1 5760 154 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 2 3701 31 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 6669 31 URIC ACID IN METABOLIC SYNDROME: DOES URIC ACID HAVE A DEFINITIVE ROLE? INCREASED SERUM URIC ACID (SUA) LEVELS ARE COMMONLY SEEN IN PATIENTS WITH METABOLIC SYNDROME AND ARE WIDELY ACCEPTED AS RISK FACTORS FOR HYPERTENSION, GOUT, NON-ALCOHOLIC FATTY LIVER DISEASE, CHRONIC KIDNEY DISEASE (CKD), AND CARDIOVASCULAR DISEASES. ALTHOUGH SOME AMBIGUITY FOR THE EXACT ROLE OF URIC ACID (UA) IN THESE DISEASES IS STILL PRESENT, SEVERAL PATHOPHYSIOLOGICAL MECHANISMS HAVE BEEN IDENTIFIED SUCH AS INCREASED OXIDATIVE STRESS, INFLAMMATION, AND APOPTOSIS. ACCUMULATING EVIDENCE IN GENOMICS ENLIGHTENS GENETIC VARIABILITIES AND SOME EPIGENETIC CHANGES THAT CAN CONTRIBUTE TO HYPERURICEMIA. HERE WE DISCUSS THE ROLE OF UA WITHIN METABOLISM AND THE CONSEQUENCES OF ASYMPTOMATIC HYPERURICEMIA WHILE PROVIDING NEWFOUND EVIDENCE FOR THE ASSOCIATIONS BETWEEN UA AND GUT MICROBIOTA AND VITAMIN D. INCREASED SUA LEVELS AND BENEFICIAL EFFECTS OF LOWERING SUA LEVELS NEED TO BE ELUCIDATED MORE TO UNDERSTAND ITS COMPLICATED FUNCTION WITHIN DIFFERENT METABOLIC PATHWAYS AND SET OPTIMAL TARGET LEVELS FOR SUA FOR REDUCING RISKS FOR METABOLIC AND CARDIOVASCULAR DISEASES. 2022 4 6667 39 URATE-INDUCED IMMUNE PROGRAMMING: CONSEQUENCES FOR GOUTY ARTHRITIS AND HYPERURICEMIA. TRAINED IMMUNITY IS A PROCESS IN WHICH INNATE IMMUNE CELLS UNDERGO FUNCTIONAL REPROGRAMMING IN RESPONSE TO PATHOGENS OR DAMAGE-ASSOCIATED MOLECULES LEADING TO AN ENHANCED NON-SPECIFIC IMMUNE RESPONSE TO SUBSEQUENT STIMULATION. WHILE THIS CAPACITY TO RESPOND MORE STRONGLY TO STIMULI IS BENEFICIAL FOR HOST DEFENSE, IN SOME CIRCUMSTANCES IT CAN LEAD TO MALADAPTIVE PROGRAMMING AND CHRONIC INFLAMMATION. GOUT IS CHARACTERIZED BY PERSISTENT LOW-GRADE INFLAMMATION AND IS ASSOCIATED WITH AN INCREASED NUMBER OF COMORBIDITIES. HYPERURICEMIA IS THE MAIN RISK FACTOR FOR GOUT AND IS LINKED TO THE DEVELOPMENT OF COMORBIDITIES. SEVERAL EXPERIMENTAL STUDIES HAVE SHOWN THAT URATE CAN MECHANISTICALLY ALTER THE INFLAMMATORY CAPACITY OF MYELOID CELLS, WHILE OBSERVATIONAL STUDIES HAVE INDICATED AN ASSOCIATION OF HYPERURICEMIA TO A WIDE SPECTRUM OF COMMON ADULT INFLAMMATORY DISEASES. IN THIS REVIEW, WE ARGUE THAT HYPERURICEMIA IS A MAIN CULPRIT IN THE DEVELOPMENT OF THE LONG-TERM SYSTEMIC INFLAMMATION SEEN IN GOUT. WE REVISIT EXISTING EVIDENCE FOR URATE-INDUCED TRANSCRIPTIONAL AND EPIGENETIC REPROGRAMMING THAT COULD LEAD TO AN ALTERED FUNCTIONAL STATE OF CIRCULATING MONOCYTES CONSISTING IN ENHANCED RESPONSIVENESS AND MALADAPTIVE IMMUNE RESPONSES. BY DISCUSSING SPECIFIC FUNCTIONAL ADAPTATIONS OF MONOCYTES AND MACROPHAGES INDUCED BY SOLUBLE URATE OR MONOSODIUM URATE CRYSTALS AND THEIR CONTRIBUTION TO INFLAMMATION IN VITRO AND IN VIVO, WE FURTHER ENFORCE THAT URATE IS A METABOLITE THAT CAN INDUCE INNATE IMMUNE MEMORY AND WE DISCUSS FUTURE RESEARCH AND POSSIBLE NEW THERAPEUTIC APPROACHES FOR GOUT AND ITS COMORBIDITIES. 