1 4041 148 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 2 6495 53 TRAINED IMMUNITY AS A POTENTIAL TARGET FOR THERAPEUTIC IMMUNOMODULATION IN DUCHENNE MUSCULAR DYSTROPHY. DYSREGULATED INFLAMMATION INVOLVING INNATE IMMUNE CELLS, PARTICULARLY OF THE MONOCYTE/MACROPHAGE LINEAGE, IS A KEY CONTRIBUTOR TO THE PATHOGENESIS OF DUCHENNE MUSCULAR DYSTROPHY (DMD). TRAINED IMMUNITY IS AN EVOLUTIONARILY ANCIENT PROTECTIVE MECHANISM AGAINST INFECTION, IN WHICH EPIGENETIC AND METABOLIC ALTERATIONS CONFER NON-SPECIFIC HYPERRESPONSIVENESS OF INNATE IMMUNE CELLS TO VARIOUS STIMULI. RECENT WORK IN AN ANIMAL MODEL OF DMD (MDX MICE) HAS SHOWN THAT MACROPHAGES EXHIBIT CARDINAL FEATURES OF TRAINED IMMUNITY, INCLUDING THE PRESENCE OF INNATE IMMUNE SYSTEM "MEMORY". THE LATTER IS REFLECTED BY EPIGENETIC CHANGES AND DURABLE TRANSMISSIBILITY OF THE TRAINED PHENOTYPE TO HEALTHY NON-DYSTROPHIC MICE BY BONE MARROW TRANSPLANTATION. MECHANISTICALLY, IT IS SUGGESTED THAT A TOLL-LIKE RECEPTOR (TLR) 4-REGULATED, MEMORY-LIKE CAPACITY OF INNATE IMMUNITY IS INDUCED AT THE LEVEL OF THE BONE MARROW BY FACTORS RELEASED FROM THE DAMAGED MUSCLES, LEADING TO EXAGGERATED UPREGULATION OF BOTH PRO- AND ANTI-INFLAMMATORY GENES. HERE WE PROPOSE A CONCEPTUAL FRAMEWORK FOR THE INVOLVEMENT OF TRAINED IMMUNITY IN DMD PATHOGENESIS AND ITS POTENTIAL TO SERVE AS A NEW THERAPEUTIC TARGET. 2023 3 1125 30 COMPLEX INHIBITION OF AUTOPHAGY BY MITOCHONDRIAL ALDEHYDE DEHYDROGENASE SHORTENS LIFESPAN AND EXACERBATES CARDIAC AGING. AUTOPHAGY, A CONSERVATIVE DEGRADATION PROCESS FOR LONG-LIVED AND DAMAGED PROTEINS, PARTICIPATES IN A CASCADE OF BIOLOGICAL PROCESSES INCLUDING AGING. A NUMBER OF AUTOPHAGY REGULATORS HAVE BEEN IDENTIFIED. HERE WE DEMONSTRATED THAT MITOCHONDRIAL ALDEHYDE DEHYDROGENASE (ALDH2), AN ENZYME WITH THE MOST COMMON SINGLE POINT MUTATION IN HUMANS, GOVERNS CARDIAC AGING THROUGH REGULATION OF AUTOPHAGY. MYOCARDIAL MECHANICAL AND AUTOPHAGY PROPERTIES WERE EXAMINED IN YOUNG (4MONTHS) AND OLD (26-28MONTHS) WILD-TYPE (WT) AND GLOBAL ALDH2 TRANSGENIC MICE. ALDH2 OVEREXPRESSION SHORTENED LIFESPAN BY 7.7% WITHOUT AFFECTING AGING-ASSOCIATED CHANGES IN PLASMA METABOLIC PROFILES. MYOCARDIAL FUNCTION WAS COMPROMISED WITH AGING ASSOCIATED WITH CARDIAC HYPERTROPHY, THE EFFECTS WERE ACCENTUATED BY ALDH2. AGING OVERTLY SUPPRESSED AUTOPHAGY AND COMPROMISED AUTOPHAGY FLUX, THE EFFECTS WERE EXACERBATED BY ALDH2. AGING DAMPENED PHOSPHORYLATION OF JNK, BCL-2, IKKBETA, AMPK AND TSC2 WHILE PROMOTING PHOSPHORYLATION OF MTOR, THE EFFECTS OF WHICH WERE EXAGGERATED BY ALDH2. CO-IMMUNOPRECIPITATION REVEALED INCREASED DISSOCIATION BETWEEN BCL-2 AND BECLIN-1 (RESULT OF DECREASED BCL-2 PHOSPHORYLATION) IN AGING, THE EFFECT OF WHICH WAS EXACERBATED WITH ALDH2. CHRONIC TREATMENT OF THE AUTOPHAGY INDUCER RAPAMYCIN ALLEVIATED AGING-INDUCED CARDIAC DYSFUNCTION IN BOTH WT AND ALDH2 MICE. MOREOVER, ACTIVATION OF JNK AND INHIBITION OF EITHER BCL-2 OR IKKBETA OVERTLY ATTENUATED ALDH2 ACTIVATION-INDUCED ACCENTUATION OF CARDIOMYOCYTE AGING. EXAMINATION OF THE OTHERWISE ELDERLY INDIVIDUALS REVEALED A POSITIVE CORRELATION BETWEEN CARDIAC FUNCTION/GEOMETRY AND ALDH2 GENE MUTATION. TAKEN TOGETHER, OUR DATA REVEALED THAT ALDH2 ENZYME MAY SUPPRESS MYOCARDIAL AUTOPHAGY POSSIBLY THROUGH A COMPLEX JNK-BCL-2 AND IKKBETA-AMPK-DEPENDENT MECHANISM EN ROUTE TO ACCENTUATION OF MYOCARDIAL REMODELING AND CONTRACTILE DYSFUNCTION IN AGING. THIS ARTICLE IS PART OF A SPECIAL ISSUE ENTITLED: GENETIC AND EPIGENETIC CONTROL OF HEART FAILURE - EDITED BY JUN REN & MEGAN YINGMEI ZHANG. 