1 4510 191 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 2 4332 54 MICRORNAS: IMPORTANT MODULATORS OF OXLDL-MEDIATED SIGNALING IN ATHEROSCLEROSIS. OXIDIZED LOW-DENSITY LIPOPROTEIN (OXLDL) IS KNOWN TO BE A MAJOR RISK FACTOR FOR THE INITIATION AND DEVELOPMENT OF ATHEROSCLEROSIS. IT CAN ELICIT AN ARRAY OF ATHEROGENIC RESPONSES IN MULTIPLE TYPES OF CELLS RESIDING IN THE ARTERIAL WALL, SUCH AS ENDOTHELIAL CELLS (ECS), MACROPHAGES, DENDRITIC CELLS (DCS), AND VASCULAR SMOOTH MUSCLE CELLS (VSMCS). ALTHOUGH THEY HAVE BEEN STUDIED FOR MANY YEARS, THE DETAILED MECHANISMS MODULATING OXLDL-INDUCED INFLAMMATION HAVE NOT BEEN FULLY ELUCIDATED. EPIGENETIC MECHANISMS CONSIST OF DNA METHYLATION, HISTONE POST-TRANSLATIONAL MODIFICATIONS (PTMS), AND MICRORNA (MIRNA) ALTERATIONS. RECENTLY, EPIGENETIC FACTORS, ESPECIALLY MIRNAS, HAVE EMERGED AS NOVEL COMPONENTS OF THE GENE EXPRESSION REGULATING OXLDL-TRIGGERED SIGNAL TRANSDUCTION. IN ADDITION TO THEIR REGULATORY ROLES IN SIGNALING MOLECULES, INCREASING EVIDENCE SUGGESTS THAT THE DIFFERENT GENETIC STABILITY AND CROSS-TALK REGULATION AMONG THESE EPIGENETIC FACTORS MAY BE PARTICULARLY IMPORTANT TO THE SUSTAINED INFLAMMATION INITIATED BY TEMPORAL OXLDL STIMULATION. THEREFORE, IN THIS REVIEW, WE PRIMARILY FOCUSED ON THE FUNCTIONAL ROLE OF MIRNAS, AS WELL AS OTHER EPIGENETIC FACTORS, ON MODULATING OXLDL-INDUCED SIGNAL TRANSDUCTION IN DIFFERENT VASCULAR CELLS, WITH A SPECIAL EMPHASIS ON THE CROSSTALK INTERACTIONS BETWEEN MIRNAS AND OTHER EPIGENETIC PLAYERS THAT HELP TRANSLATE TRANSIENT ENVIRONMENT INSULTS INTO CHRONIC INFLAMMATION. MOREOVER, WE EXTENSIVELY DISCUSSED THE POTENTIAL APPLICABILITY OF MIRNAS AS DISEASE BIOMARKERS AND THERAPEUTIC TARGETS IN DIAGNOSING AND TREATING ATHEROSCLEROSIS. 2013 3 3342 42 HISTONE DEACETYLASE9 REPRESENTS THE EPIGENETIC PROMOTION OF M1 MACROPHAGE POLARIZATION AND INFLAMMATORY RESPONSE VIA TLR4 REGULATION. ATHEROSCLEROSIS IS A CHRONIC INFLAMMATORY RESPONSE MEDIATED BY VARIOUS FACTORS, WHERE EPIGENETIC REGULATION INVOLVING HISTONE DEACETYLATION IS ENVISAGED TO MODULATE THE EXPRESSION OF RELATED PROTEINS BY REGULATING THE BINDING OF TRANSCRIPTION FACTORS TO DNA, THEREBY INFLUENCING THE DEVELOPMENT OF ATHEROSCLEROSIS. THE MECHANISM OF ATHEROSCLEROSIS BY HISTONE DEACETYLATION IS PARTLY KNOWN; HENCE, THIS PROJECT AIMED AT INVESTIGATING THE ROLE OF HISTONE DEACETYLASE 9 (HDAC9) IN ATHEROSCLEROSIS. FOR THIS PURPOSE, SERUM WAS SEPARATED FROM BLOOD SAMPLES FOLLOWING CLOTTING AND CENTRIFUGATION FROM ATHEROSCLEROTIC AND HEALTHY PATIENTS (N = 40 EACH), AND THEN, VARIOUS TESTS WERE PERFORMED. THE RESULTS INDICATED THAT TOLL-LIKE RECEPTOR 4 (TLR4) WAS NOT ONLY POSITIVELY CORRELATED TO THE HDAC9 GENE, BUT WAS ALSO UPREGULATED IN ATHEROSCLEROSIS, WHERE IT WAS ALSO SIGNIFICANTLY UPREGULATED IN THE ATHEROSCLEROSIS CELL MODEL OF OXIDIZED LOW-DENSITY LIPOPROTEIN-INDUCED MACROPHAGES. CONVERSELY, THE