2020 5 537 31 ASYMPTOMATIC HYPERURICEMIA: IS IT REALLY ASYMPTOMATIC? PURPOSE OF REVIEW: HYPERURICEMIA IS HIGHLY PREVALENT, AFFECTING APPROXIMATELY 38 MILLION INDIVIDUALS IN THE UNITED STATES. HOWEVER, THE SIGNIFICANCE OF ASYMPTOMATIC HYPERURICEMIA - HYPERURICEMIA IN THE ABSENCE OF GOUT - CONTINUES TO BE DEBATED. RECENT FINDINGS: ASYMPTOMATIC HYPERURICEMIA RESULTS IN MONOSODIUM URATE CRYSTAL DEPOSITION IN TISSUES, WHICH MAY PROMOTE CHRONIC INFLAMMATION. INTRACELLULARLY, HYPERURICEMIA INHIBITS THE MASTER REGULATOR ADENOSINE MONOPHOSPHATE (AMP)-ASSOCIATED PROTEIN KINASE AND MAY CONDITION INNATE IMMUNE RESPONSES THROUGH DURABLE EPIGENETIC MODIFICATIONS. AT THE POPULATION LEVEL, ASYMPTOMATIC HYPERURICEMIA IS ASSOCIATED WITH MULTIPLE COMORBIDITIES, INCLUDING HYPERTENSION, CHRONIC KIDNEY DISEASE, CORONARY ARTERY DISEASE, AND DIABETES; LIMITATIONS OF THESE STUDIES INCLUDE THAT MOST ARE RETROSPECTIVE AND SOME DO NOT RIGOROUSLY DISTINGUISH BETWEEN ASYMPTOMATIC HYPERURICEMIA AND GOUT. TREATMENT STUDIES SUGGEST THAT URATE LOWERING MAY REDUCE THE RISK OF INCIDENCE OR PROGRESSION OF SOME OF THESE COMORBIDITIES; UNFORTUNATELY, MANY OF THESE TREATMENT STUDIES ARE SMALL OR FLAWED, AND NOT ALL STUDY RESULTS ARE CONSISTENT. SUMMARY: ACCUMULATING EVIDENCE SUGGESTS THAT ASYMPTOMATIC HYPERURICEMIA CONTRIBUTES TO THE COMORBIDITIES WITH WHICH IT ASSOCIATES AND THAT PROPER ASYMPTOMATIC HYPERURICEMIA TREATMENT MAY REDUCE FUTURE RISK. ADDITIONAL PROSPECTIVE TRIALS ARE NEEDED TO DEFINITELY ESTABLISH CAUSALITY AND SUPPORT DECISION-MAKING AS TO WHETHER, AND WHICH PATIENTS WITH ASYMPTOMATIC HYPERURICEMIA WOULD WARRANT URATE-LOWERING TREATMENT. 2020 6 1862 43 EMERGENCE OF FIBROBLASTS WITH A PROINFLAMMATORY EPIGENETICALLY ALTERED PHENOTYPE IN SEVERE HYPOXIC PULMONARY HYPERTENSION. PERSISTENT ACCUMULATION OF MONOCYTES/MACROPHAGES IN THE PULMONARY ARTERY ADVENTITIAL/PERIVASCULAR AREAS OF ANIMALS AND HUMANS WITH PULMONARY HYPERTENSION HAS BEEN DOCUMENTED. THE CELLULAR MECHANISMS CONTRIBUTING TO CHRONIC INFLAMMATORY RESPONSES REMAIN UNCLEAR. WE HYPOTHESIZED THAT PERIVASCULAR INFLAMMATION IS PERPETUATED BY ACTIVATED ADVENTITIAL FIBROBLASTS, WHICH, THROUGH SUSTAINED PRODUCTION OF PROINFLAMMATORY CYTOKINES/CHEMOKINES AND ADHESION MOLECULES, INDUCE ACCUMULATION, RETENTION, AND ACTIVATION OF MONOCYTES/MACROPHAGES. WE FURTHER HYPOTHESIZED THAT THIS PROINFLAMMATORY PHENOTYPE IS THE RESULT OF THE ABNORMAL ACTIVITY OF HISTONE-MODIFYING ENZYMES, SPECIFICALLY, CLASS I HISTONE DEACETYLASES (HDACS). PULMONARY ADVENTITIAL FIBROBLASTS FROM CHRONICALLY HYPOXIC HYPERTENSIVE CALVES (TERMED PH-FIBS) EXPRESSED A CONSTITUTIVE AND PERSISTENT PROINFLAMMATORY PHENOTYPE DEFINED BY HIGH EXPRESSION OF IL-1BETA, IL-6, CCL2(MCP-1), CXCL12(SDF-1), CCL5(RANTES), CCR7, CXCR4, GM-CSF, CD40, CD40L, AND VCAM-1. THE PROINFLAMMATORY PHENOTYPE OF PH-FIBS WAS ASSOCIATED WITH EPIGENETIC ALTERATIONS AS DEMONSTRATED BY INCREASED ACTIVITY OF HDACS AND THE FINDINGS THAT CLASS I HDAC INHIBITORS MARKEDLY DECREASED CYTOKINE/CHEMOKINE MRNA EXPRESSION LEVELS IN THESE CELLS. PH-FIBS INDUCED INCREASED ADHESION OF THP-1 MONOCYTES AND PRODUCED SOLUBLE FACTORS THAT INDUCED INCREASED MIGRATION OF THP-1 AND MURINE BONE MARROW-DERIVED MACROPHAGES AS WELL AS ACTIVATED MONOCYTES/MACROPHAGES TO EXPRESS PROINFLAMMATORY CYTOKINES AND PROFIBROGENIC MEDIATORS (TIMP1 AND TYPE I COLLAGEN) AT THE TRANSCRIPTIONAL LEVEL. CLASS I HDAC INHIBITORS MARKEDLY REDUCED THE ABILITY OF PH-FIBS TO INDUCE