Manganese is critical for antitumor immune responses via cGAS-STING and improves the efficacy of clinical immunotherapy

Cell Research, Год журнала: 2020, Номер 30(11), С. 966 - 979

Опубликована: Авг. 24, 2020

Abstract CD8 + T cell-mediated cancer clearance is often suppressed by the interaction between inhibitory molecules like PD-1 and PD-L1, an acts brakes to prevent cell overreaction under normal conditions but exploited tumor cells escape immune surveillance. Immune checkpoint inhibitors have revolutionized therapeutics removing such brakes. Unfortunately, only a minority of patients respond immunotherapies presumably due inadequate immunity. Antitumor immunity depends on activation cGAS-STING pathway, as STING-deficient mice fail stimulate tumor-infiltrating dendritic (DCs) activate cells. STING agonists also enhance natural killer (NK) mediate cell-resistant tumors. Therefore been intensively sought after. We previously discovered that manganese (Mn) indispensable for host defense against cytosolic dsDNA activating cGAS-STING. Here we report Mn essential in innate sensing tumors enhances adaptive responses Mn-insufficient had significantly enhanced growth metastasis, with greatly reduced Mechanically, 2+ promoted DC macrophage maturation tumor-specific antigen presentation, augmented differentiation, NK activation, increased memory Combining inhibition synergistically boosted antitumor efficacies anti-PD-1 antibody dosage required mice. Importantly, completed phase 1 clinical trial combined regimen showed promising efficacy, exhibiting type I IFN induction, manageable safety revived immunotherapy most advanced metastatic solid propose this combination strategy warrants further translation.

Язык: Английский

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Manganese Increases the Sensitivity of the cGAS-STING Pathway for Double-Stranded DNA and Is Required for the Host Defense against DNA Viruses

Immunity, Год журнала: 2018, Номер 48(4), С. 675 - 687.e7

Опубликована: Апрель 1, 2018

Язык: Английский

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The role of zinc, copper, manganese and iron in neurodegenerative diseases

NeuroToxicology, Год журнала: 2019, Номер 74, С. 230 - 241

Опубликована: Авг. 1, 2019

Язык: Английский

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Parkinson's Disease and the Environment

Frontiers in Neurology, Год журнала: 2019, Номер 10

Опубликована: Март 19, 2019

Parkinson's disease (PD) is a heterogeneous neurodegenerative disorder that affects an estimated 10 million sufferers worldwide. The two forms of PD include familial and sporadic, while the etiology still largely unknown, condition likely to be multifactorial with genetic environmental factors contributing genesis. Diagnosis attained through observation cardinal clinical manifestations including resting tremor, muscle rigidity, slowness or loss movement, postural instability. Unfortunately, by time these features become apparent extensive neurological damage has already occurred. A cure for not been identified current therapy options are pharmaceutical- and/or surgical-based interventions treat symptoms. There no specific test most diagnoses confirmed combination symptoms positive responses dopaminergic drug therapies. prevalence incidence vary worldwide influenced several such as age, gender, ethnicity, susceptibilities, exposures. Here, we will present implicated in sporadic onset. By understanding mechanisms which interact with, affect brain can stride toward finding underlying cause(s) PD.

Язык: Английский

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The role of astrocytic glutamate transporters GLT-1 and GLAST in neurological disorders: Potential targets for neurotherapeutics

Neuropharmacology, Год журнала: 2019, Номер 161, С. 107559 - 107559

Опубликована: Март 6, 2019

Язык: Английский

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“Manganese-induced neurotoxicity: a review of its behavioral consequences and neuroprotective strategies”

BMC Pharmacology and Toxicology, Год журнала: 2016, Номер 17(1)

Опубликована: Ноя. 4, 2016

Manganese (Mn) is an essential heavy metal. However, Mn's nutritional aspects are paralleled by its role as a neurotoxicant upon excessive exposure. In this review, we covered recent advances in identifying mechanisms of Mn uptake and molecular actions the brain well promising neuroprotective strategies. The authors focused on reporting findings regarding transport mechanisms, effects cholinergic system, behavioral alterations induced exposure studies strategies against intoxication. We report that to may arise from environmental sources, occupational settings, food, total parenteral nutrition (TPN), methcathinone drug abuse or even genetic factors, such mutation transporter SLC30A10. Accumulation occurs mainly basal ganglia leads syndrome called manganism, whose symptoms cognitive dysfunction motor impairment resemble Parkinson's disease (PD). Various neurotransmitter systems be impaired due Mn, especially dopaminergic, but also GABAergic. Several proteins have been identified including divalent metal tranporter-1 (DMT-1), SLC30A10, transferrin ferroportin allow accumulation central nervous system. Parallel identification neurotoxic properties, reported, these include endogenous antioxidants (for instance, vitamin E), plant extracts (complex mixtures containing polyphenols non-characterized components), iron chelating agents, precursors glutathione (GSH), synthetic compounds can experimentally afford protection Mn-induced neurotoxicity.

