The IL-17 Family of Cytokines in Health and Disease

Immunity, Год журнала: 2019, Номер 50(4), С. 892 - 906

Опубликована: Апрель 1, 2019

Язык: Английский

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Neuroimmunology of Traumatic Brain Injury: Time for a Paradigm Shift

Neuron, Год журнала: 2017, Номер 95(6), С. 1246 - 1265

Опубликована: Сен. 1, 2017

Язык: Английский

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Recovery from disorders of consciousness: mechanisms, prognosis and emerging therapies

Nature Reviews Neurology, Год журнала: 2020, Номер 17(3), С. 135 - 156

Опубликована: Дек. 14, 2020

Substantial progress has been made over the past two decades in detecting, predicting and promoting recovery of consciousness patients with disorders (DoC) caused by severe brain injuries. Advanced neuroimaging electrophysiological techniques have revealed new insights into biological mechanisms underlying enabled identification preserved networks who seem unresponsive, thus raising hope for more accurate diagnosis prognosis. Emerging evidence suggests that covert consciousness, or cognitive motor dissociation (CMD), is present up to 15–20% DoC detection CMD intensive care unit can predict functional at 1 year post injury. Although fundamental questions remain about which potential recovery, novel pharmacological therapies shown reactivate injured neural promote re-emergence consciousness. In this Review, we focus on from acute subacute-to-chronic stages, discuss recent detecting We also describe developments are creating opportunities improve lives DoC. authors prediction They ongoing development designed enhance recovery.

Язык: Английский

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Repopulating Microglia Promote Brain Repair in an IL-6-Dependent Manner

Cell, Год журнала: 2020, Номер 180(5), С. 833 - 846.e16

Опубликована: Март 1, 2020

Язык: Английский

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Pathophysiology and treatment of cerebral edema in traumatic brain injury

Neuropharmacology, Год журнала: 2018, Номер 145, С. 230 - 246

Опубликована: Авг. 4, 2018

Cerebral edema (CE) and resultant intracranial hypertension are associated with unfavorable prognosis in traumatic brain injury (TBI). CE is a leading cause of in-hospital mortality, occurring >60% patients mass lesions, ∼15% those normal initial computed tomography scans. After treatment lesions severe TBI, an important focus acute neurocritical care evaluating managing the secondary process hypertension. This review focuses on contemporary understanding various pathophysiologic pathways contributing to CE, subsequent description potential targeted therapies. There discussion identified cellular/cytotoxic contributors as well mechanisms that influence blood-brain-barrier (BBB) disruption/vasogenic edema, caveat this distinction may be somewhat artificial since molecular processes these interrelated. While exhaustive all putative contributions beyond scope review, roles some key highlighted, references provided for further details. Potential future targets treating presented based mechanisms. We thus aim provide translational synopsis present strategies targeting after TBI context paradigm shift towards precision medicine. article part Special Issue entitled "Novel Treatments Traumatic Brain Injury".

Язык: Английский

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Microglial Depletion with CSF1R Inhibitor During Chronic Phase of Experimental Traumatic Brain Injury Reduces Neurodegeneration and Neurological Deficits

Journal of Neuroscience, Год журнала: 2020, Номер 40(14), С. 2960 - 2974

Опубликована: Фев. 24, 2020

Chronic neuroinflammation with sustained microglial activation occurs following severe traumatic brain injury (TBI) and is believed to contribute subsequent neurodegeneration neurological deficits. Microglia, the primary innate immune cells in brain, are dependent on colony stimulating factor 1 receptor (CSF1R) signaling for their survival. In this preclinical study, we examined effects of delayed depletion chronically activated microglia functional recovery up 3 months postinjury. A CSF1R inhibitor, Plexxikon (PLX) 5622, was administered adult male C57BL/6J mice at month after controlled cortical impact remove microglia, inhibitor withdrawn 1-week later allow repopulation. Following TBI, repopulated displayed a ramified morphology similar that Sham uninjured mice, whereas vehicle-treated TBI showed typical chronic posttraumatic hypertrophic morphology. PLX5622 treatment limited TBI-associated neuropathological changes postinjury; these included smaller lesion, reduced hippocampal neuron cell death, decreased NOX2- NLRP3 inflammasome-associated neuroinflammation. Furthermore, led widespread transcriptome altered gene pathways involved neuroinflammation, oxidative stress, neuroplasticity. Using variety complementary neurobehavioral tests, PLX5622-treated also had improved long-term motor cognitive function through Together, studies demonstrate phase removal neurotoxic using inhibitors markedly reduce associated neurodegeneration, as well related SIGNIFICANCE STATEMENT Traumatic debilitating disorder can seriously patient's quality life. Microglial-mediated induced contributes deficits on-going neurodegenerative processes. Here, investigated effect breaking neuroinflammatory loop 1-month by pharmacological 5622. Overall, show short-term elimination during followed repopulation results improvements function, suppression stress pathways, reduction persistent These clinically relevant support new concepts therapeutic window may be far longer than traditionally if evolving microglial-mediated inhibited or regulated precise manner.