MONOCYTE MIGRATION AND PROINFLAMMATORY ACTIVATION. THE EMERGENCE OF A DISTINCT ADVENTITIAL FIBROBLAST POPULATION WITH AN EPIGENETICALLY ALTERED PROINFLAMMATORY PHENOTYPE CAPABLE OF RECRUITING, RETAINING, AND ACTIVATING MONOCYTES/MACROPHAGES CHARACTERIZES PULMONARY HYPERTENSION-ASSOCIATED VASCULAR REMODELING AND THUS COULD CONTRIBUTE SIGNIFICANTLY TO CHRONIC INFLAMMATORY PROCESSES IN THE PULMONARY ARTERY WALL. 2011 7 3188 31 HBV-SPECIFIC CD8+ T-CELL TOLERANCE IN THE LIVER. HEPATITIS B VIRUS (HBV) REMAINS A LEADING CAUSE OF LIVER-RELATED MORBIDITY AND MORTALITY THROUGH CHRONIC HEPATITIS THAT MAY PROGRESS TO LIVER CIRRHOSIS AND CANCER. THE CENTRAL ROLE PLAYED BY HBV-SPECIFIC CD8+ T CELLS IN THE CLEARANCE OF ACUTE HBV INFECTION, AND HBV-RELATED LIVER INJURY IS NOW WELL ESTABLISHED. VIGOROUS, MULTIFUNCTIONAL CD8+ T CELL RESPONSES ARE USUALLY INDUCED IN MOST ADULT-ONSET HBV INFECTIONS, WHILE CHRONIC HEPATITIS B (CHB) IS CHARACTERIZED BY QUANTITATIVELY AND QUALITATIVELY WEAK HBV-SPECIFIC CD8+ T CELL RESPONSES. THE MOLECULAR BASIS OF THIS DICHOTOMY IS POORLY UNDERSTOOD. GENOMIC ANALYSIS OF DYSFUNCTIONAL HBV-SPECIFIC CD8+ T CELLS IN CHB PATIENTS AND VARIOUS MOUSE MODELS SUGGEST THAT MULTIFACETED MECHANISMS INCLUDING NEGATIVE SIGNALING AND METABOLIC ABNORMALITIES COOPERATIVELY ESTABLISH CD8+ T CELL DYSFUNCTION. IMMUNOREGULATORY CELL POPULATIONS IN THE LIVER, INCLUDING LIVER RESIDENT DENDRITIC CELLS (DCS), HEPATIC STELLATE CELLS (HSCS), MYELOID-DERIVED SUPPRESSOR CELLS (MDSCS), MAY CONTRIBUTE TO INTRAHEPATIC CD8+ T CELL DYSFUNCTION THROUGH THE PRODUCTION OF SOLUBLE MEDIATORS, SUCH AS ARGINASE, INDOLEAMINE 2,3-DIOXYGENASE (IDO) AND SUPPRESSIVE CYTOKINES AND THE EXPRESSION OF CO-INHIBITORY MOLECULES. A SERIES OF RECENT STUDIES WITH MOUSE MODELS OF HBV INFECTION SUGGEST THAT GENETIC AND EPIGENETIC CHANGES IN DYSFUNCTIONAL CD8+ T CELLS ARE THE MANIFESTATION OF PROLONGED ANTIGENIC STIMULATION, AS WELL AS THE ABSENCE OF CO-STIMULATORY OR CYTOKINE SIGNALING. THESE NEW FINDINGS MAY PROVIDE POTENTIAL NEW TARGETS FOR IMMUNOTHERAPY AIMING AT INVIGORATING HBV-SPECIFIC CD8+ T CELLS, WHICH HOPEFULLY CURES CHB. 2021 8 6891 20 [SIGNAL RECEPTORS OF CONGENITAL IMMUNITY: A NEW MOLECULAR TARGET FOR DIAGNOSTICS AND TREATMENT OF INFLAMMATORY DISEASES]. THE DISCOVERY OF SIGNAL RECEPTORS OF CONGENITAL IMMUNITY (SIGNAL PRR) NOT ONLY PROVIDED A NOVEL VIEW OF BASIC ASPECTS OF PATHOGENESIS OF CHRONIC INFLAMMATORY DISEASES BUT ALSO CREATED A BASIS FOR THE DEVELOPMENT OF ADDITIONAL DIAGNOSTIC CRITERIA FOR THESE PATHOLOGIES AND NEW PHARMACEUTICALS FOR THEIR TREATMENT. REDUCED EXPRESSION AND FUNCTION OF PRR DUE TO MUTATIONS/POLYMORPHISMS OR EPIGENETIC DISTURBANCES OF REGULATION CAN BE REGARDED AS IMMUNODEFICIENT CONDITIONS MANIFEST AS SEVERE INFECTIOUS INFLAMMATORY DISEASES. IN CONTRAST, EXCESSIVE EXPRESSION AND ACTIVATION OF PRR AS A RULE LEADS TO CHRONIC AUTOINFLAMMATORY, AUTOIMMUNE, AND ATOPIC DISEASES INVOLVING ADAPTIVE IMMUNITY AND AGGRESSION AGAINST OWN TISSUES AND CELLS. ASSESSMENT OF CERTAIN MUTATIONS IN PRR GENES, THEIR EXPRESSION AND ACTIVATION PROVIDES A POWERFUL TOOL FOR IN-DEPTH DIAGNOSTICS OF INFLAMMATORY DISEASES. SIMULTANEOUSLY, NEW LINES OF IMMUNOSTIMULATING AND ANTI-INFLAMMATORY THERAPY ARE DEVELOPED