Microglia Receptors in Animal Models of Traumatic Brain Injury

Younger, Daniel; Murugan, Madhuvika; Rao, Kakulavarapu V. Rama; Wu, Long Jun; Chandra, Namas

doi:10.1007/s12035-018-1428-7

Cited by 54 publications

(42 citation statements)

References 359 publications

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“…Microglia, the brain's resident immune cells, have emerged as important players in neural development, nervous system homeostasis, and both acute and chronic brain pathologies (Eyo and Wu, 2013;Nayak et al, 2014;Salter and Beggs, 2014;Hammond et al, 2018). In the context of seizures and epilepsy, microglial research has lagged behind other acute pathologies, such as stroke and traumatic brain injury (Karve et al, 2016;Ma et al, 2017;Younger et al, 2019), as well as chronic diseases, such as pain and Alzheimer's disease (Beggs and Salter, 2013;Eyo et al, 2017a;Sarlus and Heneka, 2017). However, because inflammatory mechanisms have recently been implicated in the pathogenesis of epilepsy (Devinsky et al, 2013;Vezzani, 2014), the role of microglia is receiving increased interest.…”

Section: Introductionmentioning

confidence: 99%

Microglial P2Y12 Receptor Regulates Seizure-Induced Neurogenesis and Immature Neuronal Projections

Eyo

Xie

et al. 2019

J. Neurosci.

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Seizures are common in humans with various etiologies ranging from congenital aberrations to acute injuries that alter the normal balance of brain excitation and inhibition. A notable consequence of seizures is the induction of aberrant neurogenesis and increased immature neuronal projections. However, regulatory mechanisms governing these features during epilepsy development are not fully understood. Recent studies show that microglia, the brain's resident immune cell, contribute to normal neurogenesis and regulate seizure phenotypes. However, the role of microglia in aberrant neurogenic seizure contexts has not been adequately investigated. To address this question, we coupled the intracerebroventricular kainic acid model with current pharmacogenetic approaches to eliminate microglia in male mice. We show that microglia promote seizure-induced neurogenesis and subsequent seizure-induced immature neuronal projections above and below the pyramidal neurons between the DG and the CA3 regions. Furthermore, we identify microglial P2Y12 receptors (P2Y12R) as a participant in this neurogenic process. Together, our results implicate microglial P2Y12R signaling in epileptogenesis and provide further evidence for targeting microglia in general and microglial P2Y12R in specific to ameliorate proepileptogenic processes.

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Section: Introductionmentioning

confidence: 99%

Microglial P2Y12 Receptor Regulates Seizure-Induced Neurogenesis and Immature Neuronal Projections

Eyo

Xie

et al. 2019

J. Neurosci.

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“…After TBI, microglia become activated, and the cells number peaks at 7 dpi [41]. Microglia release proinflammatory cytokines, including IL-1β, IL-6, IL-12, and TNF-α, and chemokines, including CCL2, CCL3, CCL5, CXCL10, and CXCL12 [50]. [50,53,54].…”

Section: Discussionmentioning

confidence: 99%

“…Microglia release proinflammatory cytokines, including IL-1β, IL-6, IL-12, and TNF-α, and chemokines, including CCL2, CCL3, CCL5, CXCL10, and CXCL12 [50]. [50,53,54]. Microglia can synthesize and respond to IL-18 [55].…”

Section: Discussionmentioning

confidence: 99%

Deficiency in interleukin-18 ameliorated glial activation and neuroinflammation after traumatic brain injury in mice

Dong¹,

Wang²,

Chen³

et al. 2020

Preprint

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Background: Neuroinflammation is recognized as one of the main pathological mechanisms of secondary injury caused by traumatic brain injury (TBI). It has been reported that interleukin (IL)-18 is expressed in glial cells and involved in the regulation of neuroinflammation. Further studies have revealed that IL-18 expression is upregulated and may contribute to pathogenesis in the later phases of TBI; however, the mechanism underlying the effect of IL-18 on TBI remains unclear. Our present study assessed the roles of IL-18 in inflammatory and neurodegenerative pathology in mice subjected to TBI.Methods: A controlled cortical impact (CCI) injury model was conducted to mimic TBI, and brains were collected at 3 and 7 days post TBI (dpi). The levels of IL-18 were detected by qRT-PCR and immunofluorescence staining. In addition, neurological severity score (NSS) was used to assess neurological deficits after TBI. Furthermore, neuronal cell death, glial activation, and inflammatory cytokine and chemokine secretion were evaluated in wild-type ( WT ) and Il18-knockout ( Il18 -KO) mice to explore the role of IL-18 in TBI.Results: IL-18 levels were upregulated post TBI, accompanied by reactive glial activation. Il-18 deficiency significantly ameliorated glial activation and improved neuronal cell death and neurological deficits. In addition, Il-18 deficiency reduced the TBI-induced M1-like microglia frequency. Interestingly, the levels of all pro- and anti-inflammatory cytokines, including IL-1α, IL-1β, IL-2, IL-3, IL-4, IL-5, IL-6, IL-9, IL-10, IL-12p40, IL-12p70, IL-13, IL17A, G-CSF, GM-CSF, IFN-γ, and TNF-α, were downregulated in Il18 -KO mice. The deletion of Il-18 attenuated the levels of most chemokines induced by TBI, including CCL2, CCL3, CCL4, CCL5, CCL7, CCL12, CCL20, CXCL1, CXCL2, CXCL10, CXCL12, CXCL13, and CXCL16.Conclusions: These data demonstrated that IL-18 is involved in TBI induced neuroinflammation, which suggests that IL-18 is important for the development of secondary injury induced by TBI.