TLR4 WAS SIGNIFICANTLY DOWNREGULATED IN INSTANCES OF LOSS OF HDAC9 FUNCTION, CEMENTING THE BRIDGING RELATIONSHIP BETWEEN HDAC9 AND MACROPHAGE POLARIZATION, WHERE THE HDAC9 WAS FOUND TO UPREGULATE M1 MACROPHAGE POLARIZATION WHICH TRANSLATED INTO THE RELEASE OF HIGHER CONTENT OF PROINFLAMMATORY CYTOKINES SUCH AS INTERLEUKIN-1BETA (IL-1BETA) AND TUMOR NECROSIS FACTOR-ALPHA (TNF-ALPHA), WHICH TEND TO SIGNIFICANTLY DECREASE FOLLOWING THE DELETION OF TLR4. HENCE, THIS STUDY REPORTS NOVEL RELATION BETWEEN EPIGENETIC CONTROL AND ATHEROSCLEROSIS, WHICH COULD PARTLY BE EXPLAINED BY HISTONE DEACETYLATION. 2022 4 6493 62 TRAINED IMMUNITY AND REACTIVITY OF MACROPHAGES AND ENDOTHELIAL CELLS. INNATE IMMUNE CELLS CAN DEVELOP EXACERBATED IMMUNOLOGIC RESPONSE AND LONG-TERM INFLAMMATORY PHENOTYPE FOLLOWING BRIEF EXPOSURE TO ENDOGENOUS OR EXOGENOUS INSULTS, WHICH LEADS TO AN ALTERED RESPONSE TOWARDS A SECOND CHALLENGE AFTER THE RETURN TO A NONACTIVATED STATE. THIS PHENOMENON IS KNOWN AS TRAINED IMMUNITY (TI). TI IS NOT ONLY IMPORTANT FOR HOST DEFENSE AND VACCINE RESPONSE BUT ALSO FOR CHRONIC INFLAMMATIONS SUCH AS CARDIOVASCULAR AND METABOLIC DISEASES SUCH AS ATHEROSCLEROSIS. TI CAN OCCUR IN INNATE IMMUNE CELLS SUCH AS MONOCYTES/MACROPHAGES, NATURAL KILLER CELLS, ENDOTHELIAL CELLS (ECS), AND NONIMMUNE CELLS, SUCH AS FIBROBLAST. IN THIS BRIEF REVIEW, WE ANALYZE THE SIGNIFICANCE OF TI IN ECS, WHICH ARE ALSO CONSIDERED AS INNATE IMMUNE CELLS IN ADDITION TO MACROPHAGES. TI CAN BE INDUCED BY A VARIETY OF STIMULI, INCLUDING LIPOPOLYSACCHARIDES, BCG (BACILLUS CALMETTE-GUERIN), AND OXLDL (OXIDIZED LOW-DENSITY LIPOPROTEIN), WHICH ARE DEFINED AS RISK FACTORS FOR CARDIOVASCULAR AND METABOLIC DISEASES. FURTHERMORE, TI IN ECS IS FUNCTIONAL FOR INFLAMMATION EFFECTIVENESS AND TRANSITION TO CHRONIC INFLAMMATION. REWIRING OF CELLULAR METABOLISM OF THE TRAINED CELLS TAKES PLACE DURING INDUCTION OF TI, INCLUDING INCREASED GLYCOLYSIS, GLUTAMINOLYSIS, INCREASED ACCUMULATION OF TRICARBOXYLIC ACID CYCLE METABOLITES AND ACETYL-COENZYME A PRODUCTION, AS WELL AS INCREASED MEVALONATE SYNTHESIS. SUBSEQUENTLY, THIS LEADS TO EPIGENETIC REMODELING, RESULTING IN IMPORTANT CHANGES IN CHROMATIN ARCHITECTURE THAT ENABLES INCREASED GENE TRANSCRIPTION AND ENHANCED PROINFLAMMATORY IMMUNE RESPONSE. HOWEVER, TI PATHWAYS AND INFLAMMATORY PATHWAYS ARE SEPARATED TO ENSURE MEMORY STAYS WHEN INFLAMMATION UNDERGOES RESOLUTION. ADDITIONALLY, REACTIVE OXYGEN SPECIES PLAY CONTEXT-DEPENDENT ROLES IN TI. THEREFORE, TI PLAYS SIGNIFICANT ROLES IN EC AND MACROPHAGE PATHOLOGY AND CHRONIC INFLAMMATION. HOWEVER, FURTHER CHARACTERIZATION OF TI IN ECS AND MACROPHAGES WOULD PROVIDE NOVEL INSIGHTS INTO CARDIOVASCULAR DISEASE PATHOGENESIS AND NEW THERAPEUTIC TARGETS. GRAPHIC ABSTRACT: A GRAPHIC ABSTRACT IS AVAILABLE FOR THIS ARTICLE. 