BASED ON THE KNOWLEDGE OF MOLECULAR PHYSIOLOGY OF PRR WITH THE USE OF SYNTHETIC AGONISTS AND ANTAGONISTS OF SIGNAL PRR. 2011 9 3688 35 INFLAMMATION: GEARING THE JOURNEY TO CANCER. CHRONIC INFLAMMATION PLAYS A MULTIFACETED ROLE IN CARCINOGENESIS. MOUNTING EVIDENCE FROM PRECLINICAL AND CLINICAL STUDIES SUGGESTS THAT PERSISTENT INFLAMMATION FUNCTIONS AS A DRIVING FORCE IN THE JOURNEY TO CANCER. THE POSSIBLE MECHANISMS BY WHICH INFLAMMATION CAN CONTRIBUTE TO CARCINOGENESIS INCLUDE INDUCTION OF GENOMIC INSTABILITY, ALTERATIONS IN EPIGENETIC EVENTS AND SUBSEQUENT INAPPROPRIATE GENE EXPRESSION, ENHANCED PROLIFERATION OF INITIATED CELLS, RESISTANCE TO APOPTOSIS, AGGRESSIVE TUMOR NEOVASCULARIZATION, INVASION THROUGH TUMOR-ASSOCIATED BASEMENT MEMBRANE AND METASTASIS, ETC. INFLAMMATION-INDUCED REACTIVE OXYGEN AND NITROGEN SPECIES CAUSE DAMAGE TO IMPORTANT CELLULAR COMPONENTS (E.G., DNA, PROTEINS AND LIPIDS), WHICH CAN DIRECTLY OR INDIRECTLY CONTRIBUTE TO MALIGNANT CELL TRANSFORMATION. OVEREXPRESSION, ELEVATED SECRETION, OR ABNORMAL ACTIVATION OF PROINFLAMMATORY MEDIATORS, SUCH AS CYTOKINES, CHEMOKINES, CYCLOOXYGENASE-2, PROSTAGLANDINS, INDUCIBLE NITRIC OXIDE SYNTHASE, AND NITRIC OXIDE, AND A DISTINCT NETWORK OF INTRACELLULAR SIGNALING MOLECULES INCLUDING UPSTREAM KINASES AND TRANSCRIPTION FACTORS FACILITATE TUMOR PROMOTION AND PROGRESSION. WHILE INFLAMMATION PROMOTES DEVELOPMENT OF CANCER, COMPONENTS OF THE TUMOR MICROENVIRONMENT, SUCH AS TUMOR CELLS, STROMAL CELLS IN SURROUNDING TISSUE AND INFILTRATED INFLAMMATORY/IMMUNE CELLS GENERATE AN INTRATUMORAL INFLAMMATORY STATE BY ABERRANT EXPRESSION OR ACTIVATION OF SOME PROINFLAMMATORY MOLECULES. MANY OF PROINFLAMMATORY MEDIATORS, ESPECIALLY CYTOKINES, CHEMOKINES AND PROSTAGLANDINS, TURN ON THE ANGIOGENIC SWITCHES MAINLY CONTROLLED BY VASCULAR ENDOTHELIAL GROWTH FACTOR, THEREBY INDUCING INFLAMMATORY ANGIOGENESIS AND TUMOR CELL-STROMA COMMUNICATION. THIS WILL END UP WITH TUMOR ANGIOGENESIS, METASTASIS AND INVASION. MOREOVER, CELLULAR MICRORNAS ARE EMERGING AS A POTENTIAL LINK BETWEEN INFLAMMATION AND CANCER. THE PRESENT ARTICLE HIGHLIGHTS THE ROLE OF VARIOUS PROINFLAMMATORY MEDIATORS IN CARCINOGENESIS AND THEIR PROMISE AS POTENTIAL TARGETS FOR CHEMOPREVENTION OF INFLAMMATION-ASSOCIATED CARCINOGENESIS. 2008 10 5592 34 ROLE OF TUMOR NECROSIS FACTOR-ALPHA IN THE HUMAN SYSTEMIC ENDOTOXIN-INDUCED TRANSCRIPTOME. TNFALPHA HAS BEEN IMPLICATED IN THE PATHOGENESIS OF VARIOUS INFLAMMATORY DISEASES. DIFFERENT STRATEGIES TO INHIBIT TNFALPHA IN PATIENTS WITH SEPSIS AND CHRONIC INFLAMMATORY CONDITIONS HAVE SHOWN CONTRASTING OUTCOMES. ALTHOUGH TNFALPHA INHIBITORS ARE WIDELY USED IN CLINICAL PRACTICE, THE IMPACT OF TNFALPHA ANTAGONISM ON WHITE BLOOD CELL GENE EXPRESSION PROFILES DURING ACUTE INFLAMMATION IN HUMANS IN VIVO HAS NOT BEEN ASSESSED. WE HERE LEVERAGED THE ESTABLISHED MODEL OF HUMAN ENDOTOXEMIA TO EXAMINE THE EFFECT OF THE TNFALPHA ANTAGONIST, ETANERCEPT, ON THE GENOME-WIDE TRANSCRIPTIONAL RESPONSES IN CIRCULATING LEUKOCYTES INDUCED BY INTRAVENOUS LPS ADMINISTRATION IN MALE SUBJECTS. ETANERCEPT PRE-TREATMENT RESULTED IN A MARKEDLY DAMPENED TRANSCRIPTIONAL RESPONSE TO LPS. GENE CO-EXPRESSION NETWORK ANALYSIS REVEALED THIS LPS-INDUCED TRANSCRIPTOME