Crosstalk between Microglia and Neurons in Neurotrauma: An Overview of the Underlying Mechanisms

2021 ◽  
Vol 19 ◽  
Author(s):  
Muhammad Ali Haidar ◽  
Stanley Ibeh ◽  
Zaynab Shakkour ◽  
Mohammad Amine Reslan ◽  
Judith Nwaiwu ◽  
...  
Keyword(s):  
Brain Injury ◽  
Microglial Activation ◽  
Trauma Treatment ◽  
Cell Contact ◽  
Clear Understanding ◽  
Neuroinflammatory Response ◽  
Proinflammatory Responses ◽  
Underlying Mechanisms ◽  
The Brain ◽  
Cns Anomalies

: Microglia are the resident immune cells of the brain and play a crucial role in housekeeping and maintaining homeostasis of the brain microenvironment. Upon injury or disease, microglial cells become activated, at least partly, via signals initiated by injured neurons. Activated microglia, thereby, contribute to both neuroprotection and neuroinflammation. However, sustained microglial activation initiates a chronic neuroinflammatory response which can disturb neuronal health and disrupt communications between neurons and microglia. Thus, microglia-neuron crosstalk is critical in a healthy brain as well as during states of injury or disease. As most studies focus on how neurons and microglia act in isolation during neurotrauma, there is a need to understand the interplay between these cells in brain pathophysiology. This review highlights how neurons and microglia reciprocally communicate under physiological conditions and during brain injury and disease. Furthermore, the modes of microglia-neuron communication are exposed, focusing on cell-contact dependent signaling and communication by the secretion of soluble factors like cytokines and growth factors. In addition, how microglia-neuron interactions could exert either beneficial neurotrophic effects or pathologic proinflammatory responses are discussed. We further explore how aberrations in microglia-neuron crosstalk may be involved in central nervous system (CNS) anomalies, namely: traumatic brain injury (TBI), neurodegeneration, and ischemic stroke. A clear understanding of how the microglia-neuron crosstalk contributes to the pathogenesis of brain pathologies may offer novel therapeutic avenues of brain trauma treatment.

scholarly journals SCIDOT-34. BRAIN INJURY SIGNALS SYSTEMIC IMMUNOSUPPRESSION THROUGH THYMIC INVOLUTION

2019 ◽  
Vol 21 (Supplement_6) ◽  
pp. vi278-vi279
Author(s):  
Katayoun Ayasoufi ◽  
Christian K Pfaller ◽  
Roman H Khadka ◽  
Fang Jin ◽  
Jiaying Zheng ◽  
...  
Keyword(s):  
Brain Injury ◽  
T Cell ◽  
Thymic Involution ◽  
Systemic Immunosuppression ◽  
Cell Counts ◽  
Immune Deficiencies ◽  
Underlying Mechanisms ◽  
Neurological Injuries ◽  
The Brain

Abstract Systemic immunosuppression following neurological insults including stroke, traumatic brain injury, and glioblastoma (GBM) causes mortality and leads to failure of immune-modulating therapies. Exact immunological nature and the underlying mechanisms of this immunosuppression are unknown. Our goal was to define effects of neurological insults given exclusively to the brain on the thymus. The thymus is the primary immune organ responsible for T-cell development and maintenance both in children and in adults. We evaluated the brain-thymus communication using the following neurological insults: physical injury, CNS viral infection, sterile injury, tumor implantation, and seizures. All insults resulted in significant thymic involution that was reversible upon clearance of the insult. Thymic involution did not occur following similar peripheral insults. We next demonstrated that the GL261 model of GBM recapitulates hallmark features of peripheral immunosuppression observed in GBM patients including low CD4 T-cell counts. Thus, we aimed to further study the immunosuppression affecting the thymus in this clinically relevant model. Principle component analysis following RNA-sequencing of thymi from naïve and glioma-bearing mice revealed unbiased separation of the groups suggesting that the thymus is directly affected by a brain tumor. To determine the extent to which thymic involution was caused by a soluble factor we employed parabiosis. We demonstrated that thymic involution was transferable from glioma-bearing to non-tumor-bearing parabionts. Similarly, serum taken from GL261 glioma-bearing mice potently inhibited proliferation of T-cells in vitro. Together our data demonstrate that CNS-specific insults, regardless of nature, cause immunosuppression by prompting thymic involution through circulating factors. This accounts at least partially for immune deficiencies observed following neurological injuries. Identification of this suppressive factor is crucial in designing future therapeutics for GBM patients, and patients with other acute and chronic neurological trauma.

scholarly journals The brain-gut axis - where are we now and how can we modulate these connections?