2021 5 4598 35 NATURAL PRODUCTS: THE ROLE AND MECHANISM IN LOW-DENSITY LIPOPROTEIN OXIDATION AND ATHEROSCLEROSIS. ATHEROSCLEROSIS IS A CHRONIC INFLAMMATORY, METABOLIC, AND EPIGENETIC DISEASE, WHICH LEADS TO THE LIFE-THREATENING CORONARY ARTERY DISEASE. EMERGING STUDIES FROM BENCH TO BEDSIDE HAVE DEMONSTRATED THE PIVOTAL ROLE OF LOW-DENSITY LIPOPROTEIN (LDL) OXIDATION IN THE INITIATION AND PROGRESSION OF ATHEROSCLEROSIS. THIS ARTICLE HEREBY REVIEWS OXIDATION MECHANISM OF LDL, AND THE PRO-ATHEROGENIC AND BIOMARKER ROLE OF OXIDIZED LDL IN ATHEROSCLEROSIS. WE ALSO REVIEW THE PHARMACOLOGICAL EFFECTS OF SEVERAL REPRESENTATIVE NATURAL PRODUCTS (VITAMIN E, RESVERATROL, QUERCETIN, PROBUCOL, TANSHINONE IIA, EPIGALLOCATECHIN GALLATE, AND LYCOPENE) IN PROTECTING AGAINST LDL OXIDATION AND ATHEROSCLEROSIS. CLINICAL AND BASIC RESEARCH SUPPORTS THE BENEFICIAL EFFECTS OF THESE NATURAL PRODUCTS IN INHIBITING LDL OXIDATION AND PREVENTING ATHEROSCLEROSIS, BUT THE DATA ARE STILL CONTROVERSIAL. THIS MAY BE RELATED TO FACTORS SUCH AS THE POPULATION AND THE DOSAGE AND TIME OF TAKING NATURAL PRODUCTS INVOLVED IN DIFFERENT STUDIES. UNDERSTANDING THE MECHANISM OF LDL OXIDATION AND EFFECT OF OXIDIZED LDL HELP RESEARCHERS TO FIND NOVEL THERAPIES AGAINST ATHEROSCLEROSIS. 2021 6 6502 45 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 7 3729 50 INHIBITION OF TET1 PREVENTS THE DEVELOPMENT OF OSTEOARTHRITIS AND REVEALS THE 5HMC LANDSCAPE THAT ORCHESTRATES PATHOGENESIS. OSTEOARTHRITIS (OA) IS A DEGENERATIVE DISEASE OF THE JOINT, WHICH RESULTS IN PAIN, LOSS OF MOBILITY, AND, EVENTUALLY, JOINT REPLACEMENT. CURRENTLY, NO DISEASE-MODIFYING DRUGS EXIST, PARTLY BECAUSE OF THE MULTIPLE LEVELS AT WHICH CARTILAGE HOMEOSTASIS IS DISRUPTED. RECENT STUDIES HAVE HIGHLIGHTED THE IMPORTANCE OF EPIGENETIC DYSREGULATION IN OA, SPARKING INTEREST IN THE EPIGENETIC MODULATION FOR THIS DISEASE. IN OUR PREVIOUS WORK, WE CHARACTERIZED A FIVEFOLD INCREASE IN CYTOSINE HYDROXYMETHYLATION (5HMC), AN OXIDIZED DERIVATIVE OF CYTOSINE METHYLATION (5MC) ASSOCIATED WITH GENE ACTIVATION, ACCUMULATING AT OA-ASSOCIATED GENES. TO TEST THE ROLE OF 5HMC IN OA, HERE, WE USED A MOUSE MODEL OF SURGICALLY INDUCED OA AND FOUND THAT OA ONSET WAS ACCOMPANIED BY A GAIN OF ~40,000 DIFFERENTIALLY HYDROXYMETHYLATED SITES BEFORE THE NOTABLE HISTOLOGICAL APPEARANCE OF DISEASE. WE DEMONSTRATED THAT TEN-ELEVEN-TRANSLOCATION ENZYME 1 (TET1) MEDIATES THE 5HMC DEPOSITION BECAUSE 98% OF SITES ENRICHED FOR 5HMC IN OA WERE LOST IN TET1(-/-) MICE. LOSS OF TET1-MEDIATED 5HMC PROTECTED THE TET1(-/-) MICE FROM OA DEVELOPMENT, INCLUDING DEGENERATION OF THE CARTILAGE SURFACE AND OSTEOPHYTE FORMATION, BY DIRECTLY PREVENTING THE ACTIVATION OF MULTIPLE OA PATHWAYS. LOSS OF TET1 IN HUMAN OA CHONDROCYTES REDUCED THE EXPRESSION OF THE MATRIX METALLOPROTEINASES MMP3 AND MMP13 AND MULTIPLE INFLAMMATORY CYTOKINES. INTRA-ARTICULAR INJECTIONS OF A DIOXYGENASES INHIBITOR, 2-HYDROXYGLUTARATE, ON MICE AFTER SURGICAL INDUCTION OF OA STALLED DISEASE PROGRESSION. TREATMENT OF HUMAN OA CHONDROCYTES WITH THE SAME INHIBITOR ALSO PHENOCOPIED TET1 LOSS. COLLECTIVELY, THESE DATA DEMONSTRATE THAT TET1-MEDIATED 5HMC DEPOSITION REGULATES MULTIPLE OA PATHWAYS AND CAN BE MODULATED FOR THERAPEUTIC INTERVENTION. 