY CLINICAL DATA SUGGEST THAT MACROPHAGES MAY SERVE AS TOOLS FOR THE DEVELOPMENT OF INNOVATIVE DIAGNOSTIC AND THERAPEUTIC STRATEGIES IN CANCER AND CHRONIC NONRESOLVING INFLAMMATORY DISEASES. 2013 6 1033 24 CITRULLINATION OF AUTOANTIGENS IMPLICATES NETOSIS IN THE INDUCTION OF AUTOIMMUNITY. TOLERANCE BLOCKS THE EXPRESSION OF AUTOANTIBODIES, WHEREAS AUTOIMMUNITY PROMOTES IT. HOW TOLERANCE BREAKS AND AUTOANTIBODY PRODUCTION BEGINS THUS ARE CRUCIAL QUESTIONS FOR UNDERSTANDING AND TREATMENT OF AUTOIMMUNE DISEASES. EVIDENCE IMPLICATES CELL DEATH AND AUTOANTIGEN MODIFICATIONS IN THE INITIATION OF AUTOIMMUNE REACTIONS. ONE FORM OF NEUTROPHIL CELL DEATH CALLED NETOSIS DESERVES ATTENTION BECAUSE IT REQUIRES THE POST-TRANSLATIONAL MODIFICATION OF HISTONES AND RESULTS IN THE EXTRACELLULAR RELEASE OF CHROMATIN. NETOSIS RECEIVED ITS NAME FROM NET, THE ACRONYM GIVEN TO NEUTROPHIL EXTRACELLULAR TRAP. THE EXTRACELLULAR CHROMATIN INCORPORATES HISTONES IN WHICH ARGININES HAVE BEEN CONVERTED TO CITRULLINES BY PEPTIDYLARGININE DEIMINASE IV (PAD4). THE DEIMINATED CHROMATIN MAY FUNCTION TO CAPTURE OR 'TRAP' BACTERIAL PATHOGENS, THUS GENERATING AN EXTRACELLULAR COMPLEX OF DEIMINATED HISTONES AND BACTERIAL CELL ADJUVANTS. THE COMPLEX OF BACTERIAL ANTIGENS AND DEIMINATED CHROMATIN MAY BE INTERNALISED BY HOST PHAGOCYTES DURING ACUTE INFLAMMATORY CONDITIONS, AS ARISE DURING BACTERIAL INFECTIONS OR CHRONIC AUTOINFLAMMATORY DISORDERS. THE UPTAKE AND PROCESSING OF DEIMINATED CHROMATIN TOGETHER WITH BACTERIAL ADJUVANTS BY PHAGOCYTES MAY INDUCE THE PRESENTATION OF MODIFIED HISTONE EPITOPES AND CO-STIMULATION, THUS YIELDING A POWERFUL STIMULUS TO BREAK TOLERANCE. AUTOANTIBODIES TO DEIMINATED HISTONES ARE PREVALENT IN FELTY'S SYNDROME PATIENTS AND ARE PRESENT IN SYSTEMIC LUPUS ERYTHEMATOSUS (SLE) AND PATIENTS WITH RHEUMATOID ARTHRITIS (RA). THESE OBSERVATIONS CLEARLY IMPLICATE HISTONE DEIMINATION AS AN EPIGENETIC MARK THAT CAN ACT AS AN AUTOANTIBODY STIMULANT. 2014 7 6394 32 THE ROLE OF THE HOST-NEUTROPHIL BIOLOGY. NEUTROPHILIC POLYMORPHONUCLEAR LEUKOCYTES (NEUTROPHILS) ARE MYELOID CELLS PACKED WITH LYSOSOMAL GRANULES (HENCE ALSO CALLED GRANULOCYTES) THAT CONTAIN A FORMIDABLE ANTIMICROBIAL ARSENAL. THEY ARE TERMINALLY DIFFERENTIATED CELLS THAT PLAY A CRITICAL ROLE IN ACUTE AND CHRONIC INFLAMMATION, AS WELL AS IN THE RESOLUTION OF INFLAMMATION AND WOUND