1  1715 148 DYSLIPIDEMIC DIET-INDUCED MONOCYTE "PRIMING" AND DYSFUNCTION IN NON-HUMAN PRIMATES IS TRIGGERED BY ELEVATED PLASMA CHOLESTEROL AND ACCOMPANIED BY ALTERED HISTONE ACETYLATION. MONOCYTES AND THE RECRUITMENT OF MONOCYTE-DERIVED MACROPHAGES INTO SITES OF INFLAMMATION PLAY A KEY ROLE IN ATHEROGENESIS AND OTHER CHRONIC INFLAMMATORY DISEASES LINKED TO CARDIOMETABOLIC SYNDROME AND OBESITY. PREVIOUS STUDIES FROM OUR GROUP HAVE SHOWN THAT METABOLIC STRESS PROMOTES MONOCYTE PRIMING, I.E., ENHANCED ADHESION AND ACCELERATED CHEMOTAXIS OF MONOCYTES IN RESPONSE TO CHEMOKINES, BOTH IN VITRO AND IN DYSLIPIDEMIC LDLR(-/-) MICE. WE ALSO SHOWED THAT METABOLIC STRESS-INDUCED MONOCYTE DYSFUNCTION IS, AT LEAST TO A LARGE EXTENT CAUSED BY THE S-GLUTATHIONYLATION, INACTIVATION, AND SUBSEQUENT DEGRADATION OF MITOGEN-ACTIVATED PROTEIN KINASE PHOSPHATASE 1. HERE, WE ANALYZED THE EFFECTS OF A WESTERN-STYLE, DYSLIPIDEMIC DIET (DD), WHICH WAS COMPOSED OF HIGH LEVELS OF SATURATED FAT, CHOLESTEROL, AND SIMPLE SUGARS, ON MONOCYTE (DYS)FUNCTION IN NON-HUMAN PRIMATES (NHPS). WE FOUND THAT SIMILAR TO MICE, A DD ENHANCES MONOCYTE CHEMOTAXIS IN NHP WITHIN 4 WEEKS, OCCURRING CONCORDANTLY WITH THE ONSET OF HYPERCHOLESTEROLEMIA BUT PRIOR TO CHANGES IN TRIGLYCERIDES, BLOOD GLUCOSE, MONOCYTOSIS, OR CHANGES IN MONOCYTE SUBSET COMPOSITION. IN ADDITION, WE IDENTIFIED TRANSITORY DECREASES IN THE ACETYLATION OF HISTONE H3 AT THE LYSINE RESIDUES 18 AND 23 IN METABOLICALLY PRIMED MONOCYTES, AND WE FOUND THAT MONOCYTE PRIMING WAS CORRELATED WITH THE ACETYLATION OF HISTONE H3 AT LYSINE 27 AFTER AN 8-WEEK DD REGIMEN. OUR DATA SHOW THAT METABOLIC STRESS PROMOTES MONOCYTE PRIMING AND HYPER-CHEMOTACTIC RESPONSES IN NHP. THE HISTONE MODIFICATIONS ACCOMPANYING MONOCYTE PRIMING IN PRIMATES SUGGEST A REPROGRAMMING OF THE EPIGENETIC LANDSCAPE, WHICH MAY LEAD TO DYSREGULATED RESPONSES AND FUNCTIONALITIES IN MACROPHAGES DERIVED FROM PRIMED MONOCYTES THAT ARE RECRUITED TO SITES OF INFLAMMATION.	2017	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
2  4275  25 MICROGLIA ACTIVATION IN THE MIDBRAIN OF THE HUMAN NEONATE: THE EFFECT OF PERINATAL HYPOXIC-ISCHEMIC INJURY. PERINATAL HYPOXIA-ISCHEMIA (PHI) IS A MAJOR RISK FACTOR FOR THE DEVELOPMENT OF NEUROPSYCHIATRIC DEFICITS LATER IN LIFE. WE PREVIOUSLY REPORTED THAT AFTER PROLONGED PHI, THE DOPAMINERGIC NEURONS OF THE HUMAN NEONATE SHOWED A DRAMATIC REDUCTION OF TYROSINE HYDROXYLASE (TH) IN THE SUBSTANTIA NIGRA, WITHOUT IMPORTANT SIGNS OF NEURONAL DEGENERATION DESPITE THE SIGNIFICANT REDUCTION IN THEIR CELL SIZE. SINCE MICROGLIA ACTIVATION COULD PRECEDE NEURONAL DEATH, WE NOW INVESTIGATED 2 MICROGLIA ACTIVATION MARKERS, IONIZED CALCIUM-BINDING ADAPTER MOLECULE 1 (IBA1), AND THE PHAGOCYTOSIS MARKER CD68. THE HIGHEST IBA1 IMMUNOREACTIVITY WAS FOUND IN NEONATES WITH NEUROPATHOLOGICAL LESIONS OF SEVERE/ABRUPT PHI, WHILE THE LOWEST IN SUBJECTS WITH MODERATE/PROLONGED OR OLDER PHI. SUBJECTS WITH VERY SEVERE/PROLONGED OR CHRONIC PHI SHOWED AN INCREASED IBA1 EXPRESSION AND VERY ACTIVATED MICROGLIAL MORPHOLOGY. HEAVY ATTACHMENT OF MICROGLIA ON TH NEURONS AND REMARKABLE EXPRESSION OF CD68 WERE ALSO OBSERVED INDICATING PHAGOCYTOSIS IN THIS GROUP. FEMALES APPEAR TO EXPRESS MORE IBA1 THAN MALES, SUGGESTING A GENDER DIFFERENCE IN MICROGLIA MATURATION AND IMMUNE REACTIVITY AFTER PHI INSULT. PHI-INDUCED MICROGLIAL "PRIMING" DURING THE SENSITIVE FOR BRAIN DEVELOPMENT PERINATAL/NEONATAL PERIOD, IN COMBINATION WITH GENETIC OR OTHER EPIGENETIC FACTORS, COULD PREDISPOSE THE SURVIVORS TO NEUROPSYCHIATRIC DISORDERS LATER IN LIFE, POSSIBLY THROUGH A SEXUALLY DIMORPHIC WAY.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