2020 8 5423 35 REGULATION OF MACROPHAGE ACTIVATION AND DIFFERENTIATION IN ATHEROSCLEROSIS. CHRONIC INFLAMMATION IS A HALLMARK OF ATHEROSCLEROSIS AND MACROPHAGES PLAY A CENTRAL ROLE IN CONTROLLING INFLAMMATION AT ALL STAGES OF ATHEROSCLEROSIS. IN ATHEROSCLEROSIS, MACROPHAGES AND MONOCYTE-DERIVED MACROPHAGES ARE CONTINUOUSLY EXPOSED TO CHOLESTEROL, OXIDIZED LIPIDS, CELL DEBRIS, CYTOKINES, AND CHEMOKINES. NOT ONLY DO THESE STIMULI INDUCE A SPECIFIC MACROPHAGE PHENOTYPE, BUT THEY ALSO INTERACT EXTENSIVELY, LEADING TO MACROPHAGE HETEROGENEITY IN ATHEROSCLEROTIC PLAQUES. HEREIN, WE REVIEW THE DIVERSE PHENOTYPES OF MACROPHAGES, THE MECHANISMS UNDERLYING MACROPHAGE ACTIVATION, AND THE CONTRIBUTIONS OF MACROPHAGES TO ATHEROSCLEROSIS IN THIS CONTEXT. WE ALSO SUMMARIZE RECENT STUDIES ON FOAMY MACROPHAGES AND MONOCYTE-DERIVED MACROPHAGES IN PLAQUE DURING DISEASE PROGRESSION. WE PROVIDE A COMPREHENSIVE OVERVIEW OF TRANSCRIPTIONAL, EPIGENETIC, AND METABOLIC REPROGRAMMING OF MACROPHAGES AND DISCUSS THE EMERGING CONCEPTS OF TARGETING CYTOKINES AND MACROPHAGES TO MODULATE ATHEROSCLEROSIS. 2021 9 3734 56 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 10 5965 30 TEN-ELEVEN-TRANSLOCATION 2 (TET2) NEGATIVELY REGULATES HOMEOSTASIS AND DIFFERENTIATION OF HEMATOPOIETIC STEM CELLS IN MICE. THE TEN-ELEVEN-TRANSLOCATION 2 (TET2) GENE ENCODES A MEMBER OF TET FAMILY ENZYMES THAT ALTERS THE EPIGENETIC STATUS OF DNA BY OXIDIZING 5-METHYLCYTOSINE TO 5-HYDROXYMETHYLCYTOSINE (5HMC). SOMATIC LOSS-OF-FUNCTION MUTATIONS OF TET2 ARE FREQUENTLY OBSERVED IN PATIENTS WITH DIVERSE MYELOID MALIGNANCIES, INCLUDING MYELODYSPLASTIC SYNDROMES, MYELOPROLIFERATIVE NEOPLASMS, AND CHRONIC MYELOMONOCYTIC LEUKEMIA. BY ANALYZING MICE WITH TARGETED DISRUPTION OF THE TET2 CATALYTIC DOMAIN, WE SHOW HERE THAT TET2 IS A CRITICAL REGULATOR OF SELF-RENEWAL AND DIFFERENTIATION OF HEMATOPOIETIC STEM CELLS (HSCS). TET2 DEFICIENCY LED TO DECREASED GENOMIC LEVELS OF 5HMC AND AUGMENTED THE SIZE OF THE HEMATOPOIETIC STEM/PROGENITOR CELL POOL IN A CELL-AUTONOMOUS MANNER. IN COMPETITIVE TRANSPLANTATION ASSAYS, TET2-DEFICIENT HSCS WERE CAPABLE OF MULTILINEAGE RECONSTITUTION AND POSSESSED A COMPETITIVE ADVANTAGE OVER WILD-TYPE HSCS, RESULTING IN ENHANCED HEMATOPOIESIS INTO BOTH LYMPHOID AND MYELOID LINEAGES. IN VITRO, TET2 DEFICIENCY DELAYED HSC DIFFERENTIATION AND SKEWED DEVELOPMENT TOWARD THE MONOCYTE/MACROPHAGE LINEAGE. OUR DATA INDICATE THAT TET2 HAS A CRITICAL ROLE IN REGULATING THE EXPANSION AND FUNCTION OF HSCS, PRESUMABLY BY CONTROLLING 5HMC LEVELS AT GENES IMPORTANT FOR THE SELF-RENEWAL, PROLIFERATION, AND DIFFERENTIATION OF HSCS. 2011 11 5981 45 TET2 PROMOTES PATHOGEN INFECTION-INDUCED MYELOPOIESIS THROUGH MRNA OXIDATION. VARIETIES OF RNA MODIFICATION FORM THE EPITRANSCRIPTOME FOR POST-TRANSCRIPTIONAL REGULATION. 