HEALING. NEUTROPHILS EXPRESS A DENSE ARRAY OF SURFACE RECEPTORS FOR MULTIPLE LIGANDS, RANGING FROM INTEGRINS TO SUPPORT THEIR EGRESS FROM BONE MARROW INTO THE CIRCULATION AND FROM THE CIRCULATION INTO TISSUES, TO CYTOKINE/CHEMOKINE RECEPTORS THAT DRIVE THEIR NAVIGATION TO THE SITE OF INFECTION OR TISSUE DAMAGE AND ALSO PRIME THEM FOR A SECOND STIMULUS, TO PATTERN RECOGNITION RECEPTORS AND IMMUNOGLOBULIN RECEPTORS TO FACILITATE THE DESTRUCTION AND REMOVAL OF INFECTIVE AGENTS OR DEBRIDEMENT OF DAMAGED TISSUES. WHEN AFFERENT NEUTROPHIL SIGNALS ARE PROPORTIONATE AND COORDINATED THEY WILL PHAGOCYTOSE OPSONIZED AND UNOPSONIZED BACTERIA, ACTIVATING THE NICOTINAMIDE ADENINE DINUCLEOTIDE PHOSPHATE OXIDASE (RESPIRATORY BURST) TO GENERATE REACTIVE OXYGEN SPECIES, WHICH AUGMENT THE PROTEOLYTIC DESTRUCTION OF MICROBES SECURED WITHIN THE PHAGOSOME. A HIGHLY ORCHESTRATED PROCESS OF APOPTOSIS FOLLOWS, FORMING MEMBRANE-BOUND SUBSTRUCTURES THAT ARE REMOVED BY MACROPHAGES. NEUTROPHILS ARE CAPABLE OF VARIOUS OTHER FORMS OF PROGRAMMED CELL DEATH, SUCH AS NETOSIS AND PYROPTOTIC CELL DEATH, AS WELL AS NONPROGRAMMED CELL DEATH BY NECROSIS. IN RECENT YEARS, RESEARCH HAS REVEALED THAT NEUTROPHILS ARE CAPABLE OF FAR MORE SUBTLE CELL-CELL INTERACTIONS THAN PREVIOUSLY THOUGHT POSSIBLE. THIS INCLUDES SYNTHESIS OF VARIOUS INFLAMMATORY MEDIATORS AND ALSO MYELOID CELL TRAINING WITHIN BONE MARROW, WHERE EPIGENETIC AND METABOLIC SIGNALS ASSOCIATED WITH RETURNING NEUTROPHILS THAT UNDERGO REVERSE EGRESS FROM TISSUES INTO THE VASCULATURE AND BACK TO BONE MARROW PROGRAM A HYPERREACTIVE SUBSET OF NEUTROPHILS DURING MYELOPOIESIS THAT ARE CAPABLE OF HYPERSENSITIVE REACTIONS TO MICROBIAL AGGRESSORS. THESE CHARACTERISTICS ARE EVIDENT IN VARIOUS NEUTROPHIL SUBSETS/SUBPOPULATIONS, CREATING BROAD HETEROGENEITY IN THE BEHAVIOR AND BIOLOGICAL REPERTOIRE OF THESE SEEMINGLY SCHIZOPHRENIC IMMUNE CELLS. MOREOVER, NEUTROPHILS ARE CRITICAL EFFECTOR CELLS OF ADAPTIVE AND INNATE IMMUNITY, BINDING TO OPSONIZED BACTERIA AND DESTROYING THEM BY EXTRACELLULAR AND INTRACELLULAR METHODS. THE FORMER CREATES SUBSTANTIAL COLLATERAL HOST TISSUE DAMAGE, AS THEY ARE LESS SPECIFIC THAN T-CYTOTOXIC CELL-KILLING MECHANISMS, AND IN CONDITIONS SUCH AS PERI-IMPLANTITIS, WHERE PLASMA CELLS AND NEUTROPHILS DOMINATE THE IMMUNE INFILTRATE, BONE AND TISSUE DESTRUCTION ARE RAPID AND APPEAR