3  4036  28 MACROPHAGE EPIGENETIC MEMORIES OF EARLY LIFE INJURY DRIVE NEONATAL NOCICEPTIVE PRIMING. THE DEVELOPING PERIPHERAL NERVOUS AND IMMUNE SYSTEMS ARE FUNCTIONALLY DISTINCT FROM ADULTS. THESE SYSTEMS ARE VULNERABLE TO EFFECTS OF EARLY LIFE INJURY WHICH CAN INFLUENCE OUTCOMES RELATED TO NOCICEPTION FOLLOWING SUBSEQUENT INJURY LATER IN LIFE (I.E. "NEONATAL NOCICEPTIVE PRIMING"). THE UNDERPINNINGS OF THIS PHENOMENON ARE LARGELY UNKNOWN, ALTHOUGH MACROPHAGES CAN BE EPIGENETICALLY TRAINED BY INJURY. WE FOUND THAT MACROPHAGES ARE BOTH NECESSARY AND PARTIALLY SUFFICIENT TO DRIVE NEONATAL NOCICEPTIVE PRIMING POSSIBLY DUE TO A LONG-LASTING EPIGENETIC REMODELING OF PERIPHERAL MACROPHAGES. THE P75 NEUROTROPHIC FACTOR RECEPTOR (NTR) WAS OBSERVED TO BE AN IMPORTANT EFFECTOR IN REGULATING NEONATAL NOCICEPTIVE PRIMING. P75NTR MODULATES THE INFLAMMATORY PROFILE AND RESPONSES OF RODENT AND HUMAN MACROPHAGES. THIS "PAIN MEMORY" WAS ABLE TO BE TRANSFERRED TO A NAIVE HOST TO ALTER SEX-SPECIFIC PAIN-RELATED BEHAVIORS. THIS STUDY REVEALS A NOVEL MECHANISM BY WHICH ACUTE POST-SURGICAL PAIN MAY TRANSITION TO CHRONIC PAIN IN CHILDREN.	2023	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
4  5568  31 ROLE OF MARIJUANA COMPONENTS ON THE REGENERATIVE ABILITY OF STEM CELLS. STEM CELL THERAPY PROMOTES TISSUE REGENERATION AND WOUND HEALING. EFFORTS HAVE BEEN MADE TO PRIME STEM CELLS TO ENHANCE THEIR REGENERATIVE ABILITIES. CERTAIN MARIJUANA COMPONENTS, NAMELY THE NON-PSYCHOACTIVE CANNABIDIOL (CBD) AND PSYCHOACTIVE TETRAHYDROCANNABINOL (THC), ARE DEFINED AS IMMUNOMODULATORS.(9) WE TEST WHETHER TWO SOURCES OF STEM CELLS, PRIMED WITH CBD OR THC, WOULD DEMONSTRATE IMPROVED REGENERATIVE ABILITIES. HUMAN ADIPOSE-DERIVED STEM CELLS (ASCS) AND BONE MARROW-DERIVED STEM CELLS (BMDSCS), NOT OBTAINED FROM THE SAME INDIVIDUAL, WERE TREATED WITH LOW (300 NM) OR HIGH (3 MUM) CONCENTRATION CBD. PORCINE ASCS AND BMDSCS WERE ISOLATED FROM A SINGLE PIG, AND TREATED WITH EITHER LOW OR HIGH CONCENTRATIONS OF CBD OR THC. TRANSWELL MIGRATION AND MTT PROLIFERATION ASSAYS WERE PERFORMED ON THE HUMAN ASCS AND BMDSCS. ALSO, TRANSWELL MIGRATION ASSAY WAS PERFORMED ON THE PORCINE ASCS AND BMDSCS. FINALLY, A WOUND HEALING SCRATCH ASSAY IN PORCINE PRIMARY FIBROBLASTS (PFS) WAS PERFORMED, CO-CULTURED WITH THE CANNABINOID-TREATED ASCS. CBD PRIMING AT LOW CONCENTRATION INDUCES MIGRATION BY 180% (P < .01) IN PORCINE ASCS, AND BY ONLY 93% (P < .02) IN PORCINE BMDSCS. IN PORCINE STEM CELLS, THC PRIMING AT LOW CONCENTRATION INDUCES MIGRATION BY 91.6% (P < .01) IN ASCS BUT BY ONLY 44.3% (P < .03) IN BMDSCS. COMPARED TO PFS CO-CULTURED WITH UNTREATED ASCS, PFS CO-CULTURED WITH LOW CBD-PRIMED ASCS HAD 75% FASTER WOUND CLOSURE AT 18 HOURS (P < .01). CBD AND THC PRIMING OF ASCS AND BMDSCS, PARTICULARLY AT LOWER DOSES, ENHANCES A NUMBER OF REGENERATIVE PARAMETERS, SUGGESTING THAT THESE MAJOR MARIJUANA COMPONENTS MAY IMPROVE STEM CELL-BASED THERAPIES. SIGNIFICANCE OF THE STUDY: OUR STUDY DEMONSTRATES THAT CANNABINOIDS CAN