2020 ◽  
Vol 18 ◽  
Author(s):  
Wojciech Dabrowski ◽  
Dorota Siwicka-Gieroba ◽  
Katarzyna Kotfis ◽  
Sami Zaid ◽  
Sylwia Terpilowska ◽  
...  
Keyword(s):  
Nervous System ◽  
Brain Injury ◽  
Gut Microbiome ◽  
Microglial Activation ◽  
Molecular Processes ◽  
Protein Extravasation ◽  
The Central Nervous System ◽  
Intensive Investigation ◽  
Cytoskeletal Rearrangements ◽  
The Brain

: A traumatic brain injury (TBI) initiates an inflammatory response with molecular cascades triggered by the presence of necrotic debris including damaged myelin, hemorrhages and injured neuronal cells. Molecular cascades prominent in TBI-induced inflammation include the release of an excess of proinflammatory cytokines and angiogenic factors, the degradation of tight junctions (TJs), cytoskeletal rearrangements and leukocyte and protein extravasation promoted by increased expression of adhesion molecules. The brain-gut axis consists of a complex network involving neuroendocrine and immunological signaling pathways and bi-directional neural mechanisms. Importantly, modifying the gut microbiome alters this axis, and in turn may influence brain injury and neuroinflammatory processes. In recent years it has been demonstrated that the activity and composition of the gastrointestinal (GI) microbiome population influences the brain through all of above mentioned pathways affecting homeostasis of the central nervous system (CNS). The GI microbiome is involved in the modulation of cellular and molecular processes which are fundamental to the progression of TBI-induced pathologies including neuroinflammation, abnormal blood brain barrier (BBB) permeability, immune system responses, microglial activation, and mitochondrial dysfunction. It has been postulated that interaction between the brain and gut microbiome occurs mainly via the enteric nervous system and the vagus nerve through neuroactive compounds including serotonin or dopamine and activation by bacterial metabolites including endotoxin, neurotransmitters, neurotrophic factors, and cytokines. In recent years the multifactorial impact of selected immunomodulatory drugs on immune processes occurring in the CNS and involving the brain-gut axis has been under intensive investigation.

Inflammatory Pathways Are Impaired in Alzheimer Disease and Differentially Associated With Apolipoprotein E Status

2021 ◽  
Author(s):  
Courtney M Kloske ◽  
Adam J Dugan ◽  
Erica M Weekman ◽  
Zachary Winder ◽  
Ela Patel ◽  
...  
Keyword(s):  
Alzheimer Disease ◽  
Apolipoprotein E ◽  
Microglial Activation ◽  
Middle Temporal Gyrus ◽  
Altered Expression ◽  
Apoe Ε4 ◽  
Apoe Isoforms ◽  
Expression Of Genes ◽  
Underlying Mechanisms ◽  
The Brain

Abstract Alzheimer disease (AD) is a neurodegenerative disease characterized by a cognitive decline leading to dementia. The most impactful genetic risk factor is apolipoprotein E (APOE). APOE-ε4 significantly increases AD risk, APOE-ε3 is the most common gene variant, and APOE-ε2 protects against AD. However, the underlying mechanisms of APOE-ε4 on AD risk remains unclear, with APOE-ε4 impacting many pathways. We investigated how the APOE isoforms associated with the neuroinflammatory state of the brain with and without AD pathology. Frozen brain tissue from the superior and middle temporal gyrus was analyzed from APOE-ε3/3 (n = 9) or APOE-ε4/4 (n = 10) participants with AD pathology and APOE-ε3/3 (n = 9) participants without AD pathology. We determined transcript levels of 757 inflammatory related genes using the NanoString Human Neuroinflammation Panel. We found significant pathways impaired in APOE-ε4/4-AD individuals compared to APOE-ε3/3-AD. Of interest, expression of genes related to microglial activation (SALL1), motility (FSCN1), epigenetics (DNMT1), and others showed altered expression. Additionally, we performed immunohistochemistry of P2RY12 to confirm reduced microglial activation. Our results suggest APOE-ε3 responds to AD pathology while potentially having a harmful long-term inflammatory response, while APOE-ε4 shows a weakened response to pathology. Overall, APOE isoforms appear to modulate the brain immune response to AD-type pathology.

scholarly journals Underlying Mechanisms of Tinnitus: Review and Clinical Implications

2014 ◽  
Vol 25 (01) ◽  
pp. 005-022 ◽  
Author(s):  
James A. Henry ◽  
Larry E. Roberts ◽  
Donald M. Caspary ◽  
Sarah M. Theodoroff ◽  
Richard J. Salvi
Keyword(s):  
Health Care Professionals ◽  
Behavioral Interventions ◽  
Auditory Pathway ◽  
Common Denominator ◽  
Clear Understanding ◽  
Underlying Mechanisms ◽  
Normal Input ◽  
Central Auditory Pathway ◽  
The Brain

