scholarly journals Microglial Metabolism After Pediatric Traumatic Brain Injury – Overlooked Bystanders or Active Participants?

2021 ◽  
Vol 11 ◽  
Author(s):  
Aria C. Shi ◽  
Ursula Rohlwink ◽  
Susanna Scafidi ◽  
Sujatha Kannan
Keyword(s):  
Traumatic Brain Injury ◽  
Immune Response ◽  
Brain Injury ◽  
Innate Immune Response ◽  
Innate Immune ◽  
Metabolic Alterations ◽  
Microglial Phenotype ◽  
Integral Role ◽  
And Behavior ◽  
The Brain

Microglia play an integral role in brain development but are also crucial for repair and recovery after traumatic brain injury (TBI). TBI induces an intense innate immune response in the immature, developing brain that is associated with acute and chronic changes in microglial function. These changes contribute to long-lasting consequences on development, neurologic function, and behavior. Although alterations in glucose metabolism are well-described after TBI, the bulk of the data is focused on metabolic alterations in astrocytes and neurons. To date, the interplay between alterations in intracellular metabolic pathways in microglia and the innate immune response in the brain following an injury is not well-studied. In this review, we broadly discuss the microglial responses after TBI. In addition, we highlight reported metabolic alterations in microglia and macrophages, and provide perspective on how changes in glucose, fatty acid, and amino acid metabolism can influence and modulate the microglial phenotype and response to injury.

scholarly journals Loss of the Antimicrobial Peptide Metchnikowin Protects Against Traumatic Brain Injury Outcomes in Drosophila melanogaster

2020 ◽  
Vol 10 (9) ◽  
pp. 3109-3119 ◽  
Author(s):  
Laura C Swanson ◽  
Stacey A Rimkus ◽  
Barry Ganetzky ◽  
David A Wassarman
Keyword(s):  
Traumatic Brain Injury ◽  
Immune Response ◽  
Drosophila Melanogaster ◽  
Transcription Factors ◽  
Brain Injury ◽  
Innate Immune Response ◽  
Defense Mechanisms ◽  
Innate Immune ◽  
Injury Outcomes ◽  
The Brain

Abstract Neuroinflammation is a major pathophysiological feature of traumatic brain injury (TBI). Early and persistent activation of innate immune response signaling pathways by primary injuries is associated with secondary cellular injuries that cause TBI outcomes to change over time. We used a Drosophila melanogaster model to investigate the role of antimicrobial peptides (AMPs) in acute and chronic outcomes of closed-head TBI. AMPs are effectors of pathogen and stress defense mechanisms mediated by the evolutionarily conserved Toll and Immune-deficiency (Imd) innate immune response pathways that activate Nuclear Factor kappa B (NF-κB) transcription factors. Here, we analyzed the effect of null mutations in 10 of the 14 known Drosophila AMP genes on TBI outcomes. We found that mutation of Metchnikowin (Mtk) was unique in protecting flies from mortality within the 24 h following TBI under two diet conditions that produce different levels of mortality. In addition, Mtk mutants had reduced behavioral deficits at 24 h following TBI and increased lifespan either in the absence or presence of TBI. Using a transcriptional reporter of gene expression, we found that TBI increased Mtk expression in the brain. Quantitative analysis of mRNA in whole flies revealed that expression of other AMPs in the Toll and Imd pathways as well as NF-κB transcription factors were not altered in Mtk mutants. Overall, these results demonstrate that Mtk plays an infection-independent role in the fly nervous system, and TBI-induced expression of Mtk in the brain activates acute and chronic secondary injury pathways that are also activated during normal aging.

scholarly journals Guilty Molecules, Guilty Minds? The Conflicting Roles of the Innate Immune Response to Traumatic Brain Injury

2012 ◽  
Vol 2012 ◽  
pp. 1-18 ◽  
Author(s):  
Sarah Claire Hellewell ◽  
Maria Cristina Morganti-Kossmann
Keyword(s):  
Traumatic Brain Injury ◽  
Immune Response ◽  
Brain Injury ◽  
Innate Immune Response ◽  
Complex Disease ◽  
Clinical Care ◽  
The Body ◽  
Innate Immune ◽  
Neuroprotective Therapy ◽  
Attractive Therapeutic Target

Traumatic brain injury (TBI) is a complex disease in the most complex organ of the body, whose victims endure lifelong debilitating physical, emotional, and psychosocial consequences. Despite advances in clinical care, there is no effective neuroprotective therapy for TBI, with almost every compound showing promise experimentally having disappointing results in the clinic. The complex and highly interrelated innate immune responses govern both the beneficial and deleterious molecular consequences of TBI and are present as an attractive therapeutic target. This paper discusses the positive, negative, and often conflicting roles of the innate immune response to TBI in both an experimental and clinical settings and highlights recent advances in the search for therapeutic candidates for the treatment of TBI.