ENHANCE THE REGENERATIVE CAPACITY OF TWO MAJOR SOURCES OF STEM CELLS, ADIPOSE- AND BONE MARROW-DERIVED, FROM HUMAN AND PORCINE DONORS. STEM CELL ISOLATION AND EXPANSION IS INVASIVE, COSTLY AND TIME CONSUMING. STEM CELLS WITH IMPROVED REGENERATIVE PROPERTIES MAY BE EFFECTIVE IN THE TREATMENT OF ACUTE OR CHRONIC WOUNDS. THIS IS THE FIRST STUDY TO COMPARE THE PRIMING POTENTIAL OF TWO SOURCES OF STEM CELLS FROM THE SAME ANIMAL, WITH THE SAME GENETIC AND EPIGENETIC PROFILE, AS WELL AS THE FIRST TO PRIME WITH THC.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                    
5  4510  40 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	
                                                                                                                                                                                                                                                                                                                
6  5760  34 SOLUBLE URIC ACID PRIMES TLR-INDUCED PROINFLAMMATORY CYTOKINE PRODUCTION BY HUMAN PRIMARY CELLS VIA INHIBITION OF IL-1RA. OBJECTIVES: THE STUDY OF THE PROINFLAMMATORY ROLE OF URIC ACID HAS FOCUSED ON THE EFFECTS OF ITS CRYSTALS OF MONOSODIUM URATE (MSU). HOWEVER, LITTLE IS KNOWN WHETHER URIC ACID ITSELF CAN DIRECTLY HAVE PROINFLAMMATORY EFFECTS. IN THIS STUDY, WE INVESTIGATE THE PRIMING EFFECTS OF URIC ACID EXPOSURE ON THE CYTOKINE PRODUCTION OF PRIMARY HUMAN CELLS UPON STIMULATION WITH GOUT-RELATED STIMULI. METHODS: PERIPHERAL BLOOD MONONUCLEAR CELLS (PBMCS) WERE HARVESTED FROM PATIENTS WITH GOUT AND HEALTHY VOLUNTEERS. CELLS WERE PRETREATED WITH OR WITHOUT URIC ACID IN SOLUBLE FORM FOR 24 H AND THEN STIMULATED FOR 24 H WITH TOLL-LIKE RECEPTOR (TLR)2 OR TLR4 LIGANDS IN THE PRESENCE OR ABSENCE OF MSU CRYSTALS. CYTOKINE PRODUCTION WAS MEASURED BY ELISA; MRNA LEVELS WERE ASSESSED USING QPCR. RESULTS: THE PRODUCTION OF INTERLEUKIN (IL)-1BETA AND IL-6 WAS HIGHER IN PATIENTS COMPARED WITH CONTROLS AND THIS CORRELATED WITH SERUM URATE LEVELS. PROINFLAMMATORY CYTOKINE PRODUCTION WAS SIGNIFICANTLY POTENTIATED WHEN CELLS FROM HEALTHY SUBJECTS WERE PRETREATED WITH URIC ACID. SURPRISINGLY, THIS WAS ASSOCIATED WITH A SIGNIFICANT DOWNREGULATION OF THE ANTI-INFLAMMATORY CYTOKINE IL-1 RECEPTOR ANTAGONIST (IL-1RA). THIS EFFECT WAS SPECIFIC TO STIMULATION BY URIC ACID AND WAS EXERTED AT THE LEVEL OF GENE TRANSCRIPTION. EPIGENETIC REPROGRAMMING AT THE LEVEL OF HISTONE METHYLATION BY URIC ACID WAS INVOLVED IN THIS EFFECT. CONCLUSIONS: IN THIS STUDY WE DEMONSTRATE A MECHANISM THROUGH WHICH HIGH CONCENTRATIONS OF URIC ACID (UP TO 50 MG/DL) INFLUENCE INFLAMMATORY RESPONSES BY FACILITATING IL-1BETA PRODUCTION IN PBMCS. WE SHOW THAT A MECHANISM FOR THE AMPLIFICATION OF IL-1BETA CONSISTS IN THE DOWNREGULATION OF IL-1RA AND THAT THIS EFFECT COULD BE EXERTED VIA EPIGENETIC MECHANISMS SUCH AS HISTONE METHYLATION. HYPERURICAEMIA CAUSES A SHIFT IN THE IL-1BETA/IL-1RA BALANCE PRODUCED BY PBMCS AFTER EXPOSURE TO MSU CRYSTALS AND TLR-MEDIATED STIMULI, AND THIS PHENOMENON IS LIKELY TO REINFORCE THE ENHANCED STATE OF CHRONIC INFLAMMATION.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                        
