Traumatic Brain Injury Causes Chronic Cortical Inflammation and Neuronal Dysfunction Mediated by Microglia

Journal of Neuroscience, Journal Year: 2021, Volume and Issue: 41(7), P. 1597 - 1616

Published: Jan. 15, 2021

Traumatic brain injury (TBI) can lead to significant neuropsychiatric problems and neurodegenerative pathologies, which develop persist years after injury. Neuroinflammatory processes evolve over this same period. Therefore, we aimed determine the contribution of microglia neuropathology at acute [1 d postinjury (dpi)], subacute (7 dpi), chronic (30 dpi) time points. Microglia were depleted with PLX5622, a CSF1R antagonist, before midline fluid percussion (FPI) in male mice cortical neuropathology/inflammation was assessed using mRNA panel. Gene expression associated inflammation robustly increased acutely (1 majority independent. At 7 30 dpi, however, microglial depletion reversed TBI-related genes inflammation, interferon signaling, neuropathology. Myriad suppressed endpoints attributed neurons. To understand relationship between microglia, neurons, other glia, single-cell RNA sequencing completed critical point evolution from pathogenesis. Cortical exhibited distinct TBI-associated clustering type-1 neurodegenerative/damage-related genes. In dopamine long-term potentiation, calcium synaptogenesis suppressed. Microglial these neuronal alterations. Furthermore, there reduced dendritic complexity connectively cognitive impairment dpi. All functional behavioral impairments prevented by depletion. Collectively, studies indicate that promote persistent homeostasis TBI.SIGNIFICANCE STATEMENT Millions traumatic injuries (TBIs) occur United States alone each year. Survivors face elevated rates psychiatric complications long inciting Recent human link neuroinflammation adverse neurologic outcomes, suggesting evolving inflammatory may be an opportunity for intervention. Here, eliminate compare effects diffuse TBI on neurons presence absence microglia-mediated inflammation. do not undergo TBI-induced changes gene transcription or structure. elimination (dpi). have role disrupting TBI, particularly timepoints.

Language: Английский

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Traumatic Brain Injury and Risk of Neurodegenerative Disorder

Biological Psychiatry, Journal Year: 2021, Volume and Issue: 91(5), P. 498 - 507

Published: June 2, 2021

Language: Английский

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Meningeal lymphatic dysfunction exacerbates traumatic brain injury pathogenesis

Nature Communications, Journal Year: 2020, Volume and Issue: 11(1)

Published: Sept. 10, 2020

Abstract Traumatic brain injury (TBI) is a leading global cause of death and disability. Here we demonstrate in an experimental mouse model TBI that mild forms trauma severe deficits meningeal lymphatic drainage begin within hours last out to at least one month post-injury. To investigate mechanism underlying impaired function TBI, examined how increased intracranial pressure (ICP) influences the lymphatics. We ICP can contribute dysfunction. Moreover, show pre-existing dysfunction before leads neuroinflammation negative cognitive outcomes. Finally, report rejuvenation aged mice ameliorate TBI-induced gliosis. These findings provide insights into both causes consequences suggest therapeutics targeting system may offer strategies treat TBI.

Language: Английский

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Cellular infiltration in traumatic brain injury

Journal of Neuroinflammation, Journal Year: 2020, Volume and Issue: 17(1)

Published: Nov. 3, 2020

Abstract Traumatic brain injury leads to cellular damage which in turn results the rapid release of damage-associated molecular patterns (DAMPs) that prompt resident cells cytokines and chemokines. These rapidly recruit neutrophils, assist limiting spread removing debris. Microglia continuously survey CNS (central nervous system) compartment identify structural abnormalities neurons contributing response. After some days, when neutrophil numbers start decline, activated microglia astrocytes assemble at site—segregating injured tissue from healthy facilitating restorative processes. Monocytes infiltrate site produce chemokines successively extend their processes towards monocytes during recovery phase. In this fashion, infiltration serves help repair brain. Neurons also moderate inflammation via downregulation cytotoxic inflammation. Depending on severity injury, T B can be recruited pathology sites later time points.

Language: Английский

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To Kill a Microglia: A Case for CSF1R Inhibitors

Trends in Immunology, Journal Year: 2020, Volume and Issue: 41(9), P. 771 - 784

Published: Aug. 10, 2020

Language: Английский

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Brain-gut axis dysfunction in the pathogenesis of traumatic brain injury

Journal of Clinical Investigation, Journal Year: 2021, Volume and Issue: 131(12)

Published: June 14, 2021

Traumatic brain injury (TBI) is a chronic and progressive disease, management requires an understanding of both the primary neurological secondary sequelae that affect peripheral organs, including gastrointestinal (GI) tract. The brain-gut axis composed bidirectional pathways through which TBI-induced neuroinflammation neurodegeneration impact gut function. resulting dysautonomia systemic inflammation contribute to GI events, dysmotility increased mucosal permeability. These effects shape, are shaped by, changes in microbiota composition activation resident recruited immune cells. Microbial products cell mediators turn modulate activity. Importantly, enteric inflammatory challenges prolong worsen neuropathology neurobehavioral deficits. importance communication maintaining homeostasis highlights it as viable therapeutic target for TBI. Currently, treatments directed toward dysautonomia, dysbiosis, and/or offer most promise.