5-METHYLCYTOSINE (5-MC) IS A SPARSE RNA MODIFICATION IN MESSENGER RNA (MRNA) UNDER PHYSIOLOGICAL CONDITIONS. THE FUNCTION OF RNA 5-HYDROXYMETHYLCYTOSINE (5-HMC) OXIDIZED BY TEN-ELEVEN TRANSLOCATION (TET) PROTEINS IN DROSOPHILA HAS BEEN REVEALED MORE RECENTLY. HOWEVER, THE TURNOVER AND FUNCTION OF 5-MC IN MAMMALIAN MRNA HAVE BEEN LARGELY UNKNOWN. TET2 SUPPRESSES MYELOID MALIGNANCIES MOSTLY IN AN ENZYMATIC ACTIVITY-DEPENDENT MANNER, AND IS IMPORTANT IN RESOLVING INFLAMMATORY RESPONSE IN AN ENZYMATIC ACTIVITY-INDEPENDENT WAY. MYELOPOIESIS IS A COMMON HOST IMMUNE RESPONSE IN ACUTE AND CHRONIC INFECTIONS; HOWEVER, ITS EPIGENETIC MECHANISM NEEDS TO BE IDENTIFIED. HERE WE DEMONSTRATE THAT TET2 PROMOTES INFECTION-INDUCED MYELOPOIESIS IN AN MRNA OXIDATION-DEPENDENT MANNER THROUGH ADAR1-MEDIATED REPRESSION OF SOCS3 EXPRESSION AT THE POST-TRANSCRIPTION LEVEL. TET2 PROMOTES BOTH ABDOMINAL SEPSIS-INDUCED EMERGENCY MYELOPOIESIS AND PARASITE-INDUCED MAST CELL EXPANSION THROUGH DECREASING MRNA LEVELS OF SOCS3, A KEY NEGATIVE REGULATOR OF THE JAK-STAT PATHWAY THAT IS CRITICAL FOR CYTOKINE-INDUCED MYELOPOIESIS. TET2 REPRESSES SOCS3 EXPRESSION THROUGH ADAR1, WHICH BINDS AND DESTABILIZES SOCS3 MRNA IN A RNA EDITING-INDEPENDENT MANNER. FOR THE UNDERLYING MECHANISM OF TET2 REGULATION AT THE MRNA LEVEL, TET2 MEDIATES OXIDATION OF 5-MC IN MRNA. TET2 DEFICIENCY LEADS TO THE TRANSCRIPTOME-WIDE APPEARANCE OF METHYLATED CYTOSINES, INCLUDING ONES IN THE 3' UNTRANSLATED REGION OF SOCS3, WHICH INFLUENCES DOUBLE-STRANDED RNA FORMATION FOR ADAR1 BINDING, PROBABLY THROUGH CYTOSINE METHYLATION-SPECIFIC READERS, SUCH AS RNA HELICASES. OUR STUDY REVEALS A PREVIOUSLY UNKNOWN REGULATORY ROLE OF TET2 AT THE EPITRANSCRIPTOMIC LEVEL, PROMOTING MYELOPOIESIS DURING INFECTION IN THE MAMMALIAN SYSTEM BY DECREASING 5-MCS IN MRNAS. MOREOVER, THE INHIBITORY FUNCTION OF CYTOSINE METHYLATION ON DOUBLE-STRANDED RNA FORMATION AND ADAR1 BINDING IN MRNA REVEALS ITS NEW PHYSIOLOGICAL ROLE IN THE MAMMALIAN SYSTEM. 2018 12 4489 40 MONOCYTE AND MACROPHAGE IMMUNOMETABOLISM IN ATHEROSCLEROSIS. ATHEROSCLEROSIS IS CHARACTERIZED BY CHRONIC LOW GRADE INFLAMMATION OF ARTERIES THAT RESULTS IN THE DEVELOPMENT OF LIPID DENSE PLAQUES. CHRONIC INFLAMMATION INDUCED BY WESTERN-TYPE DIET IS ASSOCIATED WITH THE RISK OF DEVELOPING ATHEROSCLEROSIS, AND NEW INSIGHTS SHED LIGHT ON THE IMPORTANCE OF METABOLIC AND FUNCTIONAL REPROGRAMMING IN MONOCYTES AND MACROPHAGES FOR PROGRESSION OF ATHEROSCLEROSIS. THIS REVIEW AIMS TO PROVIDE AN OVERVIEW OF OUR CURRENT UNDERSTANDING INTO HOW THE METABOLIC REPROGRAMMING OF GLUCOSE, CHOLESTEROL, FATTY ACID, AND AMINO ACID METABOLISM IN MACROPHAGES CONTRIBUTES TO INFLAMMATION DURING