7  3736  34 INNATE IMMUNE TOLERANCE IN MICROGLIA DOES NOT IMPACT ON CENTRAL NERVOUS SYSTEM PRION DISEASE. PRION DISEASES SUCH AS CREUTZFELDT-JAKOB DISEASE IN HUMANS, BOVINE SPONGIFORM ENCEPHALOPATHY IN CATTLE, AND SCRAPIE IN SHEEP, ARE INFECTIOUS AND CHRONIC NEURODEGENERATIVE DISEASES TO WHICH THERE ARE NO CURES. INFECTION WITH PRIONS IN THE CENTRAL NERVOUS SYSTEM (CNS) ULTIMATELY CAUSES EXTENSIVE NEURODEGENERATION, AND THIS IS ACCOMPANIED BY PROMINENT MICROGLIAL AND ASTROCYTIC ACTIVATION IN AFFECTED REGIONS. THE MICROGLIA ARE THE CNS MACROPHAGES AND HELP MAINTAIN NEURONAL HOMEOSTASIS, CLEAR DEAD OR DYING CELLS AND PROVIDE DEFENSE AGAINST PATHOGENS. THE MICROGLIA ALSO PROVIDE NEUROPROTECTION DURING CNS PRION DISEASE, BUT THEIR PRO-INFLAMMATORY ACTIVATION MAY EXACERBATE THE DEVELOPMENT OF THE NEUROPATHOLOGY. INNATE IMMUNE TOLERANCE INDUCED BY CONSECUTIVE SYSTEMIC BACTERIAL LIPOPOLYSACCHARIDE (LPS) TREATMENT CAN INDUCE LONG-TERM EPIGENETIC CHANGES IN THE MICROGLIA IN THE BRAIN THAT SEVERAL MONTHS LATER CAN DAMPEN THEIR RESPONSIVENESS TO SUBSEQUENT LPS TREATMENT AND IMPEDE THE DEVELOPMENT OF NEURITIC DAMAGE IN A TRANSGENIC MOUSE MODEL OF ALZHEIMER'S DISEASE-LIKE PATHOLOGY. WE THEREFORE REASONED THAT INNATE IMMUNE TOLERANCE IN MICROGLIA MIGHT SIMILARLY IMPEDE THE SUBSEQUENT DEVELOPMENT OF CNS PRION DISEASE. TO TEST THIS HYPOTHESIS GROUPS OF MICE WERE FIRST INFECTED WITH PRIONS BY INTRACEREBRAL INJECTION, AND 35 DAYS LATER GIVEN FOUR CONSECUTIVE SYSTEMIC INJECTIONS WITH LPS TO INDUCE INNATE IMMUNE TOLERANCE. OUR DATA SHOW THAT CONSECUTIVE SYSTEMIC LPS TREATMENT DID NOT AFFECT THE SUBSEQUENT DEVELOPMENT OF CNS PRION DISEASE. OUR DATA SUGGESTS INNATE IMMUNE TOLERANCE IN MICROGLIA DOES NOT INFLUENCE THE SUBSEQUENT ONSET OF PRION DISEASE-INDUCED NEUROPATHOLOGY IN MICE, DESPITE PREVIOUSLY PUBLISHED EVIDENCE OF THIS EFFECT IN AN ALZHEIMER'S DISEASE MOUSE MODEL.	2022	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
8   744  38 CANNABINOID WIN55,212-2 REPROGRAMS MONOCYTES AND MACROPHAGES TO INHIBIT LPS-INDUCED INFLAMMATION. INTRODUCTION: CHRONIC OR UNCONTROLLED ACTIVATION OF MYELOID CELLS INCLUDING MONOCYTES, MACROPHAGES AND DENDRITIC CELLS (DCS) IS A HALLMARK OF IMMUNE-MEDIATED INFLAMMATORY DISORDERS. THERE IS AN URGENT NEED FOR THE DEVELOPMENT OF NOVEL DRUGS WITH THE CAPACITY TO IMPAIR INNATE IMMUNE CELL OVERACTIVATION UNDER INFLAMMATORY CONDITIONS. COMPELLING EVIDENCE POINTED OUT CANNABINOIDS AS POTENTIAL THERAPEUTIC TOOLS WITH ANTI-INFLAMMATORY AND IMMUNOMODULATORY CAPACITY. WIN55,212-2, A NON-SELECTIVE SYNTHETIC CANNABINOID AGONIST, DISPLAYS PROTECTIVE EFFECTS IN SEVERAL INFLAMMATORY CONDITIONS BY MECHANISMS PARTIALLY DEPENDING ON THE GENERATION OF TOLEROGENIC DCS ABLE TO INDUCE FUNCTIONAL REGULATORY T CELLS (TREGS). HOWEVER, ITS IMMUNOMODULATORY CAPACITY ON OTHER MYELOID CELLS SUCH AS MONOCYTES AND MACROPHAGES REMAINS INCOMPLETELY UNDERSTOOD. METHODS: HUMAN MONOCYTE-DERIVED DCS (HMODCS) WERE DIFFERENTIATED IN THE ABSENCE (CONVENTIONAL HMODCS) OR PRESENCE OF WIN55,212-2 (WIN-HMODCS). CELLS WERE STIMULATED WITH LPS, COCULTURED WITH NAIVE T LYMPHOCYTES AND THEIR CYTOKINE PRODUCTION AND ABILITY TO INDUCE T CELL RESPONSES WERE ANALYSED BY ELISA OR FLOW CYTOMETRY. TO EVALUATE THE EFFECT OF WIN55,212-2 IN MACROPHAGE POLARIZATION, HUMAN AND MURINE MACROPHAGES WERE ACTIVATED WITH LPS OR LPS/IFNGAMMA, IN THE PRESENCE OR ABSENCE OF THE CANNABINOID. CYTOKINE, COSTIMULATORY MOLECULES AND INFLAMMASOME MARKERS WERE ASSAYED. METABOLIC AND