RELENTLESS. FINALLY, THE ROLE OF NEUTROPHILS AS CONDUITS FOR PERIODONTAL-SYSTEMIC DISEASE CONNECTIONS AND FOR OXIDATIVE DAMAGE TO ACT AS A CAUSAL LINK BETWEEN THE TWO HAS ONLY RECENTLY BEEN REALIZED. IN THIS CHAPTER, WE ATTEMPT TO EXPAND ON THESE ISSUES, EMPHASIZING THE CONTRIBUTIONS OF EUROPEAN SCIENTISTS THROUGHOUT A DETAILED APPRAISAL OF THE BENEFITS AND SIDE EFFECTS OF NEUTROPHILIC INFLAMMATION AND IMMUNE FUNCTION. 2023 8 3732 23 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 9 4044 23 MACROPHAGES IN OXIDATIVE STRESS AND MODELS TO EVALUATE THE ANTIOXIDANT FUNCTION OF DIETARY NATURAL COMPOUNDS. ANTIOXIDANT TESTING OF NATURAL PRODUCTS HAS ATTRACTED INCREASING INTEREST IN RECENT YEARS, MAINLY DUE TO THE FACT THAT AN ANTIOXIDANT-RICH DIET MIGHT PROVIDE HEALTH BENEFITS. ACTIVATED MACROPHAGES ARE A MAJOR SOURCE OF REACTIVE OXYGEN SPECIES, REACTIVE NITROGEN SPECIES, AND PEROXYNITRITE GENERATED THROUGH THE SO-CALLED RESPIRATORY BURST. CONSTITUTIVELY RELEASED PROINFLAMMATORY CYTOKINE, ESPECIALLY TUMOR NECROSIS FACTOR-ALPHA, TRIGGERS NUCLEAR FACTOR-KAPPAB, AND ACTIVATOR PROTEIN-1 TRANSLOCATION LEADING TO THE OVER PRODUCTION OF REACTIVE OXYGEN SPECIES AND REACTIVE NITROGEN SPECIES IN MACROPHAGES. ACTIVATION OF TRANSCRIPTION FACTORS IN THE LONG-LIVED TISSUE-RESIDENT MACROPHAGES AND/OR MONOCYTE-DERIVED MACROPHAGES, TRIGGER EPIGENETIC MODIFICATIONS LEADING TO THE PATHOGENESIS OF CHRONIC DISEASES. NUTRACEUTICALS INCLUDING LIPID RAFT STRUCTURE DISRUPTION AGENT, CHOLESTEROL DEPLETION AGENT, FARNESYLTRANSFERASE INHIBITOR, NUCLEAR FACTOR-KAPPAB BLOCKER (ALPHA,BETA-UNSATURATED CARBONYL COMPOUNDS), GLUCOCORTICOID RECEPTOR AGONIST, AND PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA AGONIST HAVE LONG BEEN USED TO INACTIVE MACROPHAGE. THE INHIBITION EFFECTS ON THE FORMATION OF NITRIC OXIDE, SUPEROXIDE, AND NITRITE PEROXIDE MAY BE RESPONSIBLE FOR THE ANTI-INFLAMMATORY FUNCTIONALITIES. ACTIVATED MACROPHAGE MODELS COULD BE USED TO IDENTIFY THE ACTIVE COMPONENTS FOR FUNCTIONAL DIETS DEVELOPMENT THROUGH A MULTIPLE TARGETS STRATEGY. 