Background: The study of tinnitus mechanisms has increased tenfold in the last decade. The common denominator for all of these studies is the goal of elucidating the underlying neural mechanisms of tinnitus with the ultimate purpose of finding a cure. While these basic science findings may not be immediately applicable to the clinician who works directly with patients to assist them in managing their reactions to tinnitus, a clear understanding of these findings is needed to develop the most effective procedures for alleviating tinnitus. Purpose: The goal of this review is to provide audiologists and other health-care professionals with a basic understanding of the neurophysiological changes in the auditory system likely to be responsible for tinnitus. Results: It is increasingly clear that tinnitus is a pathology involving neuroplastic changes in central auditory structures that take place when the brain is deprived of its normal input by pathology in the cochlea. Cochlear pathology is not always expressed in the audiogram but may be detected by more sensitive measures. Neural changes can occur at the level of synapses between inner hair cells and the auditory nerve and within multiple levels of the central auditory pathway. Long-term maintenance of tinnitus is likely a function of a complex network of structures involving central auditory and nonauditory systems. Conclusions: Patients often have expectations that a treatment exists to cure their tinnitus. They should be made aware that research is increasing to discover such a cure and that their reactions to tinnitus can be mitigated through the use of evidence-based behavioral interventions.

scholarly journals Acute Traumatic Brain Injury-Induced Neuroinflammatory Response and Neurovascular Disorders in the Brain

2020 ◽  
Author(s):  
Duraisamy Kempuraj ◽  
Mohammad Ejaz Ahmed ◽  
Govindhasamy Pushpavathi Selvakumar ◽  
Ramasamy Thangavel ◽  
Sudhanshu P. Raikwar ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Neuroinflammatory Response ◽  
Acute Traumatic Brain Injury ◽  
The Brain

New Insights into Oxidative Damage and Iron Associated Impairment in Traumatic Brain Injury

2020 ◽  
Vol 25 (45) ◽  
pp. 4737-4746
Author(s):  
Nicolas Toro-Urrego ◽  
Liliana F. Turner ◽  
Marco F. Avila-Rodriguez
Keyword(s):  
Reactive Oxygen Species ◽  
Traumatic Brain Injury ◽  
Brain Injury ◽  
Oxidative Damage ◽  
Brain Tissue ◽  
Reactive Oxygen ◽  
Iron Chelators ◽  
Oxygen Species ◽  
Underlying Mechanisms ◽  
The Brain

: Traumatic Brain Injury is considered one of the most prevalent causes of death around the world; more than seventy millions of individuals sustain the condition per year. The consequences of traumatic brain injury on brain tissue are complex and multifactorial, hence, the current palliative treatments are limited to improve patients’ quality of life. The subsequent hemorrhage caused by trauma and the ongoing oxidative process generated by biochemical disturbances in the in the brain tissue may increase iron levels and reactive oxygen species. The relationship between oxidative damage and the traumatic brain injury is well known, for that reason, diminishing factors that potentiate the production of reactive oxygen species have a promissory therapeutic use. Iron chelators are molecules capable of scavenging the oxidative damage from the brain tissue and are currently in use for ironoverload- derived diseases. : Here, we show an updated overview of the underlying mechanisms of the oxidative damage after traumatic brain injury. Later, we introduced the potential use of iron chelators as neuroprotective compounds for traumatic brain injury, highlighting the action mechanisms of iron chelators and their current clinical applications.

scholarly journals Role of Exosomes in Cancer-Related Cognitive Impairment

2020 ◽  
Vol 21 (8) ◽  
pp. 2755 ◽  
Author(s):  
Yong Qin Koh ◽  
Chia Jie Tan ◽  
Yi Long Toh ◽  
Siu Kwan Sze ◽  
Han Kiat Ho ◽  
...  
Keyword(s):  
Cognitive Impairment ◽  
Cognitive Functioning ◽  
Cell Communication ◽  
Clear Understanding ◽  
Functional Changes ◽  
Patients With Cancer ◽  
Neurological Processes ◽  
Underlying Mechanisms ◽  
Exocytic Pathway ◽  
The Brain

A decline in cognitive function following cancer treatment is one of the most commonly reported post-treatment symptoms among patients with cancer and those in remission, and include memory, processing speed, and executive function. A clear understanding of cognitive impairment as a result of cancer and its therapy can be obtained by delineating structural and functional changes using brain imaging studies and neurocognitive assessments. There is also a need to determine the underlying mechanisms and pathways that impact the brain and affect cognitive functioning in cancer survivors. Exosomes are small cell-derived vesicles formed by the inward budding of multivesicular bodies, and are released into the extracellular environment via an exocytic pathway. Growing evidence suggests that exosomes contribute to various physiological and pathological conditions, including neurological processes such as synaptic plasticity, neuronal stress response, cell-to-cell communication, and neurogenesis. In this review, we summarize the relationship between exosomes and cancer-related cognitive impairment. Unraveling exosomes’ actions and effects on the microenvironment of the brain, which impacts cognitive functioning, is critical for the development of exosome-based therapeutics for cancer-related cognitive impairment.