CHROMATIN IMMUNOPRECIPITATION ASSAYS WERE ALSO PERFORMED. FINALLY, THE PROTECTIVE CAPACITY OF WIN55,212-2 WAS STUDIED IN VIVO IN BALB/C MICE AFTER INTRAPERITONEAL INJECTION WITH LPS. RESULTS: WE SHOW FOR THE FIRST TIME THAT THE DIFFERENTIATION OF HMODCS IN THE PRESENCE OF WIN55,212-2 GENERATES TOLEROGENIC WIN-HMODCS THAT ARE LESS RESPONSIVE TO LPS STIMULATION AND ABLE TO PRIME TREGS. WIN55,212-2 ALSO IMPAIRS THE PRO-INFLAMMATORY POLARIZATION OF HUMAN MACROPHAGES BY INHIBITING CYTOKINE PRODUCTION, INFLAMMASOME ACTIVATION AND RESCUING MACROPHAGES FROM PYROPTOTIC CELL DEATH. MECHANISTICALLY, WIN55,212-2 INDUCED A METABOLIC AND EPIGENETIC SHIFT IN MACROPHAGES BY DECREASING LPS-INDUCED MTORC1 SIGNALING, COMMITMENT TO GLYCOLYSIS AND ACTIVE HISTONE MARKS IN PRO-INFLAMMATORY CYTOKINE PROMOTERS. WE CONFIRMED THESE DATA IN EX VIVO LPS-STIMULATED PERITONEAL MACROPHAGES (PMPHIS), WHICH WERE ALSO SUPPORTED BY THE IN VIVO ANTI-INFLAMMATORY CAPACITY OF WIN55,212-2 IN A LPS-INDUCED SEPSIS MOUSE MODEL. CONCLUSION: OVERALL, WE SHED LIGHT INTO THE MOLECULAR MECHANISMS BY WHICH CANNABINOIDS EXERT ANTI-INFLAMMATORY PROPERTIES IN MYELOID CELLS, WHICH MIGHT WELL CONTRIBUTE TO THE FUTURE RATIONAL DESIGN OF NOVEL THERAPEUTIC STRATEGIES FOR INFLAMMATORY DISORDERS.	2023	

9  2067  34 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                       
10  1482  22 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
11  6599  30 TWIST1 AND TWIST2 INDUCE HUMAN MACROPHAGE MEMORY UPON CHRONIC INNATE RECEPTOR TREATMENT BY HDAC-MEDIATED DEACETYLATION OF CYTOKINE PROMOTERS. INTESTINAL TISSUES ARE CONTINUOUSLY EXPOSED TO MICROBIAL PRODUCTS THAT STIMULATE PATTERN-RECOGNITION RECEPTORS (PRRS). ONGOING PRR STIMULATION CAN CONFER EPIGENETIC CHANGES IN MACROPHAGES, WHICH CAN THEN REGULATE SUBSEQUENT IMMUNE OUTCOMES AND ADAPTATION TO THE LOCAL ENVIRONMENT. MECHANISMS LEADING TO THESE CHANGES ARE INCOMPLETELY UNDERSTOOD. WE FOUND THAT SHORT-TERM STIMULATION OF THE PRR NOD2 IN PRIMARY HUMAN MONOCYTE-DERIVED MACROPHAGES RESULTED IN INCREASED H3 AND H4 ACETYLATION OF CYTOKINE PROMOTERS, CONSISTENT WITH THE INCREASED CYTOKINE SECRETION OBSERVED. HOWEVER, WITH PROLONGED NOD2 STIMULATION, BOTH THE ACETYLATION AND CYTOKINE SECRETION WERE DRAMATICALLY DECREASED. CHRONIC NOD2 STIMULATION UPREGULATED THE TRANSCRIPTION FACTORS TWIST1 AND TWIST2, WHICH BOUND TO THE PROMOTERS OF THE HISTONE DEACETYLASES HDAC1 AND HDAC3 AND INDUCED HDAC1 AND HDAC3 EXPRESSION. HDAC1 AND HDAC3 THEN MEDIATED HISTONE DEACETYLATION AT CYTOKINE PROMOTERS AND, IN TURN, CYTOKINE DOWNREGULATION UNDER THESE CONDITIONS. SIMILAR REGULATION WAS OBSERVED UPON CHRONIC STIMULATION OF MULTIPLE PRRS. CONSISTENT WITH THE CHRONIC MICROBIAL EXPOSURE IN THE INTESTINAL ENVIRONMENT, TWIST1, TWIST2, HDAC1, AND HDAC3 WERE UPREGULATED IN HUMAN INTESTINAL RELATIVE TO PERIPHERAL MACROPHAGES. IMPORTANTLY, COMPLEMENTING HDAC1 AND HDAC3 IN TWIST1/TWIST2-DEFICIENT MONOCYTE-DERIVED MACROPHAGES RESTORED THE REDUCED HISTONE ACETYLATION ON CYTOKINE PROMOTERS AND THE DECREASED CYTOKINE SECRETION WITH CHRONIC NOD2 STIMULATION. TAKEN TOGETHER, WE IDENTIFY MECHANISMS WHEREIN TWIST1 AND TWIST2 PROMOTE CHROMATIN MODIFICATIONS, RESULTING IN MACROPHAGE INSTRUCTION AND ADAPTATION TO CONDITIONS IN THE INTESTINAL MICROENVIRONMENT.	2019	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                              