2017 4 5539 29 ROLE OF CYSTIC FIBROSIS BRONCHIAL EPITHELIUM IN NEUTROPHIL CHEMOTAXIS. A HALLMARK OF CYSTIC FIBROSIS (CF) CHRONIC RESPIRATORY DISEASE IS AN EXTENSIVE NEUTROPHIL INFILTRATE IN THE MUCOSA FILLING THE BRONCHIAL LUMEN, STARTING EARLY IN LIFE FOR CF INFANTS. THE GENETIC DEFECT OF THE CF TRANSMEMBRANE CONDUCTANCE REGULATOR (CFTR) ION CHANNEL PROMOTES DEHYDRATION OF THE AIRWAY SURFACE LIQUID, ALTERS MUCUS PROPERTIES, AND DECREASES MUCOCILIARY CLEARANCE, FAVORING THE ONSET OF RECURRENT AND, ULTIMATELY, CHRONIC BACTERIAL INFECTION. NEUTROPHIL INFILTRATES ARE UNABLE TO CLEAR BACTERIAL INFECTION AND, AS AN ADVERSE EFFECT, CONTRIBUTE TO MUCOSAL TISSUE DAMAGE BY RELEASING PROTEASES AND REACTIVE OXYGEN SPECIES. MOREOVER, THE RAPID CELLULAR TURNOVER OF LUMENAL NEUTROPHILS RELEASES NUCLEIC ACIDS THAT FURTHER ALTER THE MUCUS VISCOSITY. A PROMINENT ROLE IN THE RECRUITMENT OF NEUTROPHIL IN BRONCHIAL MUCOSA IS PLAYED BY CF BRONCHIAL EPITHELIAL CELLS CARRYING THE DEFECTIVE CFTR PROTEIN AND ARE EXPOSED TO WHOLE BACTERIA AND BACTERIAL PRODUCTS, MAKING PHARMACOLOGICAL APPROACHES TO REGULATE THE EXAGGERATED NEUTROPHIL CHEMOTAXIS IN CF A RELEVANT THERAPEUTIC TARGET. HERE WE REVISE: (A) THE MAJOR RECEPTORS, KINASES, AND TRANSCRIPTION FACTORS LEADING TO THE EXPRESSION, AND RELEASE OF NEUTROPHIL CHEMOKINES IN BRONCHIAL EPITHELIAL CELLS; (B) THE ROLE OF INTRACELLULAR CALCIUM HOMEOSTASIS AND, IN PARTICULAR, THE CALCIUM CROSSTALK BETWEEN ENDOPLASMIC RETICULUM AND MITOCHONDRIA; (C) THE EPIGENETIC REGULATION OF THE KEY CHEMOKINES; (D) THE ROLE OF MUTANT CFTR PROTEIN AS A CO-REGULATOR OF CHEMOKINES TOGETHER WITH THE HOST-PATHOGEN INTERACTIONS; AND (E) DIFFERENT PHARMACOLOGICAL STRATEGIES TO REGULATE THE EXPRESSION OF CHEMOKINES IN CF BRONCHIAL EPITHELIAL CELLS THROUGH NOVEL DRUG DISCOVERY AND DRUG REPURPOSING. 2020 5 4109 27 MECHANISMS AND DRUG THERAPY OF PULMONARY HYPERTENSION AT HIGH ALTITUDE. PULMONARY VASOCONSTRICTION REPRESENTS A PHYSIOLOGICAL ADAPTIVE MECHANISM TO HIGH ALTITUDE. IF EXAGGERATED, HOWEVER, IT IS ASSOCIATED WITH IMPORTANT MORBIDITY AND MORTALITY. RECENT MECHANISTIC STUDIES USING SHORT-TERM ACUTE HIGH ALTITUDE EXPOSURE HAVE PROVIDED INSIGHT INTO THE IMPORTANCE OF DEFECTIVE VASCULAR ENDOTHELIAL AND RESPIRATORY EPITHELIAL NITRIC OXIDE (NO) SYNTHESIS, INCREASED ENDOTHELIN-1 BIOAVAILABILITY, AND OVERACTIVATION OF THE SYMPATHETIC NERVOUS SYSTEM IN CAUSING EXAGGERATED HYPOXIC PULMONARY HYPERTENSION IN HUMANS. BASED ON THESE STUDIES, DRUGS THAT INCREASE NO BIOAVAILABILITY, ATTENUATE ENDOTHELIN-1 INDUCED PULMONARY VASOCONSTRICTION, OR PREVENT EXAGGERATED SYMPATHETIC ACTIVATION HAVE BEEN SHOWN TO BE USEFUL FOR THE TREATMENT/PREVENTION OF EXAGGERATED PULMONARY HYPERTENSION DURING ACUTE SHORT-TERM HIGH ALTITUDE EXPOSURE. THE MECHANISMS UNDERPINNING CHRONIC PULMONARY HYPERTENSION IN HIGH ALTITUDE DWELLERS ARE LESS WELL UNDERSTOOD, BUT RECENT EVIDENCE SUGGESTS THAT THEY DIFFER IN SOME ASPECTS FROM THOSE INVOLVED IN SHORT-TERM ADAPTATION TO HIGH ALTITUDE. THESE DIFFERENCES HAVE CONSEQUENCES FOR THE CHOICE OF THE TREATMENT FOR CHRONIC PULMONARY HYPERTENSION AT HIGH ALTITUDE. FINALLY, RECENT DATA INDICATE THAT FETAL PROGRAMMING OF PULMONARY VASCULAR DYSFUNCTION IN OFFSPRING OF PREECLAMPSIA AND CHILDREN GENERATED BY ASSISTED REPRODUCTIVE TECHNOLOGIES REPRESENTS A NOVEL AND FREQUENT CAUSE OF PULMONARY HYPERTENSION AT HIGH ALTITUDE. IN ANIMAL MODELS OF FETAL PROGRAMMING OF HYPOXIC PULMONARY HYPERTENSION, EPIGENETIC MECHANISMS PLAY A ROLE, AND TARGETING OF THESE MECHANISMS WITH DRUGS LOWERS PULMONARY ARTERY PRESSURE. IF EPIGENETIC MECHANISMS ALSO ARE OPERATIONAL IN THE FETAL PROGRAMMING OF PULMONARY VASCULAR DYSFUNCTION IN HUMANS, SUCH DRUGS MAY BECOME NOVEL TOOLS FOR THE TREATMENT OF HYPOXIC PULMONARY HYPERTENSION. 2013 6 4116 34 MECHANISMS OF AIRWAY EPITHELIAL INJURY AND ABNORMAL REPAIR IN ASTHMA AND COPD. THE AIRWAY EPITHELIUM COMPRISES OF DIFFERENT CELL TYPES AND ACTS AS A PHYSICAL BARRIER PREVENTING PATHOGENS, INCLUDING INHALED PARTICLES AND MICROBES, FROM ENTERING THE LUNGS. GOBLET CELLS AND SUBMUCOSAL GLANDS PRODUCE MUCUS THAT TRAPS PATHOGENS, WHICH ARE EXPELLED FROM THE RESPIRATORY TRACT BY CILIATED CELLS. BASAL CELLS ACT AS PROGENITOR CELLS, DIFFERENTIATING INTO DIFFERENT EPITHELIAL CELL TYPES, TO MAINTAIN HOMEOSTASIS FOLLOWING INJURY. ADHERENS AND TIGHT JUNCTIONS BETWEEN CELLS MAINTAIN THE EPITHELIAL BARRIER FUNCTION AND REGULATE THE MOVEMENT OF MOLECULES ACROSS IT. IN THIS REVIEW WE DISCUSS HOW ABNORMAL EPITHELIAL STRUCTURE AND FUNCTION, CAUSED BY CHRONIC INJURY AND ABNORMAL REPAIR, DRIVES AIRWAY DISEASE AND SPECIFICALLY ASTHMA AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD). IN BOTH DISEASES, INHALED ALLERGENS, POLLUTANTS AND MICROBES DISRUPT