CAN BE CATEGORIZED AS TNFALPHA RESPONSIVE AND NON-RESPONSIVE MODULES. HIGHLY SIGNIFICANT TNFALPHA RESPONSIVE MODULES INCLUDE NF-KB SIGNALING, ANTIVIRAL RESPONSES AND T-CELL MEDIATED RESPONSES. WITHIN THESE TNFALPHA RESPONSIVE MODULES WE DELINEATE FUNDAMENTAL GENES INVOLVED IN EPIGENETIC MODIFICATIONS, TRANSCRIPTIONAL INITIATION AND ELONGATION. THUS, WE PROVIDE COMPREHENSIVE INFORMATION ABOUT MOLECULAR PATHWAYS THAT MIGHT BE TARGETED BY THERAPEUTIC INTERVENTIONS THAT SEEK TO INHIBIT TNFALPHA ACTIVITY DURING HUMAN INFLAMMATORY DISEASES. 2013 11 4044 25 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 12 2067 36 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 13 4304 32 MICRORNA-223 PROTECTS NEURONS FROM DEGENERATION IN EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS. MULTIPLE SCLEROSIS IS A CHRONIC INFLAMMATORY, DEMYELINATING, AND NEURODEGENERATIVE DISEASE AFFECTING THE BRAIN, SPINAL CORD AND OPTIC NERVES. NEURONAL DAMAGE IS TRIGGERED BY VARIOUS HARMFUL FACTORS THAT ENGAGE DIVERSE SIGNALLING CASCADES IN NEURONS; THUS, THERAPEUTIC APPROACHES TO PROTECT NEURONS WILL NEED TO FOCUS ON AGENTS THAT CAN TARGET MULTIPLE BIOLOGICAL PROCESSES. WE HAVE THEREFORE FOCUSED OUR ATTENTION ON MICRORNAS: SMALL NON-CODING RNAS THAT PRIMARILY FUNCTION AS POST-TRANSCRIPTIONAL REGULATORS THAT TARGET MESSENGER RNAS AND REPRESS THEIR TRANSLATION INTO PROTEINS. A SINGLE MICRORNA CAN TARGET MANY FUNCTIONALLY RELATED MESSENGER RNAS MAKING MICRORNAS POWERFUL EPIGENETIC REGULATORS. DYSREGULATION OF MICRORNAS HAS BEEN DESCRIBED IN MANY NEURODEGENERATIVE DISEASES INCLUDING MULTIPLE SCLEROSIS. HERE, WE REPORT THAT TWO MICRORNAS, MIR-223-3P AND MIR-27A-3P, ARE UPREGULATED IN NEURONS IN THE EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS MOUSE MODEL OF CNS INFLAMMATION AND IN GREY MATTER-CONTAINING MULTIPLE SCLEROSIS LESIONS. PRIOR WORK HAS SHOWN PERIPHERAL BLOOD MONONUCLEAR CELL CONDITIONED MEDIA CAUSES SUBLETHAL DEGENERATION OF NEURONS IN CULTURE. WE FIND OVEREXPRESSION OF MIR-27A-3P OR MIR-223-3P PROTECTS DISSOCIATED CORTICAL NEURONS FROM CONDITION MEDIA MEDIATED DEGENERATION. INTRODUCTION OF MIR-223-3P IN VIVO IN MOUSE RETINAL GANGLION CELLS PROTECTS THEIR AXONS FROM DEGENERATION IN EXPERIMENTAL AUTOIMMUNE ENCEPHALOMYELITIS. IN SILICO ANALYSIS REVEALED THAT MESSENGER RNAS INVOLVED IN GLUTAMATE RECEPTOR SIGNALLING ARE ENRICHED AS MIR-27A-3P AND MIR-223-3P TARGETS. WE OBSERVE THAT ANTAGONISM OF NMDA AND AMPA TYPE GLUTAMATE RECEPTORS PROTECTS NEURONS FROM CONDITION MEDIA DEPENDENT DEGENERATION. OUR RESULTS SUGGEST THAT MIR-223-3P AND MIR-27A-3P ARE UPREGULATED IN RESPONSE TO INFLAMMATION TO MEDIATE A COMPENSATORY NEUROPROTECTIVE GENE EXPRESSION PROGRAM THAT DESENSITIZES NEURONS TO GLUTAMATE BY TARGETING MESSENGER RNAS INVOLVED IN GLUTAMATE RECEPTOR SIGNALLING. 