12  1319  25 DEMETHYLATION OF THE PD-1 PROMOTER IS IMPRINTED DURING THE EFFECTOR PHASE OF CD8 T CELL EXHAUSTION. PD-1 IS AN INHIBITORY RECEPTOR THAT HAS A MAJOR ROLE IN T CELL DYSFUNCTION DURING CHRONIC INFECTIONS AND CANCER. WHILE DEMETHYLATION OF THE PD-1 PROMOTER DNA IS OBSERVED IN EXHAUSTED T CELLS ISOLATED FROM CHRONICALLY INFECTED INDIVIDUALS, LITTLE IS KNOWN ABOUT WHEN THIS STABLE DEMETHYLATION OF PD-1 PROMOTER DNA IS PROGRAMMED DURING THE COURSE OF A CHRONIC INFECTION. TO ASSESS IF PD-1 PROMOTER DNA DEMETHYLATION IS IMPACTED BY PROLONGED STIMULATION DURING EFFECTOR PHASE OF CHRONIC INFECTION, WE ADOPTIVELY TRANSFERRED VIRUS-SPECIFIC DAY 8 EFFECTOR CD8 T CELLS FROM MICE INFECTED WITH LYMPHOCYTIC CHORIOMENINGITIS VIRUS (LCMV) CLONE 13 INTO RECIPIENT MICE THAT HAD CLEARED AN ACUTE INFECTION. WE OBSERVED THAT LCMV-SPECIFIC CD8 T CELLS FROM CHRONICALLY INFECTED MICE MAINTAINED THEIR SURFACE EXPRESSION OF PD-1 EVEN AFTER TRANSFER INTO ACUTE IMMUNE MICE UNTIL DAY 45 POSTTRANSFER. INTERESTINGLY, THE PD-1 TRANSCRIPTIONAL REGULATORY REGION CONTINUED TO REMAIN UNMETHYLATED IN THESE DONOR CD8 T CELLS GENERATED FROM A CHRONIC INFECTION. THE OBSERVED MAINTENANCE OF PD-1 SURFACE EXPRESSION AND THE DEMETHYLATED PD-1 PROMOTER WERE NOT A RESULT OF RESIDUAL ANTIGEN IN THE RECIPIENT MICE, BECAUSE SIMILAR RESULTS WERE SEEN WHEN CHRONIC INFECTION-INDUCED EFFECTOR CELLS WERE TRANSFERRED INTO MICE INFECTED WITH A VARIANT STRAIN OF LCMV (LCMV V35A) BEARING A MUTATION IN THE COGNATE MAJOR HISTOCOMPATIBILITY COMPLEX CLASS I (MHC-I) EPITOPE THAT IS RECOGNIZED BY THE DONOR CD8 T CELLS. IMPORTANTLY, THE MAINTENANCE OF PD-1 PROMOTER DEMETHYLATION IN MEMORY CD8 T CELLS WAS COUPLED WITH IMPAIRED CLONAL EXPANSION AND HIGHER PD-1 RE-EXPRESSION UPON SECONDARY CHALLENGE. THESE DATA SHOW THAT THE IMPRINTING OF THE EPIGENETIC PROGRAM OF THE INHIBITORY RECEPTOR PD-1 OCCURS DURING THE EFFECTOR PHASE OF CHRONIC VIRAL INFECTION. IMPORTANCE: SINCE PD-1 IS A MAJOR INHIBITORY RECEPTOR REGULATING T CELL DYSFUNCTION DURING CHRONIC VIRAL INFECTION AND CANCERS, A BETTER UNDERSTANDING OF THE MECHANISMS THAT REGULATE PD-1 EXPRESSION IS IMPORTANT. IN THIS WORK, WE DEMONSTRATE THAT THE PD-1 EPIGENETIC PROGRAM IN ANTIGEN-SPECIFIC CD8 T CELLS IS FIXED DURING THE PRIMING PHASE OF CHRONIC INFECTION.	2016	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                               
13  6540  35 TRANSCRIPTIONAL, EPIGENETIC, AND FUNCTIONAL REPROGRAMMING OF MONOCYTES FROM NON-HUMAN PRIMATES FOLLOWING CHRONIC ALCOHOL DRINKING. CHRONIC HEAVY DRINKING (CHD) OF ALCOHOL IS A KNOWN RISK FACTOR FOR INCREASED SUSCEPTIBILITY TO BACTERIAL AND VIRAL INFECTION AS WELL AS IMPAIRED WOUND HEALING. EVIDENCE SUGGESTS THAT THESE DEFECTS ARE MEDIATED BY A DYSREGULATED INFLAMMATORY RESPONSE ORIGINATING FROM MYELOID CELLS, NOTABLY MONOCYTES AND MACROPHAGES, BUT THE MECHANISMS REMAIN POORLY UNDERSTOOD. OUR ABILITY TO STUDY CHD IS IMPACTED BY THE COMPLEXITIES OF HUMAN DRINKING PATTERNS AND BEHAVIOR AS WELL AS COMORBIDITIES AND CONFOUNDING RISK FACTORS FOR PATIENTS WITH ALCOHOL USE DISORDERS. TO OVERCOME THESE CHALLENGES, WE UTILIZED A TRANSLATIONAL RHESUS MACAQUE MODEL OF VOLUNTARY ETHANOL SELF-ADMINISTRATION THAT CLOSELY RECAPITULATES HUMAN DRINKING PATTERNS AND CHRONICITY. IN THIS STUDY, WE EXAMINED THE EFFECTS OF