Язык: Английский

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Inflammasomes in Tissue Damages and Immune Disorders After Trauma

Frontiers in Immunology, Год журнала: 2018, Номер 9

Опубликована: Авг. 16, 2018

Trauma remains a leading cause of death worldwide. Hemorrhagic shock and direct injury to vital organs are responsible for early mortality whereas most delayed deaths secondary complex pathophysiological processes. These processes result from imbalanced systemic reactions the multiple aggressions associated with trauma. results in uncontrolled local release endogenous mediators acting as danger signals (damage-associated molecular patterns; DAMPs). Their recognition by innate immune system triggers pro-inflammatory response paradoxically concomitant immunosuppression. responses, ranging intensity inappropriate overwhelming, promote propagation injuries remote organs, organ failure death. Some numerous DAMPs released after trauma trigger assembly intracellular multiprotein complexes named inflammasomes. Once activated ligand, inflammasomes lead activation caspase. Activated caspases allow mature forms interleukin-1β interleukin-18 specific cell termed pyroptosis. Accumulating data suggest that inflammasomes, mainly NLRP3, NLRP1 AIM2, involved generation tissue damage dysfunction Following trauma-induced DAMP(s) recognition, participate ways development exaggerated organ-specific inflammatory response, contributing damage. Inflammasomes responses traumatic brain contribute acute respiratory distress syndrome. may also play role post-trauma immunosuppression mediated dysregulated monocyte functions. Characterizing involvement pathogenesis syndrome is key issue they be potential adjuvant therapeutic targets. This review summarizes current knowledge on roles

Язык: Английский

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Mer regulates microglial/macrophage M1/M2 polarization and alleviates neuroinflammation following traumatic brain injury

Journal of Neuroinflammation, Год журнала: 2021, Номер 18(1)

Опубликована: Янв. 5, 2021

Abstract Background Traumatic brain injury (TBI) is a leading cause of death and disability worldwide. Microglial/macrophage activation neuroinflammation are key cellular events following TBI, but the regulatory functional mechanisms still not well understood. Myeloid-epithelial-reproductive tyrosine kinase (Mer), member Tyro-Axl-Mer (TAM) family receptor kinases, regulates multiple features microglial/macrophage physiology. However, its function in regulating innate immune response M1/M2 polarization TBI has been addressed. The present study aimed to evaluate role Mer TBI. Methods controlled cortical impact (CCI) mouse model was employed. siRNA intracerebroventricularly administered, recombinant protein S (PS) intravenously applied for intervention. neurobehavioral assessments, RT-PCR, Western blot, magnetic-activated cell sorting, immunohistochemistry confocal microscopy analysis, Nissl Fluoro-Jade B staining, water content measurement, contusion volume assessment were performed. Results upregulated acute stage Mechanistically, activates signal transducer activator transcription 1 (STAT1)/suppressor cytokine signaling 1/3 (SOCS1/3) pathway. Inhibition markedly decreases M2-like while increases M1-like polarization, which exacerbates secondary damage sensorimotor deficits after Recombinant PS exerts beneficial effects mice through activation. Conclusions an important regulator neuroinflammation, may be considered as potential target therapeutic intervention

Язык: Английский

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Inflammasome: Its role in traumatic brain and spinal cord injury

Journal of Cellular Physiology, Год журнала: 2017, Номер 233(7), С. 5160 - 5169

Опубликована: Ноя. 18, 2017

Traumatic brain injury (TBI) and spinal cord (SCI) are pathological events that lead to neuropathological conditions which have in consequence the initiation of pro-inflammatory cytokine production. Neuroinflammation plays a key role secondary phase both TBI SCI after initial cell death. Activation cytoplasmic inflammasome complexes is regarded as essential step neuroinflammation trigger for neuronal death called pyroptosis. Inflammasome involved activation caspase-1 catalyzes cleavage pro-interleukins into their active forms (including interleukin-18 [IL-18] IL-1β). The focus this article discuss time-course regulation assembly during targeting designing therapeutic approaches. We particularly on inflammasomes NLRP1 NLRP3 play pivotal function central nervous system (CNS).

Язык: Английский

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Catalytically potent and selective clusterzymes for modulation of neuroinflammation through single-atom substitutions

Nature Communications, Год журнала: 2021, Номер 12(1)

Опубликована: Янв. 7, 2021

Emerging artificial enzymes with reprogrammed and augmented catalytic activity substrate selectivity have long been pursued sustained efforts. The majority of current candidates rely on noble metals or transition metal oxides rather poor compared natural molecules. To tackle this limitation, we strategically designed a novel enzyme based structurally well-defined Au25 cluster, namely clusterzyme, which is endowed intrinsic high driven by single-atom substitutions modulated bond lengths. 3-mercaptopropionic acid (MPA)-stabilized Au24Cu1 Au24Cd1 clusterzymes exhibit 137 160 times higher antioxidant capacities than the trolox, respectively. Meanwhile, each demonstrate preferential enzyme-mimicking activities compelling selectivity: exhibits superior glutathione peroxidase-like (GPx-like) activity; shows distinct advantage towards catalase-like (CAT-like) its Cu single active site; preferably acts as superoxide dismutase-like (SOD-like) via Cd site. This unique diversified landscape manifests distinctive reactions against inflammation in brain. behaves an endogenous multi-enzyme mimic that directly decreases peroxide injured brain reactions, while Au24Cd1, catalyzes nitrogenous signal molecules preference, significantly factors such IL-1\b{eta}, IL-6, TNF{\alpha}, indicative important role mitigating neuroinflammation.

Язык: Английский

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