Язык: Английский

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Heavy Metals Exposure and Alzheimer’s Disease and Related Dementias

Journal of Alzheimer s Disease, Год журнала: 2020, Номер 76(4), С. 1215 - 1242

Опубликована: Июль 10, 2020

Alzheimer's disease and related dementias lack effective treatment or cures are major public health challenges. Risk for is partially attributable to environmental factors. The heavy metals lead, cadmium, manganese widespread persistent in o ur environments. Once persons exposed these metals, they adept at entering cells reaching the brain. Lead cadmium associated with numerous outcomes even low levels of exposure. Although an essential metal, deficiency exposure high metal can be toxic. In cell animal model systems, well documented neurotoxicants that contribute canonical pathologies. Adult human epidemiologic studies have consistently shown impaired cognitive function decline. No longitudinal epidemiology study has assessed lead on specifically though two reported a link between mortality. More high-quality time course data incident cases warranted confirm estimate proportion risk exposures. Given global manganese, small increases risks would population impact burden disease. This article reviews experimental literature associations makes recommendations critical areas future investment.

Язык: Английский

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Brain manganese and the balance between essential roles and neurotoxicity

Journal of Biological Chemistry, Год журнала: 2020, Номер 295(19), С. 6312 - 6329

Опубликована: Март 18, 2020

Manganese (Mn) is an essential micronutrient required for the normal development of many organs, including brain. Although its roles as a cofactor in several enzymes and maintaining optimal physiology are well-known, overall biological functions Mn rather poorly understood. Alterations body status associated with altered neuronal cognition humans, either overexposure or (more rarely) insufficiency can cause neurological dysfunction. The resultant balancing act be viewed hormetic U-shaped relationship brain health, changes leading to physiological effects throughout vice versa. This review discusses homeostasis, biomarkers, molecular mechanisms cellular transport, neuropathological disruptions especially excess, identifies gaps our understanding biochemical underlying homeostasis neurotoxicity.

Язык: Английский

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Mn2+ Directly Activates cGAS and Structural Analysis Suggests Mn2+ Induces a Noncanonical Catalytic Synthesis of 2′3′-cGAMP

Cell Reports, Год журнала: 2020, Номер 32(7), С. 108053 - 108053

Опубликована: Авг. 1, 2020

DNA binding allosterically activates the cytosolic sensor cGAS (cyclic GMP-AMP [cGAMP] synthase) to synthesize 2′3′-cGAMP, using Mg2+ as metal cofactor that catalyzes two nucleotidyl-transferring reactions. We previously found Mn2+ potentiates activation, but underlying mechanism remains unclear. Here, we report directly cGAS. Structural analysis reveals Mn2+-activated undergoes globally similar conformational changes DNA-activated forms a unique η1 helix widen catalytic pocket, allowing substrate entry and cGAMP synthesis. Strikingly, in cGAS, linear intermediates pppGpG pGpA take an inverted orientation active suggesting noncanonical accelerated cyclization without flip-over. Moreover, unlike octahedral coordination around Mg2+, are coordinated by triphosphate moiety of substrate, independent triad residues. Our findings thus uncover activator initiates 2′3′-cGAMP

Язык: Английский

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Manganese-Induced Neurotoxicity: New Insights Into the Triad of Protein Misfolding, Mitochondrial Impairment, and Neuroinflammation

Frontiers in Neuroscience, Год журнала: 2019, Номер 13

Опубликована: Июнь 26, 2019

Occupational or environmental exposure to manganese (Mn) can lead the development of "Manganism", a neurological condition showing certain motor symptoms similar Parkinson's disease (PD). Like PD, Mn toxicity is seen in central nervous system mainly affecting nigrostriatal neuronal circuitry and subsequent behavioral impairments. Since first report Mn-induced 1837, various experimental epidemiological studies have been conducted understand this disorder. While early investigations focused on impact high concentrations mitochondria oxidative stress, current attempted elucidate cellular molecular pathways involved toxicity. In fact, recent reports suggest involvement misfolding proteins such as α-synuclein amyloid, thus providing credence theory that toxicants either initiate propagate neurodegenerative processes by interfering with disease-specific proteins. Besides manganism has also implicated other diseases Huntington's Prion diseases. many reviews homeostasis, aim review concisely synthesize what we know about its effect primarily respect role protein misfolding, mitochondrial dysfunction, consequently, neuroinflammation neurodegeneration. Based evidence, propose 'Mn Mechanistic Neurotoxic Triad' comprising 1) dysfunction 2) trafficking 3) neuroinflammation.

Язык: Английский

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