ATHEROSCLEROSIS. RECENT INSIGHTS SUGGEST THAT TRANSCRIPTIONAL AND EPIGENETIC ADAPTATION WITHIN INNATE IMMUNE CELLS (TERMED TRAINED IMMUNITY) PLAY AN IMPORTANT ROLE IN THE PATHOGENESIS OF ATHEROSCLEROSIS. WE PROPOSE THAT METABOLIC CHANGES INDUCED BY PRO-ATHEROGENIC LIPOPROTEINS PARTLY MEDIATE THESE CHANGES IN TRAINED MACROPHAGES. FINALLY, WE DISCUSS THE POSSIBILITY OF MANIPULATING CELLULAR METABOLISM OF IMMUNE CELLS FOR TARGETED THERAPEUTIC INTERVENTION AGAINST ATHEROSCLEROSIS. 2018 13 4044 41 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 14 5975 37 TET1 IS AN IMPORTANT TRANSCRIPTIONAL ACTIVATOR OF TNFALPHA EXPRESSION IN MACROPHAGES. ACTIVATION OF MACROPHAGES AND OVEREXPRESSION OF TNFALPHA IS ASSOCIATED WITH THE PATHOGENESIS OF CHRONIC INFLAMMATORY DISEASES. HOWEVER, THE MECHANISMS LEADING TO TNFALPHA OVEREXPRESSION ARE STILL UNKNOWN. 5-METHYLOCYTOSINE (5-MC) IS AN EPIGENETIC MODIFICATION THAT IS ASSOCIATED WITH SILENCED GENES. RECENT STUDIES SHOWED THAT IT IS CONVERTED TO 5-HYDROXYLMETHYLOCYTOSINE (5-HMC) AND REACTIVATES GENE EXPRESSION THROUGH THE ACTION OF THE FAMILY OF TEN-ELEVEN-TRANSLOCATION (TET1-3) ENZYMES. IN THIS STUDY, WE SHOW THAT 5-HMC LEVELS ARE INCREASED GLOBALLY AND SPECIFICALLY IN THE TNFALPHA PROMOTER DURING THE DIFFERENTIATION OF MONOCYTES TO MACROPHAGES. IN ADDITION, THE LEVELS OF 5-HMC ARE INCREASED UPON LPS STIMULATION OF MACROPHAGES. FURTHERMORE, CRIPSR STABLE KNOCKOUT OF TET1 DECREASES THE EXPRESSION OF TNFALPHA AND OTHER PRO-INFLAMMATORY CYTOKINES. IN CONCLUSION, WE SHOWED THAT TET1 CONTRIBUTES TO THE ACTIVATION OF MACROPHAGES POSSIBLY THROUGH REGULATION OF 5-HYDROXYMETHYLATION IN THE PROMOTER OF PRO-INFLAMMATORY CYTOKINE GENES. THE TET1 ENZYME COULD BE A PROMISING THERAPEUTIC TARGET TO INHIBIT THE PERSISTENT INFLAMMATION CAUSED BY MACROPHAGES IN CHRONIC INFLAMMATORY DISEASES. 2019 15 5052 38 PHARMACOLOGICAL TARGETING OF HEME OXYGENASE-1 IN OSTEOARTHRITIS. OSTEOARTHRITIS (OA) IS A COMMON AGING-ASSOCIATED DISEASE THAT CLINICALLY MANIFESTS AS JOINT PAIN, MOBILITY LIMITATIONS, AND COMPROMISED QUALITY OF LIFE. TODAY, OA TREATMENT IS LIMITED TO PAIN MANAGEMENT AND JOINT ARTHROPLASTY AT THE LATER STAGES OF DISEASE PROGRESSION. OA PATHOGENESIS IS PREDOMINANTLY MEDIATED BY OXIDATIVE DAMAGE TO JOINT CARTILAGE EXTRACELLULAR MATRIX AND LOCAL CELLS SUCH AS CHONDROCYTES, OSTEOCLASTS, OSTEOBLASTS, AND SYNOVIAL FIBROBLASTS. UNDER NORMAL CONDITIONS, CELLS PREVENT THE ACCUMULATION OF REACTIVE OXYGEN SPECIES (ROS) UNDER OXIDATIVELY STRESSFUL CONDITIONS THROUGH THEIR ADAPTIVE CYTOPROTECTIVE MECHANISMS. HEME OXYGENASE-1 (HO-1) IS AN IRON-DEPENDENT CYTOPROTECTIVE ENZYME THAT FUNCTIONS AS THE INDUCIBLE FORM OF HO. HO-1 AND ITS METABOLITES CARBON MONOXIDE AND BILIVERDIN CONTRIBUTE TOWARDS THE MAINTENANCE OF REDOX HOMEOSTASIS. HO-1 EXPRESSION IS PRIMARILY REGULATED AT THE TRANSCRIPTIONAL LEVEL THROUGH TRANSCRIPTIONAL FACTOR NUCLEAR