2017 10 5423 23 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 11 6502 22 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 12 4041 26 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 13 1349 30 DETERMINANTS OF INNATE IMMUNITY IN VISCERAL LEISHMANIASIS AND THEIR IMPLICATION IN VACCINE DEVELOPMENT. LEISHMANIASIS IS ENDEMIC TO THE TROPICAL AND SUBTROPICAL REGIONS OF THE WORLD AND IS TRANSMITTED BY THE BITE OF AN INFECTED SAND FLY. THE MULTIFACETED INTERACTIONS BETWEEN LEISHMANIA, THE HOST INNATE IMMUNE CELLS, AND THE ADAPTIVE IMMUNITY DETERMINE THE SEVERITY OF PATHOGENESIS AND DISEASE DEVELOPMENT. LEISHMANIA PARASITES ESTABLISH A CHRONIC INFECTION BY SUBVERSION AND ATTENUATION OF THE MICROBICIDAL FUNCTIONS OF PHAGOCYTIC INNATE IMMUNE CELLS SUCH AS NEUTROPHILS, MACROPHAGES AND DENDRITIC CELLS (DCS). OTHER INNATE CELLS SUCH AS INFLAMMATORY MONOCYTES, MAST CELLS AND NK CELLS, ALSO CONTRIBUTE TO RESISTANCE AND/OR SUSCEPTIBILITY TO LEISHMANIA INFECTION. IN ADDITION TO THE CYTOKINE/CHEMOKINE SIGNALS FROM THE INNATE IMMUNE CELLS, RECENT STUDIES IDENTIFIED THE SUBTLE SHIFTS IN THE METABOLIC PATHWAYS OF THE INNATE CELLS THAT ACTIVATE DISTINCT IMMUNE SIGNAL CASCADES. THE NEXUS BETWEEN METABOLIC PATHWAYS, EPIGENETIC REPROGRAMMING AND THE IMMUNE SIGNALING CASCADES THAT DRIVE THE DIVERGENT INNATE IMMUNE RESPONSES, REMAINS TO BE FULLY UNDERSTOOD IN LEISHMANIA PATHOGENESIS. FURTHER, DEVELOPMENT OF SAFE AND EFFICACIOUS VACCINES AGAINST LEISHMANIASIS REQUIRES A BROADER UNDERSTANDING OF THE EARLY INTERACTIONS BETWEEN THE PARASITES AND INNATE IMMUNE CELLS. IN THIS REVIEW WE FOCUS ON THE CURRENT UNDERSTANDING OF THE SPECIFIC ROLE OF INNATE IMMUNE CELLS, THE METABOLOMIC AND EPIGENETIC REPROGRAMMING AND IMMUNE REGULATION THAT OCCURS DURING VISCERAL LEISHMANIASIS, AND THE STRATEGIES USED BY THE PARASITE TO EVADE AND MODULATE HOST IMMUNITY. WE HIGHLIGHT HOW SUCH PATHWAYS COULD BE EXPLOITED IN THE DEVELOPMENT OF SAFE AND EFFICACIOUS LEISHMANIA VACCINES. 2021 14 2067 26 EPIGENETIC CONTROL OF MACROPHAGE SHAPE TRANSITION TOWARDS AN ATYPICAL ELONGATED PHENOTYPE BY HISTONE DEACETYLASE ACTIVITY. INFLAMMATORY CHRONIC PATHOLOGIES ARE COMPLEX PROCESSES CHARACTERIZED BY AN IMBALANCE BETWEEN THE RESOLUTION OF THE INFLAMMATORY PHASE AND THE ESTABLISHMENT OF TISSUE REPAIR. THE MAIN PLAYERS IN THESE INFLAMMATORY PATHOLOGIES ARE BONE MARROW DERIVED MONOCYTES (BMDMS). HOWEVER, HOW MONOCYTE DIFFERENTIATION IS MODULATED TO GIVE RISE TO SPECIFIC MACROPHAGE SUBPOPULATIONS (M1 OR M2) THAT MAY EITHER MAINTAIN THE CHRONIC INFLAMMATORY PROCESS OR LEAD TO WOUND HEALING IS STILL UNCLEAR. CONSIDERING THAT INHIBITORS OF HISTONE DEACETYLASE (HDAC) HAVE