2019 14 1701 42 DYNAMIC IMMUNE/INFLAMMATION PRECISION MEDICINE: THE GOOD AND THE BAD INFLAMMATION IN INFECTION AND CANCER. NORMAL OR "GOOD" INFLAMMATION PROCESS STARTS FROM A LOCAL CELLULAR RESPONSE AGAINST INJURY OR ANY INFECTIOUS AGENT, WITH THE ACTIVATION OF NEUTROPHILS, MACROPHAGES, LANGERHANS CELLS, DENDRITIC CELLS, AND INNATE IMMUNE CELLS. CYTOKINES AND CHEMOKINES ARE PRODUCED TO AMPLIFY THE LOCAL INFLAMMATORY PROCESS FOLLOWED BY THE MIGRATION OF IMMUNE CELLS TO THE REGIONAL LYMPH NODES WHERE ADAPTIVE IMMUNE RESPONSE IS INITIATED. SYSTEMIC INFLAMMATION ENHANCES THE BIOLOGICAL RESPONSE TO MOBILIZE ADDITIONAL CELLS FROM CENTRAL AND PERIPHERAL IMMUNE/HEMATOPOIETIC SYSTEM. LOCAL MECHANISMS TO LIMIT INFLAMMATION ARE INITIATED AND LEAD TO HEALING. DURING THE NORMAL INFLAMMATORY PROCESS, THERE IS A BALANCE BETWEEN THE PRODUCTION OF INFLAMMATORY CHEMOKINES/CYTOKINES SUCH AS TUMOR NECROSIS FACTOR (TNF)-ALPHA, INTERLEUKIN (IL)-6 AND IL-1 AND THE PRODUCTION OF COMPOUNDS THAT LIMIT INFLAMMATION AND HAVE AN IMMUNE SUPPRESSIVE EFFECT, SUCH AS IL-10 AND TRANSFORMING FACTOR (TGF) BETA. IL-6 AND IL-6/SOLUBLE IL-6 RECEPTOR (R) COMPLEX STIMULATE LIVER CELLS TO PRODUCE INFLAMMATORY PROTEINS, WHICH REPRESENTS THE SYSTEMIC INFLAMMATION RESPONSE. THE MAGNITUDE AND THE DURATION OF THE SYSTEMIC INFLAMMATORY RESPONSE ARE LINKED TO THE CAUSE, UNDER GENETIC AND EPIGENETIC CONTROL. SIGNIFICANT INFLAMMATION AS SEEN IN SEPTIC SHOCK, IN SEVERE FORMS OF INFECTIONS OR IN CERTAIN ACTIVE CANCERS, REPRESENTS THE "BAD INFLAMMATION", CORRELATED WITH A POOR PROGNOSIS. IN ADDITION, THE PERSISTENCE OF A CHRONIC SMOLDERING INFLAMMATION MAY LEAD TO PATHOLOGICAL SITUATIONS WHICH ARE OBSERVED IN THE MAJORITY OF INFLAMMATORY, DEGENERATIVE, DYSMETABOLIC, OR DYSIMMUNE DISEASES AND CANCER. CHRONIC SMOLDERING INFLAMMATION IS A CROSS BETWEEN DIFFERENT PATHOLOGICAL SITUATIONS POSSIBLY LINKED. IN ADDITION, WITHIN THE TUMOR MICROENVIRONMENT, INFLAMMATORY PROCESS RESULTS FROM DIFFERENT CELLULAR MECHANISMS MODULATED BY METABOLIC AND VASCULAR CHANGES. ON THE CONTRARY, A LIMITED AND BALANCED INFLAMMATION INITIATES THE NORMAL IMMUNE RESPONSE, INCLUDING THE ADAPTIVE RESPONSE WHICH AMPLIFIES ANY IMMUNOTHERAPY, INCLUDING VACCINES. IMMUNE CHECKPOINT INHIBITORS AND CHIMERIC ANTIGEN RECEPTOR (CAR) T-CELLS ARE ASSOCIATED WITH CYTOKINE RELEASE SYNDROME, A CLINICAL RISK LEADING TO THE USE OF ANTI-CYTOKINE DRUGS. NOWADAYS, IT IS TIME TO MONITOR THE DYNAMIC INFLAMMATORY PROCESS FOR A BETTER IMMUNE PRECISION MEDICINE IN BOTH INFECTIONS AND CANCER. 2021 15 3678 35 INFLAMMATION AND REGENERATION IN THE DENTIN-PULP COMPLEX: A DOUBLE-EDGED SWORD. DENTAL TISSUE INFECTION AND DISEASE RESULT IN ACUTE AND CHRONIC ACTIVATION OF THE INNATE IMMUNE RESPONSE, WHICH IS MEDIATED BY MOLECULAR AND CELLULAR SIGNALING. DIFFERENT CELL TYPES WITHIN THE DENTIN-PULP COMPLEX ARE ABLE TO DETECT INVADING BACTERIA AT ALL STAGES OF THE INFECTION. INDEED, AT RELATIVELY EARLY DISEASE STAGES, ODONTOBLASTS WILL RESPOND TO BACTERIAL COMPONENTS, AND AS THE DISEASE PROGRESSES, CORE PULPAL CELLS INCLUDING FIBROBLASTS, STEMS CELLS, ENDOTHELIAL CELLS, AND IMMUNE CELLS WILL BECOME INVOLVED. PATTERN RECOGNITION RECEPTORS, SUCH AS TOLL-LIKE RECEPTORS EXPRESSED ON THESE CELL TYPES, ARE RESPONSIBLE FOR DETECTING BACTERIAL COMPONENTS, AND THEIR LIGAND BINDING LEADS TO THE ACTIVATION OF THE NUCLEAR FACTOR-KAPPA B AND P38 MITOGEN-ACTIVATED PROTEIN (MAP) KINASE INTRACELLULAR SIGNALING CASCADES. SUBSEQUENT NUCLEAR TRANSLOCATION OF THE TRANSCRIPTION FACTOR SUBUNITS FROM THESE PATHWAYS WILL LEAD TO PROINFLAMMATORY MEDIATOR EXPRESSION, INCLUDING INCREASES IN CYTOKINES AND CHEMOKINES, WHICH TRIGGER HOST