CHD ON BLOOD MONOCYTES IN CONTROL AND CHD FEMALE MACAQUES AFTER 12 MONTHS OF DAILY ETHANOL CONSUMPTION. WHILE MONOCYTES FROM CHD FEMALE MACAQUES GENERATED A HYPER-INFLAMMATORY RESPONSE TO EX VIVO LPS STIMULATION, THEIR RESPONSE TO E. COLI WAS DAMPENED. IN DEPTH SCRNA-SEQ ANALYSIS OF PURIFIED MONOCYTES REVEALED SIGNIFICANT SHIFTS IN CLASSICAL MONOCYTE SUBSETS WITH ACCUMULATION OF CELLS EXPRESSING MARKERS OF HYPOXIA (HIF1A) AND INFLAMMATION (NFKB SIGNALING PATHWAY) IN CHD MACAQUES. THE INCREASED PRESENCE OF MONOCYTE SUBSETS SKEWED TOWARDS INFLAMMATORY PHENOTYPES WAS COMPLEMENTED BY EPIGENETIC ANALYSIS, WHICH REVEALED HIGHER ACCESSIBILITY OF PROMOTER REGIONS THAT REGULATE GENES INVOLVED IN CYTOKINE SIGNALING PATHWAYS. COLLECTIVELY, DATA PRESENTED IN THIS MANUSCRIPT DEMONSTRATE THAT CHD SHIFTS CLASSICAL MONOCYTE SUBSET COMPOSITION AND PRIMES THE MONOCYTES TOWARDS A MORE HYPER-INFLAMMATORY RESPONSE TO LPS, BUT COMPROMISED PATHOGEN RESPONSE.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                             
14  6502  25 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                         
15  4041  36 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                            
16  2365  30 EPIGENETIC REGULATION OF SPINAL CXCR2 SIGNALING IN INCISIONAL HYPERSENSITIVITY IN MICE. BACKGROUND: THE REGULATION OF GENE EXPRESSION IN NOCICEPTIVE PATHWAYS CONTRIBUTES TO THE INDUCTION AND MAINTENANCE OF PAIN SENSITIZATION. HISTONE ACETYLATION IS A KEY EPIGENETIC MECHANISM CONTROLLING CHROMATIN STRUCTURE AND GENE EXPRESSION. CHEMOKINE CC MOTIF RECEPTOR 2 (CXCR2) IS A PROINFLAMMATORY RECEPTOR IMPLICATED IN NEUROPATHIC AND INFLAMMATORY PAIN AND IS KNOWN TO BE REGULATED BY HISTONE ACETYLATION IN SOME SETTINGS. THE AUTHORS SOUGHT TO INVESTIGATE THE ROLE OF HISTONE ACETYLATION ON SPINAL CXCR2 SIGNALING AFTER INCISION. METHODS: GROUPS OF 5-8 MICE UNDERWENT HIND PAW INCISION. SUBEROYLANILIDE HYDROXAMIC ACID AND ANACARDIC ACID WERE USED TO INHIBIT HISTONE DEACETYLASE AND HISTONE ACETYLTRANSFERASE, RESPECTIVELY. BEHAVIORAL MEASURES OF THERMAL AND MECHANICAL SENSITIZATION AS WELL AS HYPERALGESIC PRIMING WERE USED. BOTH MESSAGE RNA QUANTIFICATION AND CHROMATIN IMMUNOPRECIPITATION ANALYSIS WERE USED TO STUDY THE REGULATION OF CXCR2 AND LIGAND EXPRESSION. FINALLY, THE SELECTIVE CXCR2 ANTAGONIST SB225002 WAS ADMINISTERED INTRATHECALLY TO REVEAL THE FUNCTION OF SPINAL CXCR2 RECEPTORS AFTER HIND PAW INCISION. RESULTS: SUBEROYLANILIDE HYDROXAMIC ACID SIGNIFICANTLY EXACERBATED MECHANICAL SENSITIZATION AFTER INCISION. CONVERSELY, ANACARDIC ACID REDUCED INCISIONAL SENSITIZATION AND ALSO ATTENUATED INCISION-INDUCED HYPERALGESIC PRIMING. OVERALL, ACETYLATED HISTONE H3 AT LYSINE 9 WAS INCREASED IN SPINAL CORD TISSUES AFTER INCISION, AND ENHANCED ASSOCIATION OF ACETYLATED HISTONE H3 AT LYSINE 9 WITH THE PROMOTER REGIONS OF CXCR2 AND KERATINOCYTE-DERIVED CHEMOKINE (CXCL1) WAS OBSERVED AS WELL. BLOCKING CXCR2 REVERSED MECHANICAL HYPERSENSITIVITY AFTER HIND PAW INCISION. CONCLUSIONS: HISTONE MODIFICATION IS AN IMPORTANT EPIGENETIC MECHANISM REGULATING INCISION-INDUCED NOCICEPTIVE SENSITIZATION. THE SPINAL CXCR2 SIGNALING PATHWAY IS ONE EPIGENETICALLY REGULATED PATHWAY CONTROLLING EARLY AND LATENT SENSITIZATION AFTER INCISION.	2013	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                