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“…We also quantified microglia/macrophages and neutrophils in the ipsilateral cortex and hippocampus using immunohistochemistry at DPI 3 ( Figure 1A ). DPI 3 was chosen based on previous literature demonstrating robust increases in microglia/macrophages and neutrophils at this time-point (Jin et al, 2012 ; Younger et al, 2019 ). Our second research strategy included the evaluation of behavioral outcomes during and following an extended treatment protocol ( Figure 1B ).…”

Section: Methodsmentioning

confidence: 99%

“…Peripheral monocyte and neutrophil infiltration are associated with increased edema, exaggerated inflammatory responses, and poorer functional outcomes following brain injury (Kenne et al, 2012 ; Ma et al, 2016 ). Quantification of total microglia/macrophages and neutrophils show peak levels within the first week after injury with robust increases within the first few days (Jin et al, 2012 ; Younger et al, 2019 ). Due to their dynamic response to injury, tissue-resident and peripheral immune cells are essential to the early secondary injury cascade and a target for anti-inflammatory compounds.…”

Section: Introductionmentioning

confidence: 99%

Cosyntropin Attenuates Neuroinflammation in a Mouse Model of Traumatic Brain Injury

Siebold

Krueger

Abdala

et al. 2020

Front. Mol. Neurosci.

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Aim : Traumatic brain injury (TBI) is a leading cause of mortality/morbidity and is associated with chronic neuroinflammation. Melanocortin receptor agonists including adrenocorticotropic hormone (ACTH) ameliorate inflammation and provide a novel therapeutic approach. We examined the effect of long-acting cosyntropin (CoSyn), a synthetic ACTH analog, on the early inflammatory response and functional outcome following experimental TBI. Methods : The controlled cortical impact model was used to induce TBI in mice. Mice were assigned to injury and treatment protocols resulting in four experimental groups including sham + saline, sham + CoSyn, TBI + saline, and TBI + CoSyn. Treatment was administered subcutaneously 3 h post-injury and daily injections were given for up to 7 days post-injury. The early inflammatory response was evaluated at 3 days post-injury through the evaluation of cytokine expression (IL1β and TNFα) and immune cell response. Quantification of immune cell response included cell counts of microglia/macrophages (Iba1+ cells) and neutrophils (MPO+ cells) in the cortex and hippocampus. Behavioral testing ( n = 10–14 animals/group) included open field (OF) and novel object recognition (NOR) during the first week following injury and Morris water maze (MWM) at 10–15 days post-injury. Results : Immune cell quantification showed decreased accumulation of Iba1+ cells in the perilesional cortex and CA1 region of the hippocampus for CoSyn-treated TBI animals compared to saline-treated. Reduced numbers of MPO+ cells were also found in the perilesional cortex and hippocampus in CoSyn treated TBI mice compared to their saline-treated counterparts. Furthermore, CoSyn treatment reduced IL1β expression in the cortex of TBI mice. Behavioral testing showed a treatment effect of CoSyn for NOR with CoSyn increasing the discrimination ratio in both TBI and Sham groups, indicating increased memory performance. CoSyn also decreased latency to find platform during the early training period of the MWM when comparing CoSyn to saline-treated TBI mice suggesting moderate improvements in spatial memory following CoSyn treatment. Conclusion : Reduced microglia/macrophage accumulation and neutrophil infiltration in conjunction with moderate improvements in spatial learning in our CoSyn treated TBI mice suggests a beneficial anti-inflammatory effect of CoSyn following TBI.

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Microglia Receptors in Animal Models of Traumatic Brain Injury

Cited by 54 publications

References 359 publications

Microglial P2Y12 Receptor Regulates Seizure-Induced Neurogenesis and Immature Neuronal Projections

Microglial P2Y12 Receptor Regulates Seizure-Induced Neurogenesis and Immature Neuronal Projections

Deficiency in interleukin-18 ameliorated glial activation and neuroinflammation after traumatic brain injury in mice

Cosyntropin Attenuates Neuroinflammation in a Mouse Model of Traumatic Brain Injury

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