JUNCTIONAL COMPLEXES AND PROMOTE CELL DEATH, IMPAIRING THE BARRIER FUNCTION AND LEADING TO INCREASED PENETRATION OF PATHOGENS AND A CONSTANT AIRWAY IMMUNE RESPONSE. IN ASTHMA, THE INFLAMMATORY RESPONSE PRECIPITATES THE EPITHELIAL INJURY AND DRIVES ABNORMAL BASAL CELL DIFFERENTIATION. THIS LEADS TO REDUCED CILIATED CELLS, GOBLET CELL HYPERPLASIA AND INCREASED EPITHELIAL MESENCHYMAL TRANSITION, WHICH CONTRIBUTE TO IMPAIRED MUCOCILIARY CLEARANCE AND AIRWAY REMODELLING. IN COPD, CHRONIC OXIDATIVE STRESS AND INFLAMMATION TRIGGER PREMATURE EPITHELIAL CELL SENESCENCE, WHICH CONTRIBUTES TO LOSS OF EPITHELIAL INTEGRITY AND AIRWAY INFLAMMATION AND REMODELLING. INCREASED NUMBERS OF BASAL CELLS SHOWING DEREGULATED DIFFERENTIATION, CONTRIBUTES TO CILIARY DYSFUNCTION AND MUCOUS HYPERPRODUCTION IN COPD AIRWAYS. DEFECTIVE ANTIOXIDANT, ANTIVIRAL AND DAMAGE REPAIR MECHANISMS, POSSIBLY DUE TO GENETIC OR EPIGENETIC FACTORS, MAY CONFER SUSCEPTIBILITY TO AIRWAY EPITHELIAL DYSFUNCTION IN THESE DISEASES. THE CURRENT EVIDENCE SUGGESTS THAT A CONSTANT CYCLE OF INJURY AND ABNORMAL REPAIR OF THE EPITHELIUM DRIVES CHRONIC AIRWAY INFLAMMATION AND REMODELLING IN ASTHMA AND COPD. MECHANISTIC UNDERSTANDING OF INJURY SUSCEPTIBILITY AND DAMAGE RESPONSE MAY LEAD TO IMPROVED THERAPIES FOR THESE DISEASES. 2023 7 5837 28 STRESSED MITOCHONDRIA: A TARGET TO INTRUDE ALZHEIMER'S DISEASE. ALZHEIMER'S DISEASE (AD) IS THE INOPERABLE, INCAPACITATING, NEUROPSYCHIATRIC, AND DEGENERATIVE MANIFESTATION THAT DRASTICALLY AFFECTS HUMAN LIFE QUALITY. THE CURRENT MEDICATIONS TARGET EXTRA-NEURONAL SENILE PLAQUES, OXIDATIVE STRESS, NEUROINFLAMMATION, INTRANEURONAL NEUROFIBRILLARY TANGLES, CHOLINERGIC DEFICITS, AND EXCITOTOXICITY. AMONG NOVEL PATHWAYS AND TARGETS, BIOENERGETIC AND RESULTANT MITOCHONDRIAL DYSFUNCTION HAS BEEN RECOGNIZED AS ESSENTIAL FACTORS THAT DECIDE THE NEURONAL FATE AND CONSEQUENT NEURODEGENERATION IN AD. THE CRUCIAL ATTRIBUTES OF MITOCHONDRIA, INCLUDING BIOENERGESIS, SIGNALING, SENSING, INTEGRATING, AND TRANSMITTING BIOLOGICAL SIGNALS CONTRIBUTE TO OPTIMUM NETWORKING OF NEURONAL DYNAMICS AND MAKE THEM INDISPENSABLE FOR CELL SURVIVAL. IN AD, MITOCHONDRIAL DYSFUNCTION AND MITOPHAGY ARE A PRELIMINARY AND CRITICAL EVENT THAT AGGRAVATES THE PATHOLOGICAL CASCADE. STRESS IS KNOWN TO PROMOTE AND EXAGGERATE THE NEUROPATHOLOGICAL ALTERATION DURING NEURODEGENERATION AND METABOLIC IMPAIRMENTS, ESPECIALLY IN THE CORTICO-LIMBIC SYSTEM, BESIDES ADVERSELY AFFECTING THE NORMAL PHYSIOLOGY AND MITOCHONDRIAL DYNAMICS. STRESS INVOLVES THE ALLOCATION OF ENERGY RESOURCES FOR NEURONAL SURVIVAL. CHRONIC AND AGGRAVATED STRESS RESPONSE LEADS TO EXCESSIVE RELEASE OF GLUCOCORTICOIDS BY ACTIVATION OF THE HYPOTHALAMIC-PITUITARYADRENAL (HPA) AXIS. BY ACTING THROUGH THEIR RECEPTORS, GLUCOCORTICOIDS INFLUENCE ADVERSE MITOCHONDRIAL CHANGES AND ALTER MTDNA TRANSCRIPTION, MTRNA EXPRESSION, HIPPOCAMPAL MITOCHONDRIAL NETWORK, AND ULTIMATELY MITOCHONDRIAL PHYSIOLOGY. CHRONIC STRESS ALSO AFFECTS MITOCHONDRIAL DYNAMICS BY CHANGING METABOLIC AND NEURO-ENDOCRINAL SIGNALLING, AGGRAVATING OXIDATIVE STRESS, PROVOKING INFLAMMATORY MEDIATORS, ALTERING TROPIC FACTORS, INFLUENCING GENE EXPRESSION, AND MODIFYING EPIGENETIC PATHWAYS. THUS, EXPLORING CHRONIC STRESS-INDUCED GLUCOCORTICOID DYSREGULATION AND RESULTANT BIO-BEHAVIORAL AND PSYCHOSOMATIC MITOCHONDRIAL ALTERATIONS MAY BE A FEASIBLE NARRATIVE TO INVESTIGATE AND UNRAVEL THE MYSTERIOUS PATHOBIOLOGY OF AD. 2021 8 6126 42 THE EPIGENETIC MODIFIER PBRM1 RESTRICTS THE BASAL ACTIVITY OF THE INNATE IMMUNE SYSTEM BY REPRESSING RETINOIC ACID-INDUCIBLE GENE-I-LIKE RECEPTOR SIGNALLING AND IS A POTENTIAL PROGNOSTIC BIOMARKER FOR COLON CANCER. IT HAS LONG BEEN KNOWN THAT PATIENTS SUFFERING FROM INFLAMMATORY BOWEL DISEASE (IBD) HAVE AN INCREASED RISK OF DEVELOPING COLORECTAL CANCER (CRC). THE INNATE IMMUNE SYSTEM OF HOST CELLS PROVIDES A FIRST-LINE DEFENCE AGAINST PATHOGENIC INFECTION, WHEREAS AN UNCONTROLLED INFLAMMATORY RESPONSE UNDER HOMEOSTATIC CONDITIONS USUALLY LEADS TO PATHOLOGICAL CONSEQUENCES, AS EXEMPLIFIED BY THE CHRONIC INFLAMMATION OF IBD. THE KEY MOLECULES AND PATHWAYS KEEPING INNATE IMMUNITY IN