AN ANTI-INFLAMMATORY ACTIVITY, WE ASKED WHETHER THIS ENZYME WOULD PLAY A ROLE ON MONOCYTE DIFFERENTIATION INTO M1 OR M2 PHENOTYPE AND IN THE CELL SHAPE TRANSITION THAT FOLLOWS. WE THEN INDUCED MURINE BONE MARROW PROGENITORS INTO MONOCYTE/MACROPHAGE DIFFERENTIATION PATHWAY USING MEDIA CONTAINING GM-CSF AND THE HDAC BLOCKER, TRICHOSTATIN A (TSA). WE FOUND THAT THE PHARMACOLOGICAL INHIBITION OF HDAC ACTIVITY LED TO A SHAPE TRANSITION FROM THE TYPICAL MACROPHAGE PANCAKE-LIKE SHAPE INTO AN ELONGATED MORPHOLOGY, WHICH WAS CORRELATED TO A MIXED M1/M2 PROFILE OF CYTOKINE AND CHEMOKINE SECRETION. OUR RESULTS PRESENT, FOR THE FIRST TIME, THAT HDAC ACTIVITY ACTS AS A REGULATOR OF MACROPHAGE DIFFERENTIATION IN THE ABSENCE OF LYMPHOCYTE STIMULI. WE PROPOSE THAT HDAC ACTIVITY DOWN REGULATES MACROPHAGE PLASTICITY FAVORING THE PRO-INFLAMMATORY PHENOTYPE. 2015 15 2342 23 EPIGENETIC REGULATION OF MACROPHAGE POLARIZATION AND FUNCTION. MACROPHAGE POLARIZATION REFERS TO DEVELOPMENT OF A SPECIFIC PHENOTYPE IMPORTANT FOR TISSUE HOMEOSTASIS OR HOST DEFENSE IN RESPONSE TO ENVIRONMENTAL CUES. ENVIRONMENTAL FACTORS THAT INDUCE MACROPHAGE POLARIZATION INCLUDE CYTOKINES AND MICROBIAL FACTORS PRODUCED BY PATHOGENS OR COMMENSAL MICROBIOTA. SIGNALING PATHWAYS UTILIZED BY THESE POLARIZING FACTORS HAVE BEEN WELL CHARACTERIZED, BUT IT IS LESS CLEAR HOW SIGNALS ARE CONVERTED INTO COMPLEX AND SUSTAINED PATTERNS OF GENE EXPRESSION, AND HOW MACROPHAGES ARE REPROGRAMMED DURING POLARIZATION TO ALTER THEIR RESPONSES TO SUBSEQUENT ENVIRONMENTAL CHALLENGES. EMERGING EVIDENCE, REVIEWED HERE, SUGGESTS AN IMPORTANT ROLE FOR EPIGENETIC MECHANISMS IN MODULATING AND TRANSMITTING SIGNALS DURING MACROPHAGE POLARIZATION AND REPROGRAMMING. DEEPER UNDERSTANDING OF EPIGENETIC REGULATION OF MACROPHAGE PHENOTYPE WILL ENABLE DEVELOPMENT OF GENE-SPECIFIC THERAPEUTIC APPROACHES TO ENHANCE HOST DEFENSE WHILE PRESERVING TISSUE INTEGRITY AND PREVENTING CHRONIC INFLAMMATORY DISEASES. 2013 16 6376 27 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 17 3734 30 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 18 4510 37 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 19 2697 23 EX VIVO MODELS OF CHRONIC GRANULOMATOUS DISEASE. INDUCED PLURIPOTENT STEM CELLS (IPSCS) ARE PLURIPOTENT STEM CELLS THAT CAN BE ESTABLISHED FROM DEDIFFERENTIATION OF ALL SOMATIC CELL TYPES BY