17  6376  31 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	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                 
18  4278  31 MICROGLIAL INNATE MEMORY AND EPIGENETIC REPROGRAMMING IN NEUROLOGICAL DISORDERS. MICROGLIA ARE MYELOID-DERIVED CELLS RECOGNIZED AS BRAIN-RESIDENT MACROPHAGES. THEY ACT AS THE FIRST AND MAIN LINE OF IMMUNE DEFENSE IN THE CENTRAL NERVOUS SYSTEM (CNS). MICROGLIA HAVE HIGH PHENOTYPIC PLASTICITY AND ARE ESSENTIAL FOR REGULATING HEALTHY BRAIN HOMEOSTASIS, AND THEIR DYSREGULATION UNDERLIES THE ONSET AND PROGRESSION OF SEVERAL CNS PATHOLOGIES THROUGH IMPAIRED INFLAMMATORY RESPONSES. ABERRANT MICROGLIAL ACTIVATION, FOLLOWING AN INFLAMMATORY INSULT, IS ASSOCIATED WITH EPIGENETIC DYSREGULATION IN VARIOUS CNS PATHOLOGIES. EMERGING DATA SUGGEST THAT CERTAIN STIMULI TO MYELOID CELLS DETERMINE ENHANCED OR ATTENUATED RESPONSES TO SUBSEQUENT STIMULI. THESE PHENOMENA, GENERALLY TERMED INNATE IMMUNE MEMORY (IIM), ARE HIGHLY DEPENDENT ON EPIGENETIC REPROGRAMMING. MICROGLIAL PRIMING HAS BEEN REPORTED IN SEVERAL NEUROLOGICAL DISEASES AND CORRESPONDS TO A STATE OF INCREASED PERMISSIVENESS OR EXACERBATED RESPONSE, PROMOTED BY CONTINUOUS EXPOSURE TO A CHRONIC PRO-INFLAMMATORY ENVIRONMENT. IN THIS ARTICLE, WE PROVIDE EXTENSIVE EVIDENCE OF THESE EPIGENETIC-MEDIATED PHENOMENA UNDER NEUROLOGICAL CONDITIONS AND DISCUSS THEIR CONTRIBUTION TO PATHOGENESIS AND THEIR CLINICAL IMPLICATIONS, INCLUDING THOSE CONCERNING POTENTIAL NOVEL THERAPEUTIC APPROACHES.	2021	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                     
19  2026  31 EPIGENETIC CHANGES IN BONE MARROW PROGENITOR CELLS INFLUENCE THE INFLAMMATORY PHENOTYPE AND ALTER WOUND HEALING IN TYPE 2 DIABETES. CLASSICALLY ACTIVATED (M1) MACROPHAGES ARE KNOWN TO PLAY A ROLE IN THE DEVELOPMENT OF CHRONIC INFLAMMATION ASSOCIATED WITH IMPAIRED WOUND HEALING IN TYPE 2 DIABETES (T2D); HOWEVER, THE MECHANISM RESPONSIBLE FOR THE DOMINANT PROINFLAMMATORY (M1) MACROPHAGE PHENOTYPE IN T2D WOUNDS IS UNKNOWN. SINCE EPIGENETIC ENZYMES CAN DIRECT MACROPHAGE PHENOTYPES, WE ASSESSED THE ROLE OF HISTONE METHYLATION IN BONE MARROW (BM) STEM/PROGENITOR CELLS IN THE PROGRAMMING OF MACROPHAGES TOWARD A PROINFLAMMATORY PHENOTYPE. WE HAVE FOUND THAT A REPRESSIVE HISTONE METHYLATION MARK, H3K27ME3, IS DECREASED AT THE PROMOTER OF THE IL-12 GENE IN BM PROGENITORS AND THIS EPIGENETIC SIGNATURE IS PASSED DOWN TO WOUND MACROPHAGES IN A MURINE MODEL OF GLUCOSE INTOLERANCE (DIET-INDUCED OBESE). THESE EPIGENETICALLY "PREPROGRAMMED" MACROPHAGES RESULT IN POISED MACROPHAGES IN PERIPHERAL TISSUE AND NEGATIVELY IMPACT WOUND REPAIR. WE FOUND THAT IN DIABETIC CONDITIONS THE H3K27 DEMETHYLASE JMJD3 DRIVES IL-12 PRODUCTION IN MACROPHAGES AND THAT IL-12 PRODUCTION CAN BE MODULATED BY INHIBITING JMJD3. USING HUMAN T2D TISSUE AND MURINE MODELS, WE HAVE IDENTIFIED A PREVIOUSLY UNRECOGNIZED MECHANISM BY WHICH MACROPHAGES ARE PROGRAMMED TOWARD A PROINFLAMMATORY PHENOTYPE, ESTABLISHING A PATTERN OF UNRESTRAINED INFLAMMATION ASSOCIATED WITH NONHEALING WOUNDS. HENCE, HISTONE DEMETHYLASE INHIBITOR-BASED THERAPY MAY REPRESENT A NOVEL TREATMENT OPTION FOR DIABETIC WOUNDS.	2015	
                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                                  
20  6505  27 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