CHECK ARE STILL POORLY DEFINED. HERE, WE REPORT THAT THE CHROMATIN REMODELLER POLYBROMO-1 (PBRM1) IS A REPRESSOR OF INNATE IMMUNE SIGNALLING MEDIATED BY RETINOIC ACID-INDUCIBLE GENE-I (RIG-I)-LIKE RECEPTORS (RLRS). KNOCKDOWN OF PBRM1 IN COLON CANCER CELLS INCREASED THE EXPRESSION OF TWO RECEPTOR GENES (RIG-I AND MDA5) AND UPREGULATED INTERFERON (IFN)-RELATED AND INFLAMMATION-RELATED GENE SIGNATURES. THE INNATE IMMUNE SIGNAL STIMULATED BY A DOUBLE-STRANDED RNA VIRAL MIMIC WAS EXAGGERATED BY PBRM1 SUPPRESSION. PBRM1 COOPERATED WITH POLYCOMB PROTEIN EZH2 TO DIRECTLY BIND THE CIS-REGULATORY ELEMENTS OF RIG-I AND MDA5, THEREBY SUPPRESSING THEIR TRANSCRIPTION. MOREOVER, UPREGULATION OF RIG-I AND MDA5 IS REQUIRED FOR IFN RESPONSE ACTIVATION INDUCED BY PBRM1 SILENCING. TRIM25, A PROTEIN STIMULATED BY THE RLR PATHWAY AND IFN PRODUCTION, PHYSICALLY INTERACTED WITH PBRM1 AND INDUCED PBRM1 PROTEIN DESTABILIZATION BY PROMOTING ITS UBIQUITINATION. THESE FINDINGS REVEAL A PBRM1-RLR REGULATORY CIRCUIT THAT CAN KEEP INNATE IMMUNE ACTIVITY AT A MINIMAL LEVEL IN RESTING CELLS, AND ALSO ENSURE A ROBUST INFLAMMATORY RESPONSE IN THE CASE OF PATHOGEN INVASION. PBRM1 WAS FOUND TO BE DOWNREGULATED IN PRIMARY TISSUES FROM PATIENTS WITH CRC OR IBD, AND ITS EXPRESSION CORRELATED NEGATIVELY WITH THAT OF RLR GENES AND INTERFERON-STIMULATED GENES IN CRC SAMPLES. LOWER PBRM1 EXPRESSION WAS ASSOCIATED WITH ADVANCED PATHOLOGICAL GRADE AND POORER SURVIVAL OF CRC PATIENTS, INDICATING THAT PBRM1 COULD SERVE AS A POTENTIAL PROGNOSTIC BIOMARKER FOR CRC. COPYRIGHT (C) 2017 PATHOLOGICAL SOCIETY OF GREAT BRITAIN AND IRELAND. PUBLISHED BY JOHN WILEY & SONS, LTD. 2018 9 4138 41 MECHANISMS OF MICROGLIAL ACTIVATION IN MODELS OF INFLAMMATION AND HYPOXIA: IMPLICATIONS FOR CHRONIC INTERMITTENT HYPOXIA. CHRONIC INTERMITTENT HYPOXIA (CIH) IS A HALLMARK OF SLEEP APNOEA, A CONDITION ASSOCIATED WITH DIVERSE CLINICAL DISORDERS. CIH AND SLEEP APNOEA ARE CHARACTERIZED BY INCREASED REACTIVE OXYGEN SPECIES FORMATION, PERIPHERAL AND CNS INFLAMMATION, NEURONAL DEATH AND NEUROCOGNITIVE DEFICITS. FEW STUDIES HAVE EXAMINED THE ROLE OF MICROGLIA, THE RESIDENT CNS IMMUNE CELLS, IN MODELS OF CIH. THUS, LITTLE IS KNOWN CONCERNING THEIR DIRECT CONTRIBUTIONS TO NEUROPATHOLOGY OR THE CELLULAR MECHANISMS REGULATING THEIR ACTIVITIES DURING OR FOLLOWING PATHOLOGICAL CIH. IN THIS REVIEW, WE IDENTIFY GAPS IN KNOWLEDGE REGARDING CIH-INDUCED MICROGLIAL ACTIVATION, AND PROPOSE MECHANISMS BASED ON DATA FROM RELATED MODELS OF HYPOXIA AND/OR HYPOXIA-REOXYGENATION. CIH MAY DIRECTLY AFFECT MICROGLIA, OR MAY HAVE INDIRECT EFFECTS VIA THE PERIPHERY OR OTHER CNS CELLS. PERIPHERAL INFLAMMATION MAY INDIRECTLY ACTIVATE MICROGLIA VIA ENTRY OF PRO-INFLAMMATORY MOLECULES INTO THE CNS, AND/OR ACTIVATION OF VAGAL AFFERENTS THAT TRIGGER CNS INFLAMMATION. CIH-INDUCED RELEASE OF DAMAGE-ASSOCIATED MOLECULAR PATTERNS FROM INJURED CNS CELLS MAY ALSO ACTIVATE MICROGLIA VIA INTERACTIONS WITH PATTERN RECOGNITION RECEPTORS EXPRESSED ON MICROGLIA. FOR EXAMPLE, TOLL-LIKE RECEPTORS ACTIVATE MITOGEN-ACTIVATED PROTEIN KINASE/TRANSCRIPTION FACTOR PATHWAYS REQUIRED FOR MICROGLIAL INFLAMMATORY GENE EXPRESSION. ALTHOUGH EPIGENETIC EFFECTS FROM CIH HAVE NOT YET BEEN STUDIED IN MICROGLIA, POTENTIAL EPIGENETIC MECHANISMS IN MICROGLIAL REGULATION ARE DISCUSSED, INCLUDING MICRORNAS, HISTONE MODIFICATIONS AND DNA METHYLATION. EPIGENETIC EFFECTS CAN OCCUR DURING CIH, OR LONG AFTER IT HAS ENDED. A BETTER UNDERSTANDING OF CIH EFFECTS ON MICROGLIAL ACTIVITIES MAY BE IMPORTANT TO REVERSE CIH-INDUCED NEUROPATHOLOGY IN PATIENTS WITH SLEEP DISORDERED BREATHING. 