scholarly journals The Neuroinflammatory Response in ALS: The Roles of Microglia and T Cells

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Coral-Ann Lewis ◽  
John Manning ◽  
Fabio Rossi ◽  
Charles Krieger
Keyword(s):  
T Cells ◽  
Microglial Activation ◽  
Neuroinflammatory Response ◽  
Activated Microglia ◽  
Familial Form ◽  
Advanced Stages ◽  
Brain And Spinal Cord ◽  
The Brain ◽  
Lateral Sclerosis ◽  
Trophic Role

Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease characterized by upper and lower motoneuron death. Mutations in the gene for superoxide dismutase 1 (SOD1) cause a familial form of ALS and have been used to develop transgenic mice which overexpress human mutant SOD1 (mSOD) and these mice exhibit a motoneuron disease which is pathologically and phenotypically similar to ALS. Neuroinflammation is a pathological hallmark of many neurodegenerative diseases including ALS and is typified by the activation and proliferation of microglia and the infiltration of T cells into the brain and spinal cord. Although the neuroinflammatory response has been considered a consequence of neuronal dysfunction and death, evidence indicates that manipulation of this response can alter disease progression. Previously viewed as deleterious to neuronal survival, recent reports suggest a trophic role for activated microglia in the mSOD mouse during the early stages of disease that is dependent on instructive signals from infiltrating T cells. However, at advanced stages of disease, activated microglia acquire increased neurotoxic potential, warranting further investigation into factors capable of skewing microglial activation towards a neurotrophic phenotype as a means of therapeutic intervention in ALS.

scholarly journals Active Life for Brain Health: A Narrative Review of the Mechanism Underlying the Protective Effects of Physical Activity on the Brain

2021 ◽  
Vol 13 ◽  
Author(s):  
Hiroyuki Umegaki ◽  
Takashi Sakurai ◽  
Hidenori Arai
Keyword(s):  
Physical Activity ◽  
Brain Volume ◽  
Clear Understanding ◽  
Protective Effects ◽  
Brain Health ◽  
Beneficial Effects ◽  
Active Life ◽  
Two Factors ◽  
Underlying Mechanisms ◽  
The Brain

A growing body of evidence clearly indicates the beneficial effects of physical activity (PA) on cognition. The importance of PA is now being reevaluated due to the increase in sedentary behavior in older adults during the COVID-19 pandemic. Although many studies in humans have revealed that PA helps to preserve brain health, the underlying mechanisms have not yet been fully elucidated. In this review, which mainly focuses on studies in humans, we comprehensively summarize the mechanisms underlying the beneficial effects of PA or exercise on brain health, particularly cognition. The most intensively studied mechanisms of the beneficial effects of PA involve an increase in brain-derived neurotrophic factor (BDNF) and preservation of brain volume, especially that of the hippocampus. Nonetheless, the mutual associations between these two factors remain unclear. For example, although BDNF presumably affects brain volume by inhibiting neuronal death and/or increasing neurogenesis, human data on this issue are scarce. It also remains to be determined whether PA modulates amyloid and tau metabolism. However, recent advances in blood-based biomarkers are expected to help elucidate the beneficial effects of PA on the brain. Clinical data suggest that PA functionally modulates cognition independently of neurodegeneration, and the mechanisms involved include modulation of functional connectivity, neuronal compensation, neuronal resource allocation, and neuronal efficiency. However, these mechanisms are as yet not fully understood. A clear understanding of the mechanisms involved could help motivate inactive persons to change their behavior. More accumulation of evidence in this field is awaited.

scholarly journals Biomarkers for Microglial Activation in Alzheimer's Disease

2011 ◽  
Vol 2011 ◽  
pp. 1-5 ◽  
Author(s):  
Ronald Lautner ◽  
Niklas Mattsson ◽  
Michael Schöll ◽  
Kristin Augutis ◽  
Kaj Blennow ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Microglial Activation ◽  
Inflammatory Responses ◽  
Innate Immune ◽  
First Line ◽  
The Central Nervous System ◽  
Underlying Mechanisms ◽  
The Brain ◽  
Neuroimaging Techniques

Intensive research over the last decades has provided increasing evidence for neuroinflammation as an integral part in the pathogenesis of neurodegenerative diseases such as Alzheimer's disease (AD). Inflammatory responses in the central nervous system (CNS) are initiated by activated microglia, representing the first line of the innate immune defence of the brain. Therefore, biochemical markers of microglial activation may help us understand the underlying mechanisms of neuroinflammation in AD as well as the double-sided qualities of microglia, namely, neuroprotection and neurotoxicity. In this paper we summarize candidate biomarkers of microglial activation in AD along with a survey of recent neuroimaging techniques.

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