scholarly journals Survival Following Traumatic Brain Injury in Drosophila Is Increased by Heterozygosity for a Mutation of the NF-κB Innate Immune Response Transcription Factor Relish

Genetics ◽  
2020 ◽  
Vol 216 (4) ◽  
pp. 1117-1136 ◽  
Author(s):  
Laura C. Swanson ◽  
Edna A. Trujillo ◽  
Gene H. Thiede ◽  
Rebeccah J. Katzenberger ◽  
Evgenia Shishkova ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Immune Response ◽  
Brain Injury ◽  
Innate Immune Response ◽  
Genetic Background ◽  
Cellular Response ◽  
Expression Profiles ◽  
Innate Immune ◽  
Immune Response Genes ◽  
Secondary Injuries

Traumatic brain injury (TBI) pathologies are caused by primary and secondary injuries. Primary injuries result from physical damage to the brain, and secondary injuries arise from cellular responses to primary injuries. A characteristic cellular response is sustained activation of inflammatory pathways commonly mediated by nuclear factor-κB (NF-κB) transcription factors. Using a Drosophila melanogaster TBI model, we previously found that the main proximal transcriptional response to primary injuries is triggered by activation of Toll and Imd innate immune response pathways that engage NF-κB factors Dif and Relish (Rel), respectively. Here, we found by mass spectrometry that Rel protein level increased in fly heads at 4–8 hr after TBI. To investigate the necessity of Rel for secondary injuries, we generated a null allele, Reldel, by CRISPR/Cas9 editing. When heterozygous but not homozygous, the Reldel mutation reduced mortality at 24 hr after TBI and increased the lifespan of injured flies. Additionally, the effect of heterozygosity for Reldel on mortality was modulated by genetic background and diet. To identify genes that facilitate effects of Reldel on TBI outcomes, we compared genome-wide mRNA expression profiles of uninjured and injured +/+, +/Reldel, and Reldel/Reldel flies at 4 hr following TBI. Only a few genes changed expression more than twofold in +/Reldel flies relative to +/+ and Reldel/Reldel flies, and they were not canonical innate immune response genes. Therefore, Rel is necessary for TBI-induced secondary injuries but in complex ways involving Rel gene dose, genetic background, diet, and possibly small changes in expression of innate immune response genes.

scholarly journals Effects of Therapeutic Hypothermia on Inflammasome Signaling after Traumatic Brain Injury

2012 ◽  
Vol 32 (10) ◽  
pp. 1939-1947 ◽  
Author(s):  
Satoshi Tomura ◽  
Juan Pablo de Rivero Vaccari ◽  
Robert W Keane ◽  
Helen M Bramlett ◽  
W Dalton Dietrich
Keyword(s):  
Traumatic Brain Injury ◽  
Immune Response ◽  
Brain Injury ◽  
Therapeutic Hypothermia ◽  
Innate Immune Response ◽  
Cortical Neurons ◽  
Purinergic Receptor ◽  
Innate Immune ◽  
Inflammasome Activation ◽  
Caspase 1

Traumatic brain injury (TBI) activates the NALP1/NLRP1 inflammasome, which is an important component of the early innate inflammatory response to injury. We investigated the influence of therapeutic hypothermia on inflammasome activation after TBI. Adult male Sprague–Dawley rats were subjected to moderate fluid percussion brain injury. Temperature manipulation (33°C or 37°C) was initiated 30 minutes after TBI and maintained for 4 hours. At 4 or 24 hours after TBI, traumatized cortex and hippocampus were prepared for immunoblot or immunohistochemical analysis. In the normothermic groups, caspase-1, caspase-11 and expression of the purinergic receptor P2X7 increased at 24 hours after TBI. Posttraumatic hypothermia lead to decreased expression of these proteins at 24 hours compared with normothermic levels. Immunocytochemical studies showed that posttraumatic hypothermia also decreased caspase-1 staining in cerebral cortical neurons compared with normothermic TBI. Cultured cortical neurons subjected to stretch injury demonstrated significant secretion of caspase-1 into the culture medium and caspase-3 activation, both results reduced by hypothermic treatment. Posttraumatic hypothermia decreases inflammasome signaling in neurons and reduces the innate immune response to TBI at 24 hours after injury. Therapeutic hypothermia may protect the injured central nervous system by targeting the detrimental consequences of the innate immune response to injury.