2016 10 2772 37 EXTRACELLULAR ATP AND NEURODEGENERATION. ATP IS A POTENT SIGNALING MOLECULE ABUNDANTLY PRESENT IN THE CNS. IT ELICITS A WIDE ARRAY OF PHYSIOLOGICAL EFFECTS AND IS REGARDED AS THE PHYLOGENETICALLY MOST ANCIENT EPIGENETIC FACTOR PLAYING CRUCIAL BIOLOGICAL ROLES IN SEVERAL DIFFERENT TISSUES. THESE CAN RANGE FROM NEUROTRANSMISSION, SMOOTH MUSCLE CONTRACTION, CHEMOSENSORY SIGNALING, SECRETION AND VASODILATATION, TO MORE COMPLEX PHENOMENA SUCH AS IMMUNE RESPONSES, PAIN, MALE REPRODUCTION, FERTILIZATION AND EMBRYONIC DEVELOPMENT. ATP IS RELEASED INTO THE EXTRACELLULAR SPACE EITHER EXOCYTOTICALLY OR FROM DAMAGED AND DYING CELLS. IT IS OFTEN CO-RELEASED WITH OTHER NEUROTRANSMITTERS AND IT CAN INTERACT WITH GROWTH FACTORS AT BOTH RECEPTOR- AND/OR SIGNAL TRANSDUCTION-LEVEL. ONCE IN THE EXTRACELLULAR ENVIRONMENT, ATP BINDS TO SPECIFIC RECEPTORS TERMED P2. BASED ON PHARMACOLOGICAL PROFILES, ON SELECTIVITY OF COUPLING TO SECOND-MESSENGER PATHWAYS AND ON MOLECULAR CLONING, TWO MAIN SUBCLASSES WITH MULTIPLE SUBTYPES HAVE BEEN DISTINGUISHED. THEY ARE P2X, I.E. FAST CATION-SELECTIVE RECEPTOR CHANNELS (NA+, K+, CA2+), POSSESSING LOW AFFINITY FOR ATP AND RESPONSIBLE FOR FAST EXCITATORY NEUROTRANSMISSION, AND P2Y, I.E. SLOW G PROTEIN-COUPLED METABOTROPIC RECEPTORS, POSSESSING HIGHER AFFINITY FOR THE LIGAND. IN THE NERVOUS SYSTEM, THEY ARE BROADLY EXPRESSED IN BOTH NEURONS AND GLIAL CELLS AND CAN MEDIATE DUAL EFFECTS: SHORT-TERM SUCH AS NEUROTRANSMISSION, AND LONG-TERM SUCH AS TROPHIC ACTIONS. SINCE MASSIVE EXTRACELLULAR RELEASE OF ATP OFTEN OCCURS AFTER METABOLIC STRESS, BRAIN ISCHEMIA AND TRAUMA, PURINERGIC MECHANISMS ARE ALSO CORRELATED TO AND INVOLVED IN THE ETIOPATHOLOGY OF MANY NEURODEGENERATIVE CONDITIONS. FURTHERMORE, EXTRACELLULAR ATP PER SE IS TOXIC FOR PRIMARY NEURONAL DISSOCIATED AND ORGANOTYPIC CNS CULTURES FROM CORTEX, STRIATUM AND CEREBELLUM AND P2 RECEPTORS CAN MEDIATE AND AGGRAVATE HYPOXIC SIGNALING IN MANY CNS NEURONS. CONVERSELY, SEVERAL P2 RECEPTOR ANTAGONISTS ABOLISH THE CELL DEATH FATE OF PRIMARY NEURONAL CULTURES EXPOSED TO EXCESSIVE GLUTAMATE, SERUM/POTASSIUM DEPRIVATION, HYPOGLYCEMIA AND CHEMICAL HYPOXIA. IN PARALLEL WITH THESE DETRIMENTAL EFFECTS, ALSO TROPHIC FUNCTIONS HAVE BEEN EXTENSIVELY DESCRIBED FOR EXTRACELLULAR PURINES (BOTH FOR NEURONAL AND NON-NEURONAL CELLS), BUT THESE MIGHT EITHER AGGRAVATE OR AMELIORATE THE NORMAL CELLULAR CONDITIONS. IN SUMMARY, EXTRACELLULAR ATP PLAYS A VERY COMPLEX ROLE NOT ONLY IN THE REPAIR, REMODELING AND SURVIVAL OCCURRING IN THE NERVOUS SYSTEM, BUT EVEN IN CELL DEATH AND THIS CAN OCCUR EITHER AFTER NORMAL DEVELOPMENTAL CONDITIONS, AFTER INJURY, OR ACUTE AND CHRONIC DISEASES. 2003 11 4044 23 MACROPHAGES IN OXIDATIVE STRESS AND MODELS TO EVALUATE THE ANTIOXIDANT FUNCTION OF DIETARY NATURAL COMPOUNDS. ANTIOXIDANT TESTING OF NATURAL PRODUCTS HAS ATTRACTED INCREASING INTEREST IN RECENT YEARS, MAINLY DUE TO THE FACT THAT AN ANTIOXIDANT-RICH DIET MIGHT PROVIDE HEALTH BENEFITS. ACTIVATED MACROPHAGES ARE A MAJOR SOURCE OF REACTIVE OXYGEN SPECIES, REACTIVE NITROGEN SPECIES, AND PEROXYNITRITE GENERATED THROUGH THE SO-CALLED RESPIRATORY BURST. CONSTITUTIVELY RELEASED PROINFLAMMATORY CYTOKINE, ESPECIALLY TUMOR NECROSIS FACTOR-ALPHA, TRIGGERS NUCLEAR FACTOR-KAPPAB, AND ACTIVATOR PROTEIN-1 TRANSLOCATION LEADING TO THE OVER PRODUCTION OF REACTIVE OXYGEN SPECIES AND REACTIVE NITROGEN SPECIES IN MACROPHAGES. ACTIVATION OF TRANSCRIPTION FACTORS IN THE LONG-LIVED TISSUE-RESIDENT MACROPHAGES AND/OR MONOCYTE-DERIVED MACROPHAGES, TRIGGER EPIGENETIC MODIFICATIONS LEADING TO THE PATHOGENESIS OF CHRONIC DISEASES. NUTRACEUTICALS INCLUDING LIPID RAFT STRUCTURE DISRUPTION AGENT, CHOLESTEROL DEPLETION AGENT, FARNESYLTRANSFERASE INHIBITOR, NUCLEAR FACTOR-KAPPAB BLOCKER (ALPHA,BETA-UNSATURATED CARBONYL COMPOUNDS), GLUCOCORTICOID RECEPTOR AGONIST, AND PEROXISOME PROLIFERATOR-ACTIVATED RECEPTOR-GAMMA AGONIST HAVE LONG BEEN USED TO INACTIVE MACROPHAGE. THE INHIBITION EFFECTS ON THE FORMATION OF NITRIC OXIDE, SUPEROXIDE, AND NITRITE PEROXIDE MAY BE RESPONSIBLE FOR THE ANTI-INFLAMMATORY FUNCTIONALITIES. ACTIVATED MACROPHAGE MODELS COULD BE USED TO IDENTIFY THE ACTIVE COMPONENTS FOR FUNCTIONAL DIETS DEVELOPMENT THROUGH A MULTIPLE TARGETS STRATEGY. 