Language: Английский

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Delayed microglial depletion after spinal cord injury reduces chronic inflammation and neurodegeneration in the brain and improves neurological recovery in male mice

Theranostics, Journal Year: 2020, Volume and Issue: 10(25), P. 11376 - 11403

Published: Jan. 1, 2020

Neuropsychological deficits, including impairments in learning and memory, occur after spinal cord injury (SCI). In experimental SCI models, we others have reported that such changes reflect sustained microglia activation the brain is associated with progressive neurodegeneration. present study, examined effect of pharmacological depletion on posttraumatic cognition, depressive-like behavior, pathology mice. Methods: Young adult male C57BL/6 mice were subjected to moderate/severe thoracic contusion. Microglial was induced colony-stimulating factor 1 receptor (CSF1R) antagonist PLX5622 administered starting either 3 weeks before or one day post-injury continuing through 6 SCI. Neuroinflammation injured assessed using flow cytometry NanoString technology. Neurological function evaluated a battery neurobehavioral tests motor function, depression. Lesion volume neuronal counts quantified by unbiased stereology. Results: Flow analysis demonstrated pre-treatment significantly reduced number microglia, as well infiltrating monocytes neutrophils, decreased reactive oxygen species production these cells from at 2-days post-injury. Post-injury treatment both CD45int CD45hi myeloid 7-days. Following six treatment, there substantial transcriptomes, those involved neuroinflammation. These alterations improved survival neurological recovery. Conclusion: findings indicate microglia-deletion reduces neuroinflammation brain, improving recovery function.

Language: Английский

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Traumatic Brain Injury: Mechanisms of Glial Response

Frontiers in Physiology, Journal Year: 2021, Volume and Issue: 12

Published: Oct. 22, 2021

Traumatic brain injury (TBI) is a heterogeneous disorder that involves damage due to external forces. TBI the main factor of death and morbidity in young males with high incidence worldwide. causes central nervous system (CNS) under variety mechanisms, including synaptic dysfunction, protein aggregation, mitochondrial oxidative stress, neuroinflammation. Glial cells comprise most CNS, which are mediators brain’s response TBI. In CNS present astrocytes, microglia, oligodendrocytes, polydendrocytes (NG2 cells). Astrocytes play critical roles ion water homeostasis, energy metabolism, blood-brain barrier, immune response. TBI, astrocytes change their morphology expression. Microglia primary phagocytic activity. After microglia also release both pro anti-inflammatory mediators. Oligodendrocytes myelin producers promoting axonal support. oligodendrocyte apoptosis, demyelination, transport disruption. There various interactions between these glial neurons contribute pathophysiology this review, we summarize several hallmarks relevant for understanding neuronal conditions.

Language: Английский

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Neuroinflammation and the Kynurenine Pathway in CNS Disease: Molecular Mechanisms and Therapeutic Implications

Cells, Journal Year: 2021, Volume and Issue: 10(6), P. 1548 - 1548

Published: June 19, 2021

Diseases of the central nervous system (CNS) remain a significant health, social and economic problem around globe. The development therapeutic strategies for CNS conditions has suffered due to poor understanding underlying pathologies that manifest them. Understanding common etiological origins at cellular molecular level is essential enhance efficacious targeted treatment options. Over years, neuroinflammation been posited as link between multiple neurological, neurodegenerative neuropsychiatric disorders. Processes precipitate neuroinflammatory including genetics, infections, physical injury psychosocial factors, like stress trauma, closely dysregulation in kynurenine pathway (KP) tryptophan metabolism possible pathophysiological factor 'fuel fire' diseases. In this study, we aim review emerging evidence provide mechanistic insights different disorders, KP. We thorough overview branches KP pertinent disease pathology have implications selected strategies.

Language: Английский

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Origins, Biology, and Diseases of Tissue Macrophages

Annual Review of Immunology, Journal Year: 2021, Volume and Issue: 39(1), P. 313 - 344

Published: April 26, 2021

Tissue-resident macrophages are present in most tissues with developmental, self-renewal, or functional attributes that do not easily fit into a textbook picture of plastic and multifunctional macrophage originating from hematopoietic stem cells; nor does it pro- versus anti-inflammatory paradigm. This review presents discusses current knowledge on the developmental biology an evolutionary perspective focused function macrophages, which may aid study inflammatory, tumoral, degenerative diseases. We also propose framework to investigate functions vivo discuss how inherited germline somatic mutations contribute roles

Language: Английский

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