CELLULAR DEFENSE MECHANISMS. THE COMPLEX MOLECULAR SIGNALING WILL RESULT IN THE RECRUITMENT OF IMMUNE SYSTEM CELLS TARGETED AT COMBATING THE INVADING MICROBES; HOWEVER, THE TRAFFICKING AND ANTIBACTERIAL ACTIVITY OF THESE CELLS CAN LEAD TO COLLATERAL TISSUE DAMAGE. RECENT EVIDENCE SUGGESTS THAT IF INFLAMMATION IS RESOLVED RELATIVELY LOW LEVELS OF PROINFLAMMATORY MEDIATORS MAY PROMOTE TISSUE REPAIR, WHEREAS IF CHRONIC INFLAMMATION ENSUES REPAIR MECHANISMS BECOME INHIBITED. THUS, THE EFFECTS OF MEDIATORS ARE TEMPORAL CONTEXT DEPENDENT. ALTHOUGH CONTAINMENT AND REMOVAL OF THE INFECTION ARE KEYS TO ENABLE DENTAL TISSUE REPAIR, IT IS FEASIBLE THAT THE DEVELOPMENT OF ANTI-INFLAMMATORY AND IMMUNOMODULATORY APPROACHES, BASED ON MOLECULAR, EPIGENETIC, AND PHOTOBIOMODULATORY TECHNOLOGIES, MAY ALSO BE BENEFICIAL FOR FUTURE ENDODONTIC TREATMENTS. 2014 16 3540 30 IMMUNE-DERIVED CYTOKINES IN THE NERVOUS SYSTEM: EPIGENETIC INSTRUCTIVE SIGNALS OR NEUROPATHOGENIC MEDIATORS? THE INVESTIGATION OF THE EFFECTS OF INFLAMMATORY CYTOKINES (IC) ON THE GROWTH AND DIFFERENTIATION OF NEURAL CELLS HAS PROVIDED NEW INSIGHTS ON THE ROLE OF SUCH SOLUBLE MEDIATORS IN NERVOUS SYSTEM DEVELOPMENT AND/OR PLASTIC REMODELING AS WELL AS IN THE PATHOGENESIS OF INFLAMMATORY NEURODEGENERATIVE DISORDERS, WHICH ARE CHARACTERIZED BY CHRONIC IC DYSREGULATION IN THE CENTRAL NERVOUS SYSTEM (CNS). THUS, THE STUDY OF THE INTERACTION BETWEEN CNS AND IMMUNE-DERIVED SOLUBLE SIGNALS IN PHYSIOLOGICAL OR PATHOLOGICAL CONDITIONS IS OF INCREASING INTEREST. THIS REVIEW FIRST DISCUSSES EXPERIMENTAL EVIDENCE SUPPORTING THE INSTRUCTIVE/PERMISSIVE ROLE OF IMMUNE-DERIVED CYTOKINES ON CNS DEVELOPMENT AND PLASTICITY. NEXT, WE FOCUS ON HUMAN NEUROLOGICAL DISEASE STATES SUCH AS MULTIPLE SCLEROSIS AND THE NEURODEGENERATION ASSOCIATED TO THE ACQUIRED IMMUNE DEFICIENCY SYNDROME IN WHICH DIFFERENT INFLAMMATORY CYTOKINES HAVE BEEN PROPOSED AS POTENTIAL NEUROPATHOGENIC MEDIATORS. 1999 17 6502 27 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 18 6591 24 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 19 6887 37 [ROLE OF METAFLAMMATION AS A SYSTEMIC MANIFESTATION OF METABOLIC DISEASES]. VISCERAL OBESITY AS A COMPONENT OF THE METABOLIC SYNDROME IS CHARACTERIZED BY SYSTEMIC AND LOCAL INFLAMMATION, WHICH CAN BE QUANTIFIED IN ORGANS (METAFLAMMATION). THIS PROCESS CAN BE REGARDED AS A CHRONIC, STERILE, AND LOW-GRADE STATE OF INFLAMMATION WITHOUT INFECTION, TRAUMA, TUMOR OR AUTOIMMUNITY. IT IS CAUSED BY AN INFLAMMATION OF THE VISCERAL ADIPOSE TISSUE (ADIPOSE INFLAMMATION OR ADIPOFLAMMATION) DUE TO ADIPOCYTE HYPERTROPHY AND HYPERPLASIA WITH INCREASED INFILTRATION BY MONOCYTES AND MACROPHAGES. IMPORTANT IS THE PRESENCE OF PROINFLAMMATORY, SO-CALLED POLARIZED M1 MACROPHAGES THAT ARE INDUCED BY INTERFERON GAMMA (IFN-GAMMA) AND LIPOPOLYSACCHARIDES (LPS) WITH SECRETION OF INTERLEUKIN (IL)-6, TUMOR NECROSIS FACTOR (TNF) AND IL?1. IN CONTRAST, THE ANTI-INFLAMMATORY, SO-CALLED POLARIZED M2 MACROPHAGES INDUCED BY IL?4 AND IL-13 WITH SECRETION OF IL?8 AND IL-10 DECREASE. IN ADDITION, THE SECRETED ADIPOKINE PATTERN CHANGES FROM ANTI-INFLAMMATORY TO PROINFLAMMATORY. ADIPOCYTE NECROSIS, LOCAL HYPOXIA, DYSREGULATED AUTOPHAGY, ACTIVATION OF INFLAMMASOMES, MODULATION