2017 12 5327 30 PULSED GLUCOCORTICOIDS ENHANCE DYSTROPHIC MUSCLE PERFORMANCE THROUGH EPIGENETIC-METABOLIC REPROGRAMMING. IN HUMANS, CHRONIC GLUCOCORTICOID USE IS ASSOCIATED WITH SIDE EFFECTS LIKE MUSCLE WASTING, OBESITY, AND METABOLIC SYNDROME. INTERMITTENT STEROID DOSING HAS BEEN PROPOSED IN DUCHENNE MUSCULAR DYSTROPHY PATIENTS TO MITIGATE THE SIDE EFFECTS SEEN WITH DAILY STEROID INTAKE. WE EVALUATED BIOMARKERS FROM DUCHENNE MUSCULAR DYSTROPHY PATIENTS, FINDING THAT, COMPARED WITH CHRONIC DAILY STEROID USE, WEEKEND STEROID USE WAS ASSOCIATED WITH REDUCED SERUM INSULIN, FREE FATTY ACIDS, AND BRANCHED CHAIN AMINO ACIDS, AS WELL AS REDUCTION IN FAT MASS DESPITE HAVING SIMILAR BMIS. WE REASONED THAT INTERMITTENT PREDNISONE ADMINISTRATION IN DYSTROPHIC MICE WOULD ALTER MUSCLE EPIGENOMIC SIGNATURES, AND WE IDENTIFIED THE COORDINATED ACTION OF THE GLUCOCORTICOID RECEPTOR, KLF15 AND MEF2C AS MEDIATORS OF A GENE EXPRESSION PROGRAM DRIVING METABOLIC REPROGRAMMING AND ENHANCED NUTRIENT UTILIZATION. MUSCLE LACKING KLF15 FAILED TO RESPOND TO INTERMITTENT STEROIDS. FURTHERMORE, COADMINISTRATION OF THE HISTONE ACETYLTRANSFERASE INHIBITOR ANACARDIC ACID WITH STEROIDS IN MDX MICE ELIMINATED STEROID-SPECIFIC EPIGENETIC MARKS AND ABROGATED THE STEROID RESPONSE. TOGETHER, THESE FINDINGS INDICATE THAT INTERMITTENT, REPEATED EXPOSURE TO GLUCOCORTICOIDS PROMOTES PERFORMANCE IN DYSTROPHIC MUSCLE THROUGH AN EPIGENETIC PROGRAM THAT ENHANCES NUTRIENT UTILIZATION. 2019 13 2067 41 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 14 6502 32 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 4603 40 NEGATIVE ALLOSTERIC MODULATION OF MGLUR5 PARTIALLY CORRECTS PATHOPHYSIOLOGY IN A MOUSE MODEL OF RETT SYNDROME. RETT SYNDROME (RTT) IS CAUSED BY MUTATIONS IN THE GENE ENCODING METHYL-CPG BINDING PROTEIN 2 (MECP2), AN EPIGENETIC REGULATOR OF MRNA TRANSCRIPTION. HERE, WE REPORT A TEST OF THE HYPOTHESIS OF SHARED PATHOPHYSIOLOGY OF RTT AND FRAGILE X, ANOTHER MONOGENIC CAUSE OF AUTISM AND INTELLECTUAL DISABILITY. IN FRAGILE X, THE LOSS OF THE MRNA TRANSLATIONAL REPRESSOR FMRP LEADS TO EXAGGERATED PROTEIN SYNTHESIS DOWNSTREAM OF METABOTROPIC GLUTAMATE RECEPTOR 5 (MGLUR5). WE FOUND THAT MGLUR5- AND PROTEIN-SYNTHESIS-DEPENDENT SYNAPTIC PLASTICITY WERE SIMILARLY ALTERED IN AREA CA1 OF MECP2 KO MICE. CA1 PYRAMIDAL CELL-TYPE-SPECIFIC, GENOME-WIDE PROFILING OF RIBOSOME-BOUND MRNAS WAS PERFORMED IN WILD-TYPE AND MECP2 KO HIPPOCAMPAL CA1 NEURONS TO REVEAL THE MECP2-REGULATED "TRANSLATOME." WE FOUND SIGNIFICANT OVERLAP BETWEEN RIBOSOME-BOUND TRANSCRIPTS OVEREXPRESSED IN THE MECP2 KO AND FMRP MRNA TARGETS. THESE TENDED TO ENCODE LONG GENES THAT WERE FUNCTIONALLY RELATED TO EITHER CYTOSKELETON ORGANIZATION OR THE DEVELOPMENT OF NEURONAL CONNECTIVITY. IN THE FMR1 KO MOUSE, CHRONIC TREATMENT WITH MGLUR5-NEGATIVE ALLOSTERIC MODULATORS (NAMS) HAS BEEN SHOWN TO AMELIORATE MANY MUTANT PHENOTYPES BY CORRECTING EXCESSIVE PROTEIN SYNTHESIS. IN MECP2 KO MICE, WE FOUND THAT MGLUR5 NAM TREATMENT SIGNIFICANTLY REDUCED THE LEVEL OF OVEREXPRESSED RIBOSOME-ASSOCIATED TRANSCRIPTS, PARTICULARLY THOSE THAT WERE ALSO FMRP TARGETS. SOME RETT PHENOTYPES WERE ALSO AMELIORATED BY TREATMENT, MOST NOTABLY HIPPOCAMPAL CELL SIZE AND LIFESPAN. TOGETHER, THESE RESULTS SUGGEST A POTENTIAL MECHANISTIC LINK BETWEEN MECP2-MEDIATED TRANSCRIPTION REGULATION AND MGLUR5/FMRP-MEDIATED PROTEIN TRANSLATION REGULATION THROUGH COREGULATION OF A SUBSET OF GENES RELEVANT TO SYNAPTIC FUNCTIONS. SIGNIFICANCE STATEMENT: ALTERED REGULATION OF SYNAPTIC PROTEIN SYNTHESIS HAS BEEN HYPOTHESIZED TO CONTRIBUTE TO THE PATHOPHYSIOLOGY THAT UNDERLIES MULTIPLE FORMS OF INTELLECTUAL DISABILITY AND AUTISM SPECTRUM DISORDER. HERE, WE SHOW IN A MOUSE MODEL OF RETT SYNDROME (MECP2 KO) THAT METABOTROPIC GLUTAMATE RECEPTOR 5 (MGLUR5)- AND PROTEIN-SYNTHESIS-DEPENDENT SYNAPTIC PLASTICITY ARE ABNORMAL IN THE HIPPOCAMPUS. WE FOUND THAT A SUBSET OF RIBOSOME-BOUND MRNAS WAS ABERRANTLY UPREGULATED IN HIPPOCAMPAL CA1 NEURONS OF MECP2 KO MICE, THAT THESE SIGNIFICANTLY OVERLAPPED WITH FMRP DIRECT TARGETS AND/OR SFARI HUMAN AUTISM GENES, AND THAT CHRONIC TREATMENT OF MECP2 KO MICE WITH AN MGLUR5-NEGATIVE ALLOSTERIC MODULATOR TUNES DOWN UPREGULATED RIBOSOME-BOUND MRNAS AND PARTIALLY IMPROVES MUTANT MICE PHENOTYPES. 