FACTOR ERYTHROID 2 (NF-E2)-RELATED FACTOR 2 (NRF2), SPECIFICITY PROTEIN 1 (SP1), TRANSCRIPTIONAL REPRESSOR BTB-AND-CNC HOMOLOGY 1 (BACH1), AND EPIGENETIC REGULATION. SEVERAL STUDIES REPORT THAT HO-1 EXPRESSION CAN BE REGULATED USING VARIOUS ANTIOXIDATIVE FACTORS AND CHEMICAL COMPOUNDS, SUGGESTING THERAPEUTIC IMPLICATIONS IN OA PATHOGENESIS AS WELL AS IN THE WIDER CONTEXT OF JOINT DISEASE. HERE, WE REVIEW THE PROTECTIVE ROLE OF HO-1 IN OA WITH A FOCUS ON THE REGULATORY MECHANISMS THAT MEDIATE HO-1 ACTIVITY. 2021 16 3550 49 IMMUNOSENESCENCE IN ATHEROSCLEROSIS: A ROLE FOR CHRONIC VIRAL INFECTIONS. IMMUNE SYSTEM IS A VERSATILE AND DYNAMIC BODY ORGAN WHICH OFFERS SURVIVAL AND ENDURANCE OF HUMAN BEINGS IN THEIR HOSTILE LIVING ENVIRONMENT. HOWEVER, SIMILAR TO OTHER CELLS, IMMUNE CELLS ARE HIJACKED BY SENESCENCE. THE AGEING IMMUNE CELLS LOSE THEIR BENEFICIAL FUNCTIONS BUT CONTINUE TO PRODUCE INFLAMMATORY MEDIATORS WHICH DRAW OTHER IMMUNE AND NON-IMMUNE CELLS TO THE SENESCENCE LOOP. IMMUNOSENESCENCE HAS BEEN SHOWN TO BE ASSOCIATED WITH DIFFERENT PATHOLOGICAL CONDITIONS AND DISEASES, AMONG WHICH ATHEROSCLEROSIS HAS RECENTLY COME TO LIGHT. THERE ARE COMMON DRIVERS OF BOTH IMMUNOSENESCENCE AND ATHEROSCLEROSIS; E.G. INFLAMMATION, REACTIVE OXYGEN SPECIES (ROS), CHRONIC VIRAL INFECTIONS, GENOMIC DAMAGE, OXIDIZED-LDL, HYPERTENSION, CIGARETTE SMOKE, HYPERGLYCAEMIA, AND MITOCHONDRIAL FAILURE. CHRONIC VIRAL INFECTIONS INDUCE INFLAMMAGING, SUSTAINED CYTOKINE SIGNALING, ROS GENERATION AND DNA DAMAGE WHICH ARE ASSOCIATED WITH ATHEROGENESIS. ACCUMULATING EVIDENCE SHOWS THAT SEVERAL DNA AND RNA VIRUSES ARE STIMULATORS OF IMMUNOSENESCENCE AND ATHEROSCLEROSIS IN AN INTERRELATED NETWORK. DNA VIRUSES SUCH AS CMV, EBV AND HBV UPREGULATE P16, P21 AND P53 SENESCENCE-ASSOCIATED MOLECULES; INDUCE INFLAMMAGING, METABOLIC REPROGRAMMING OF INFECTED CELLS, REPLICATIVE SENESCENCE AND TELOMERE SHORTENING. RNA VIRUSES SUCH AS HCV AND HIV INDUCE ROS GENERATION, DNA DAMAGE, INDUCTION OF SENESCENCE-ASSOCIATED SECRETORY PHENOTYPE (SASP), METABOLIC REPROGRAMMING OF INFECTED CELLS, G1 CELL CYCLE ARREST, TELOMERE SHORTENING, AS WELL AS EPIGENETIC MODIFICATIONS OF DNA AND HISTONES. THE NEWLY EMERGED SARS-COV-2 VIRUS IS ALSO A POTENT INDUCER OF CYTOKINE STORM AND SASP. THE SPIKE PROTEIN OF SARS-COV-2 PROMOTES SENESCENCE PHENOTYPE IN ENDOTHELIAL CELLS BY AUGMENTING P16, P21, SENESCENCE-ASSOCIATED BETA-GALACTOSIDASE (SA-BETA-GAL) AND ADHESION MOLECULES EXPRESSION. THE IMPACT OF SARS-COV-2 MEGA-INFLAMMATION ON ATHEROGENESIS, HOWEVER, REMAINS TO BE INVESTIGATED. IN THIS REVIEW WE FOCUS ON THE COMMON PROCESSES IN IMMUNOSENESCENCE AND ATHEROGENESIS CAUSED BY CHRONIC VIRAL INFECTIONS AND DISCUSS THE CURRENT KNOWLEDGE ON THIS TOPIC. 