scholarly journals Age and Diet Affect Genetically Separable Secondary Injuries that Cause Acute Mortality Following Traumatic Brain Injury in Drosophila

2016 ◽  
Vol 6 (12) ◽  
pp. 4151-4166 ◽  
Author(s):  
Rebeccah J Katzenberger ◽  
Barry Ganetzky ◽  
David A Wassarman
Keyword(s):  
Traumatic Brain Injury ◽  
Immune Response ◽  
Brain Injury ◽  
Innate Immune Response ◽  
Traumatic Event ◽  
Expression Profiles ◽  
Innate Immune ◽  
Peak Period ◽  
Immune Response Genes ◽  
Secondary Injuries

Abstract Outcomes of traumatic brain injury (TBI) vary because of differences in primary and secondary injuries. Primary injuries occur at the time of a traumatic event, whereas secondary injuries occur later as a result of cellular and molecular events activated in the brain and other tissues by primary injuries. We used a Drosophila melanogaster TBI model to investigate secondary injuries that cause acute mortality. By analyzing mortality percentage within 24 hr of primary injuries, we previously found that age at the time of primary injuries and diet afterward affect the severity of secondary injuries. Here, we show that secondary injuries peaked in activity 1–8 hr after primary injuries. Additionally, we demonstrate that age and diet activated distinct secondary injuries in a genotype-specific manner, and that concurrent activation of age- and diet-regulated secondary injuries synergistically increased mortality. To identify genes involved in secondary injuries that cause mortality, we compared genome-wide mRNA expression profiles of uninjured and injured flies under age and diet conditions that had different mortalities. During the peak period of secondary injuries, innate immune response genes were the predominant class of genes that changed expression. Furthermore, age and diet affected the magnitude of the change in expression of some innate immune response genes, suggesting roles for these genes in inhibiting secondary injuries that cause mortality. Our results indicate that the complexity of TBI outcomes is due in part to distinct, genetically controlled, age- and diet-regulated mechanisms that promote secondary injuries and that involve a subset of innate immune response genes.

Mincle Signaling in the Innate Immune Response after Traumatic Brain Injury

2015 ◽  
Vol 32 (4) ◽  
pp. 228-236 ◽  
Author(s):  
Juan Carlos de Rivero Vaccari ◽  
Frank J. Brand ◽  
Aldo F. Berti ◽  
Ofelia F. Alonso ◽  
M. Ross Bullock ◽  
...  
Keyword(s):  
Traumatic Brain Injury ◽  
Immune Response ◽  
Brain Injury ◽  
Innate Immune Response ◽  
Innate Immune

scholarly journals IL-33 ameliorates Alzheimer’s disease-like pathology and cognitive decline

2016 ◽  
Vol 113 (19) ◽  
pp. E2705-E2713 ◽  
Author(s):  
Amy K. Y. Fu ◽  
Kwok-Wang Hung ◽  
Michael Y. F. Yuen ◽  
Xiaopu Zhou ◽  
Deejay S. Y. Mak ◽  
...  
Keyword(s):  
Alzheimer’S Disease ◽  
Alzheimer's Disease ◽  
Immune Response ◽  
Innate Immune Response ◽  
Memory Loss ◽  
Neuronal Loss ◽  
Innate Immune ◽  
Therapeutic Role ◽  
Potential Therapeutic Role ◽  
The Brain

Alzheimer’s disease (AD) is a devastating condition with no known effective treatment. AD is characterized by memory loss as well as impaired locomotor ability, reasoning, and judgment. Emerging evidence suggests that the innate immune response plays a major role in the pathogenesis of AD. In AD, the accumulation of β-amyloid (Aβ) in the brain perturbs physiological functions of the brain, including synaptic and neuronal dysfunction, microglial activation, and neuronal loss. Serum levels of soluble ST2 (sST2), a decoy receptor for interleukin (IL)-33, increase in patients with mild cognitive impairment, suggesting that impaired IL-33/ST2 signaling may contribute to the pathogenesis of AD. Therefore, we investigated the potential therapeutic role of IL-33 in AD, using transgenic mouse models. Here we report that IL-33 administration reverses synaptic plasticity impairment and memory deficits in APP/PS1 mice. IL-33 administration reduces soluble Aβ levels and amyloid plaque deposition by promoting the recruitment and Aβ phagocytic activity of microglia; this is mediated by ST2/p38 signaling activation. Furthermore, IL-33 injection modulates the innate immune response by polarizing microglia/macrophages toward an antiinflammatory phenotype and reducing the expression of proinflammatory genes, including IL-1β, IL-6, and NLRP3, in the cortices of APP/PS1 mice. Collectively, our results demonstrate a potential therapeutic role for IL-33 in AD.

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