2016 16 4953 34 PATHOGENESIS OF CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) INDUCED BY CIGARETTE SMOKE. CHRONIC OBSTRUCTIVE PULMONARY DISEASE (COPD) IS A COMMON RESPIRATORY DISEASE THAT IS CHARACTERIZED BY FUNCTIONAL AND STRUCTURAL ALTERATIONS PRIMARILY CAUSED BY LONG-TERM INHALATION OF HARMFUL PARTICLES. CIGARETTE SMOKE (CS) INDUCES AIRWAY INFLAMMATION IN COPD, WHICH IS KNOWN TO PERSIST EVEN AFTER SMOKING CESSATION. THIS REVIEW DISCUSSES THE BASIC PATHOGENESIS OF COPD, WITH PARTICULAR FOCUS ON AN ENDOGENOUS PROTECTIVE MECHANISM AGAINST OXIDATIVE STRESS VIA NRF2, ALTERED IMMUNE RESPONSE OF THE AIRWAY INFLAMMATORY CELLS, EXAGGERATED CELLULAR SENESCENCE OF THE LUNG STRUCTURAL CELLS, AND CELL DEATH WITH EXPANDED INFLAMMATION. RECENTLY, CS-INDUCED MITOCHONDRIA AUTOPHAGY IS REPORTED TO INITIATE PROGRAMMED NECROSIS (NECROPTOSIS). NECROPTOSIS IS A NEW CONCEPT OF CELL DEATH WHICH IS DRIVEN BY A DEFINED MOLECULAR PATHWAY ALONG WITH EXAGGERATED INFLAMMATION. THIS NEW CELL DEATH MECHANISM IS OF IMPORTANCE DUE TO ITS ABILITY TO PRODUCE MORE INFLAMMATORY SUBSTANCES DURING THE PROCESS OF EPITHELIAL DEATH, CONTRIBUTING TO PERSISTENT AIRWAY INFLAMMATION THAT CANNOT BE EXPLAINED BY APOPTOSIS-DERIVED CELL DEATH. AUTOPHAGY IS AN AUTO-CELL COMPONENT DEGRADATION SYSTEM EXECUTED BY LYSOSOMES THAT CONTROLS PROTEIN AND ORGANELLE DEGRADATION FOR SUCCESSFUL HOMEOSTASIS. AS WELL AS IN THE PROCESS OF NECROPTOSIS, AUTOPHAGY IS ALSO OBSERVED DURING CELLULAR SENESCENCE. AGING OF THE LUNGS RESULTS IN THE ACQUISITION OF SENESCENCE-ASSOCIATED SECRETORY PHENOTYPES (SASP) THAT ARE KNOWN TO SECRETE INFLAMMATORY CYTOKINES, CHEMOKINES, GROWTH FACTORS, AND MATRIX METALLOPROTEINASES RESULTING IN CHRONIC LOW-GRADE INFLAMMATION. IN FUTURE RESEARCH, WE INTEND TO HIGHLIGHT THE GENETIC AND EPIGENETIC APPROACHES THAT CAN FACILITATE THE UNDERSTANDING OF DISEASE SUSCEPTIBILITY. THE GOAL OF PRECISION MEDICINE IS TO ESTABLISH MORE ACCURATE DIAGNOSIS AND TREATMENT METHODS BASED ON THE PATIENT-SPECIFIC PATHOGENIC CHARACTERISTICS. THIS REVIEW PROVIDES INSIGHTS INTO CS-INDUCED COPD PATHOGENESIS, WHICH CONTRIBUTES TO A VERY COMPLEX DISEASE. INVESTIGATING THE MECHANISM OF DEVELOPING COPD, ALONG WITH THE AVAILABILITY OF THE PARTICULAR INHIBITORS, WILL LEAD TO NEW THERAPEUTIC APPROACHES IN COPD TREATMENT. 2019 17 5315 34 PSYCHOLOGICAL STRESS IN CHILDHOOD AND SUSCEPTIBILITY TO THE CHRONIC DISEASES OF AGING: MOVING TOWARD A MODEL OF BEHAVIORAL AND BIOLOGICAL MECHANISMS. AMONG PEOPLE EXPOSED TO MAJOR PSYCHOLOGICAL STRESSORS IN EARLY LIFE, THERE ARE ELEVATED RATES OF MORBIDITY AND MORTALITY FROM CHRONIC DISEASES OF AGING. THE MOST COMPELLING DATA COME FROM STUDIES OF CHILDREN RAISED IN POVERTY OR MALTREATED BY THEIR PARENTS, WHO SHOW HEIGHTENED VULNERABILITY TO VASCULAR DISEASE, AUTOIMMUNE DISORDERS, AND PREMATURE MORTALITY. THESE FINDINGS RAISE CHALLENGING THEORETICAL QUESTIONS. HOW DOES CHILDHOOD STRESS GET UNDER THE SKIN, AT THE MOLECULAR LEVEL, TO AFFECT RISK FOR LATER DISEASES? AND HOW DOES IT INCUBATE THERE, GIVING RISE TO DISEASES SEVERAL DECADES LATER? HERE WE PRESENT A BIOLOGICAL EMBEDDING MODEL, WHICH ATTEMPTS TO ADDRESS THESE QUESTIONS BY SYNTHESIZING KNOWLEDGE ACROSS SEVERAL BEHAVIORAL AND BIOMEDICAL LITERATURES. THIS MODEL MAINTAINS THAT CHILDHOOD STRESS GETS "PROGRAMMED" INTO MACROPHAGES THROUGH EPIGENETIC MARKINGS, POSTTRANSLATIONAL MODIFICATIONS, AND TISSUE REMODELING. AS A CONSEQUENCE THESE CELLS ARE ENDOWED WITH PROINFLAMMATORY TENDENCIES, MANIFEST IN EXAGGERATED CYTOKINE RESPONSES TO CHALLENGE AND DECREASED SENSITIVITY TO INHIBITORY HORMONAL SIGNALS. THE MODEL GOES ON TO PROPOSE THAT OVER THE LIFE COURSE, THESE PROINFLAMMATORY TENDENCIES ARE EXACERBATED BY BEHAVIORAL PROCLIVITIES AND HORMONAL DYSREGULATION, THEMSELVES THE PRODUCTS OF EXPOSURE TO EARLY STRESS. BEHAVIORALLY, THE MODEL POSITS THAT CHILDHOOD STRESS GIVES RISE TO EXCESSIVE THREAT VIGILANCE, MISTRUST OF OTHERS, POOR SOCIAL RELATIONSHIPS, IMPAIRED SELF-REGULATION, AND UNHEALTHY LIFESTYLE CHOICES. HORMONALLY, EARLY STRESS CONFERS ALTERED PATTERNS OF ENDOCRINE AND AUTONOMIC DISCHARGE. THIS MILIEU AMPLIFIES THE PROINFLAMMATORY ENVIRONMENT ALREADY INSTANTIATED BY MACROPHAGES. ACTING IN CONCERT WITH OTHER EXPOSURES AND GENETIC LIABILITIES, THE RESULTING INFLAMMATION DRIVES FORWARD PATHOGENIC MECHANISMS THAT ULTIMATELY FOSTER CHRONIC DISEASE. 