2022 17 2067 40 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 18 6505 51 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 19 2950 32 GENETIC AND EPIGENETIC DAMAGE INDUCED BY REACTIVE NITROGEN SPECIES: IMPLICATIONS IN CARCINOGENESIS. CHRONIC INFECTION AND INFLAMMATION ARE RECOGNIZED RISK FACTORS FOR HUMAN CANCER AT VARIOUS SITES. INFECTION AND INFLAMMATION CAN ACTIVATE AND INDUCE A VARIETY OF OXIDANT-GENERATING ENZYMES, INCLUDING NADPH OXIDASE AND INDUCIBLE NITRIC OXIDE SYNTHASE. REACTIVE OXYGEN AND NITROGEN SPECIES PRODUCED BY SUCH ENZYMES REACT WITH EACH OTHER TO GENERATE NEW AND MORE POTENT REACTIVE SPECIES. THESE OXIDANTS NOT ONLY CAN DAMAGE DNA AND INDUCE MUTATIONS, BUT ALSO CAN ACTIVATE ONCOGENE PRODUCTS AND/OR INACTIVATE TUMOR-SUPPRESSOR PROTEINS, THUS CONTRIBUTING TO MOST PROCESSES OF CARCINOGENESIS. APPROPRIATE TREATMENT OF INFLAMMATION SHOULD BE FURTHER EXPLORED FOR CHEMOPREVENTION OF HUMAN CANCERS, ESPECIALLY THOSE ASSOCIATED WITH CHRONIC INFLAMMATION. 2003 20 6214 44 THE INTRACELLULAR SIGNALING PATHWAYS GOVERNING MACROPHAGE ACTIVATION AND FUNCTION IN HUMAN ATHEROSCLEROSIS. ATHEROSCLEROSIS IS A CHRONIC INFLAMMATORY DISEASE CHARACTERIZED BY LIPID ACCUMULATION AND PLAQUE FORMATION IN ARTERIAL VESSEL WALLS. ATHEROSCLEROTIC PLAQUES NARROW THE ARTERIAL LUMEN TO INCREASE THE RISK OF HEART ATTACKS, ISCHEMIC STROKE AND PERIPHERAL VASCULAR DISEASE, WHICH ARE MAJOR AND WORLDWIDE HEALTH AND ECONOMIC BURDENS. MACROPHAGE ACCUMULATION WITHIN PLAQUES IS CHARACTERISTIC OF ALL STAGES OF ATHEROSCLEROSIS AND THEIR PRESENCE IS A POTENTIAL MARKER OF DISEASE ACTIVITY AND PLAQUE STABILITY. MACROPHAGES ENGULF LIPIDS AND MODIFIED LIPOPROTEINS TO FORM FOAM CELLS THAT EXPRESS PRO-INFLAMMATORY AND CHEMOTACTIC EFFECTOR MOLECULES, STRESS INDUCING FACTORS AND REACTIVE OXYGEN SPECIES. THEY CONTROL PLAQUE STABILITY AND RUPTURE THROUGH SECRETION OF METALLOPROTEINASES AND EXTRACELLULAR MATRIX DEGRADATION. ALTHOUGH MACROPHAGES CAN WORSEN DISEASE BY PROPAGATING INFLAMMATION, THEY CAN STABILIZE ATHEROSCLEROTIC PLAQUES THROUGH TISSUE REMODELING, PROMOTING THE FORMATION OF A FIBROUS CAP, CLEARING APOPTOTIC CELLS TO PREVENT NECROTIC CORE FORMATION AND THROUGH VASCULAR REPAIR. IN ATHEROSCLEROSIS, MACROPHAGES RESPOND TO DYSLIPIDAEMIA, CYTOKINES, DYING CELLS, METABOLIC FACTORS, LIPIDS, PHYSICAL STIMULI AND EPIGENETIC FACTORS AND EXHIBIT HETEROGENEITY IN THEIR ACTIVATION DEPENDING ON THE STIMULI THEY RECEIVE. UNDERSTANDING THESE SIGNALS AND THE PATHWAYS DRIVING MACROPHAGE FUNCTION WITHIN DEVELOPING AND ESTABLISHED PLAQUES AND HOW THEY CAN BE PHARMACOLOGICALLY MODULATED, REPRESENTS A STRATEGY FOR THE PREVENTION AND TREATMENT OF ATHEROSCLEROSIS. THIS REVIEW FOCUSSES ON THE CURRENT UNDERSTANDING OF FACTORS CONTROLLING MACROPHAGE HETEROGENEITY AND FUNCTION IN ATHEROSCLEROSIS. PARTICULAR ATTENTION IS GIVEN TO THE MACROPHAGE INTRACELLULAR SIGNALING PATHWAYS AND TRANSCRIPTION FACTORS ACTIVATED BY BIOCHEMICAL AND BIOPHYSICAL STIMULI WITHIN PLAQUES, AND HOW THEY ARE INTEGRATED TO REGULATE PLAQUE FORMATION AND STABILITY. 2022