EPIGENETIC PHENOMENA. IPSCS CAN BE DIFFERENTIATED INTO ANY MATURE CELLS LIKE NEURONS, HEPATOCYTES, OR PANCREATIC CELLS THAT HAVE NOT BEEN EASILY AVAILABLE TO DATE. THUS, IPSCS ARE WIDELY USED FOR DISEASE MODELING, DRUG DISCOVERY, AND CELL THERAPY DEVELOPMENT. HERE, WE DESCRIBE A PROTOCOL TO OBTAIN HUMAN MATURE AND FUNCTIONAL NEUTROPHILS AND MACROPHAGES AS EX VIVO MODELS OF X-LINKED CHRONIC GRANULOMATOUS DISEASE (X-CGD). THIS METHOD CAN BE APPLIED TO MODEL THE OTHER GENETIC FORMS OF CGD. WE ALSO DESCRIBE METHODS FOR TESTING THE CHARACTERISTICS AND FUNCTIONS OF NEUTROPHILS AND MACROPHAGES BY MORPHOLOGY, PHAGOCYTOSIS ASSAY, RELEASE OF GRANULE MARKERS OR CYTOKINES, CELL SURFACE MARKERS, AND NADPH OXIDASE ACTIVITY. 2019 20 3184 27 HARNESSING METABOLISM OF HEPATIC MACROPHAGES TO AID LIVER REGENERATION. LIVER REGENERATION IS A DYNAMIC AND REGULATED PROCESS THAT INVOLVES INFLAMMATION, GRANULATION, AND TISSUE REMODELING. HEPATIC MACROPHAGES, ABUNDANTLY DISTRIBUTED IN THE LIVER, ARE ESSENTIAL COMPONENTS THAT ACTIVELY PARTICIPATE IN EACH STEP TO ORCHESTRATE LIVER REGENERATION. IN THE HOMEOSTATIC LIVER, RESIDENT MACROPHAGES (KUPFFER CELLS) ACQUIRE A TOLEROGENIC PHENOTYPE AND CONTRIBUTE TO IMMUNOLOGICAL TOLERANCE. FOLLOWING TOXICITY-INDUCED DAMAGE OR PHYSICAL RESECTION, KUPFFER CELLS AS WELL AS MONOCYTE-DERIVED MACROPHAGES CAN BE ACTIVATED AND PROMOTE AN INFLAMMATORY PROCESS THAT SUPPORTS THE SURVIVAL AND ACTIVATION OF HEPATIC MYOFIBROBLASTS AND THUS PROMOTES SCAR TISSUE FORMATION. SUBSEQUENTLY, THESE MACROPHAGES, IN TURN, EXHIBIT THE ANTI-INFLAMMATORY EFFECTS CRITICAL TO EXTRACELLULAR MATRIX REMODELING DURING THE RESOLUTION STAGE. HOWEVER, CONTINUOUS DAMAGE-INDUCED CHRONIC INFLAMMATION GENERALLY LEADS TO HEPATIC MACROPHAGE DYSFUNCTION, WHICH EXACERBATES HEPATOCELLULAR INJURY AND TRIGGERS FURTHER LIVER FIBROSIS AND EVEN CIRRHOSIS. EMERGING MACROPHAGE-TARGETING STRATEGIES HAVE SHOWN EFFICACY IN BOTH PRECLINICAL AND CLINICAL STUDIES. INCREASING EVIDENCE INDICATES THAT METABOLIC REWIRING PROVIDES SUBSTRATES FOR EPIGENETIC MODIFICATION, WHICH ENDOWS MONOCYTES/MACROPHAGES WITH PROLONGED "INNATE IMMUNE MEMORY". THEREFORE, IT IS REASONABLE TO CONCEIVE NOVEL THERAPEUTIC STRATEGIES FOR METABOLICALLY REPROGRAMMING MACROPHAGES AND THUS MEDIATE A HOMEOSTATIC OR REPARATIVE PROCESS FOR HEPATIC INFLAMMATION MANAGEMENT AND LIVER REGENERATION. 2023