2011 18 593 42 BET PROTEIN INHIBITION REGULATES CYTOKINE PRODUCTION AND PROMOTES NEUROPROTECTION AFTER SPINAL CORD INJURY. BACKGROUND: SPINAL CORD INJURY (SCI) USUALLY CAUSES A DEVASTATING LIFELONG DISABILITY FOR PATIENTS. AFTER A TRAUMATIC LESION, DISRUPTION OF THE BLOOD-SPINAL CORD BARRIER INDUCES THE INFILTRATION OF MACROPHAGES INTO THE LESION SITE AND THE ACTIVATION OF RESIDENT GLIAL CELLS, WHICH RELEASE CYTOKINES AND CHEMOKINES. THESE EVENTS RESULT IN A PERSISTENT INFLAMMATION, WHICH HAS BOTH DETRIMENTAL AND BENEFICIAL EFFECTS, BUT EVENTUALLY LIMITS FUNCTIONAL RECOVERY AND CONTRIBUTES TO THE APPEARANCE OF NEUROPATHIC PAIN. BROMODOMAIN AND EXTRA-TERMINAL DOMAIN (BET) PROTEINS ARE EPIGENETIC READERS THAT REGULATE THE EXPRESSION OF INFLAMMATORY GENES BY INTERACTING WITH ACETYLATED LYSINE RESIDUES. WHILE BET INHIBITORS ARE A PROMISING THERAPEUTIC STRATEGY FOR CANCER, LITTLE IS KNOWN ABOUT THEIR IMPLICATION AFTER SCI. THUS, THE CURRENT STUDY WAS AIMED TO INVESTIGATE THE ANTI-INFLAMMATORY ROLE OF BET INHIBITORS IN THIS PATHOLOGIC CONDITION. METHODS: WE EVALUATED THE EFFECTIVENESS OF THE BET INHIBITOR JQ1 TO MODIFY MACROPHAGE REACTIVITY IN VITRO AND TO MODULATE INFLAMMATION IN A SCI MICE MODEL. WE ANALYZED THE EFFECTS OF BET INHIBITION IN PRO-INFLAMMATORY AND ANTI-INFLAMMATORY CYTOKINE PRODUCTION IN VITRO AND IN VIVO. WE DETERMINED THE EFFECTIVENESS OF BET INHIBITION IN TISSUE SPARING, INFLAMMATION, NEURONAL PROTECTION, AND BEHAVIORAL OUTCOME AFTER SCI. RESULTS: WE HAVE FOUND THAT THE BET INHIBITOR JQ1 REDUCED THE LEVELS OF PRO-INFLAMMATORY MEDIATORS AND INCREASED THE EXPRESSION OF ANTI-INFLAMMATORY CYTOKINES. A PROLONGED TREATMENT WITH JQ1 ALSO DECREASED REACTIVITY OF MICROGLIA/MACROPHAGES, ENHANCED NEUROPROTECTION AND FUNCTIONAL RECOVERY, AND ACUTELY REDUCED NEUROPATHIC PAIN AFTER SCI. CONCLUSIONS: BET PROTEIN INHIBITION IS AN EFFECTIVE TREATMENT TO REGULATE CYTOKINE PRODUCTION AND PROMOTE NEUROPROTECTION AFTER SCI. THESE NOVEL RESULTS DEMONSTRATE FOR THE FIRST TIME THAT TARGETING BET PROTEINS IS AN ENCOURAGING APPROACH FOR SCI REPAIR AND A POTENTIAL STRATEGY TO TREAT OTHER INFLAMMATORY PATHOLOGIES. 2019 19 6376 32 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 20 3587 33 IMPACT OF TLR4 ON BEHAVIORAL AND COGNITIVE DYSFUNCTIONS ASSOCIATED WITH ALCOHOL-INDUCED NEUROINFLAMMATORY DAMAGE. TOLL-LIKE RECEPTORS (TLRS) PLAY AN IMPORTANT ROLE IN THE INNATE IMMUNE RESPONSE, AND EMERGING EVIDENCE INDICATES THEIR ROLE IN BRAIN INJURY AND NEURODEGENERATION. OUR RECENT RESULTS HAVE DEMONSTRATED THAT ETHANOL IS CAPABLE OF ACTIVATING GLIAL TLR4 RECEPTORS AND THAT THE ELIMINATION OF THESE RECEPTORS IN MICE PROTECTS AGAINST ETHANOL-INDUCED GLIAL ACTIVATION, INDUCTION OF INFLAMMATORY MEDIATORS AND APOPTOSIS. THIS STUDY WAS DESIGNED TO ASSESS WHETHER ETHANOL-INDUCED INFLAMMATORY DAMAGE CAUSES BEHAVIORAL AND COGNITIVE CONSEQUENCES, AND IF BEHAVIORAL ALTERATIONS ARE DEPENDENT OF TLR4 FUNCTIONS. HERE WE SHOW IN MICE DRINKING ALCOHOL FOR 5MONTHS, FOLLOWED BY A 15-DAY WITHDRAWAL PERIOD, THAT ACTIVATION OF THE ASTROGLIAL AND MICROGLIAL CELLS IN FRONTAL CORTEX AND STRIATUM IS MAINTAINED AND THAT THESE EVENTS ARE ASSOCIATED WITH COGNITIVE AND ANXIETY-RELATED BEHAVIORAL IMPAIRMENTS IN WILD-TYPE (WT) MICE, AS DEMONSTRATED BY TESTING THE ANIMALS WITH OBJECT MEMORY RECOGNITION, CONDITIONED TASTE AVERSION AND DARK AND LIGHT BOX ANXIETY TASKS. MICE LACKING TLR4 RECEPTORS ARE PROTECTED AGAINST ETHANOL-INDUCED INFLAMMATORY DAMAGE, AND BEHAVIORAL ASSOCIATED EFFECTS. WE FURTHER ASSESS THE POSSIBILITY OF THE EPIGENETIC MODIFICATIONS PARTICIPATING IN SHORT- OR LONG-TERM BEHAVIORAL EFFECTS ASSOCIATED WITH NEUROINFLAMMATORY DAMAGE. WE SHOW THAT CHRONIC ALCOHOL TREATMENT DECREASES H4 HISTONE ACETYLATION AND HISTONE ACETYLTRANSFERASES ACTIVITY IN FRONTAL CORTEX, STRIATUM AND HIPPOCAMPUS OF WT MICE. ALTERATIONS IN CHROMATIN STRUCTURE WERE NOT OBSERVED IN TLR4(-/-) MICE. THESE RESULTS PROVIDE THE FIRST EVIDENCE OF THE ROLE THAT TLR4 FUNCTIONS PLAY IN THE BEHAVIORAL CONSEQUENCES OF ALCOHOL-INDUCED INFLAMMATORY DAMAGE AND SUGGEST THAT THE EPIGENETIC MODIFICATIONS MEDIATED BY TLR4 COULD CONTRIBUTE TO SHORT- OR LONG-TERM ALCOHOL-INDUCED BEHAVIORAL OR COGNITIVE DYSFUNCTIONS. 2011