OF TOLL-LIKE RECEPTORS, AND EPIGENETIC FACTORS PLAY A COMPLEX ROLE. THIS MECHANISM RESULTS IN LOCAL INSULIN RESISTANCE AND SUBSEQUENTLY A SYSTEMIC INSULIN RESISTANCE OF PERIPHERAL ORGANS AS WELL AS A SPILLOVER OF LOCAL MEDIATORS OF INFLAMMATION INTO THE SYSTEMIC CIRCULATION (MEASURED AS OBESITY C?REACTIVE PROTEIN, CRP). THE ACTIVATION OF INFLAMMATORY SIGNAL TRANSDUCTION CASCADES LEADS TO INHIBITORY PHOSPHORYLATION OF THE INSULIN SIGNALING PATHWAY AND A WEAKENING OF THE EFFECT OF INSULIN. IN PARALLEL, ECTOPIC LIPID ACCUMULATION OCCURS IN THE LIVER, MUSCULATURE, PANCREAS, PERICARDIUM AND LUNGS. DIACYLGLYCEROL (DAG) ACTIVATES SPECIFIC ISOFORMS OF PROTEIN KINASE C (EPSILON IN THE LIVER AND TAU IN THE MUSCULATURE), WHICH IN TURN LEAD TO INHIBITION OF THE INSULIN SIGNALING PATHWAY. INSULIN RESISTANCE IN OBESITY AND TYPE 2 DIABETES MELLITUS IS AN INFLAMMATORY DISEASE. THE AIM OF FUTURE TRANSLATIONAL APPROACHES IS AN ANTI-INFLAMMATORY, MOLECULARLY INDIVIDUALIZED (PRECISION MEDICINE) TREATMENT IN ADIPOSE TISSUE (TARGETED THERAPY) AND IN ORGANS OF INSULIN RESISTANCE. 2023 20 706 49 BUTYRATE AND DIETARY SOLUBLE FIBER IMPROVE NEUROINFLAMMATION ASSOCIATED WITH AGING IN MICE. AGING RESULTS IN CHRONIC SYSTEMIC INFLAMMATION THAT CAN ALTER NEUROINFLAMMATION OF THE BRAIN. SPECIFICALLY, MICROGLIA SHIFT TO A PRO-INFLAMMATORY PHENOTYPE PREDISPOSING THEM TO HYPERACTIVATION UPON STIMULATION BY PERIPHERAL IMMUNE SIGNALS. IT IS PROPOSED THAT CERTAIN NUTRIENTS CAN DELAY BRAIN AGING BY PREVENTING OR REVERSING MICROGLIAL HYPERACTIVATION. BUTYRATE, A SHORT-CHAIN FATTY ACID (SCFA) PRODUCED PRIMARILY BY BACTERIAL FERMENTATION OF FIBER IN THE COLON, HAS BEEN EXTENSIVELY STUDIED PHARMACOLOGICALLY AS A HISTONE DEACETYLASE INHIBITOR AND SERVES AS AN ATTRACTIVE THERAPEUTIC CANDIDATE, AS BUTYRATE HAS ALSO BEEN SHOWN TO BE ANTI-INFLAMMATORY AND IMPROVE MEMORY IN ANIMAL MODELS. IN THIS STUDY, WE DEMONSTRATE THAT BUTYRATE CAN ATTENUATE PRO-INFLAMMATORY CYTOKINE EXPRESSION IN MICROGLIA IN AGED MICE. IT IS STILL NOT FULLY UNDERSTOOD, HOWEVER, IF AN INCREASE IN BUTYRATE-PRODUCING BACTERIA IN THE GUT AS A CONSEQUENCE OF A DIET HIGH IN SOLUBLE FIBER COULD AFFECT MICROGLIAL ACTIVATION DURING AGING. ADULT AND AGED MICE WERE FED EITHER A 1% CELLULOSE (LOW FIBER) OR 5% INULIN (HIGH FIBER) DIET FOR 4 WEEKS. FINDINGS INDICATE THAT MICE FED INULIN HAD AN ALTERED GUT MICROBIOME AND INCREASED BUTYRATE, ACETATE, AND TOTAL SCFA PRODUCTION. IN ADDITION, HISTOLOGICAL SCORING OF THE DISTAL COLON DEMONSTRATED THAT AGED ANIMALS ON THE LOW FIBER DIET HAD INCREASED INFLAMMATORY INFILTRATE THAT WAS SIGNIFICANTLY REDUCED IN ANIMALS CONSUMING THE HIGH FIBER DIET. FURTHERMORE, GENE EXPRESSION OF INFLAMMATORY MARKERS, EPIGENETIC REGULATORS, AND THE MICROGLIAL SENSORY APPARATUS (I.E., THE SENSOME) WERE ALTERED BY BOTH DIET AND AGE, WITH AGED ANIMALS EXHIBITING A MORE ANTI-INFLAMMATORY MICROGLIAL PROFILE ON THE HIGH FIBER DIET. TAKEN TOGETHER, HIGH FIBER SUPPLEMENTATION IN AGING IS A NON-INVASIVE STRATEGY TO INCREASE BUTYRATE LEVELS, AND THESE DATA SUGGEST THAT AN INCREASE IN BUTYRATE THROUGH ADDED SOLUBLE FIBER SUCH AS INULIN COULD COUNTERBALANCE THE AGE-RELATED MICROBIOTA DYSBIOSIS, POTENTIALLY LEADING TO NEUROLOGICAL BENEFITS. 2018