Microglial cell depletion is fatal with low level picornavirus infection of the central nervous system

Sanchez, John Michael S.; DePaula-Silva, Ana Beatriz; Doty, Daniel J.; Truong, Amanda; Libbey, Jane E.; Fujinami, Robert S.

doi:10.1007/s13365-019-00740-3

Cited by 40 publications

(64 citation statements)

References 14 publications

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“…The early inflammasome activation of microglia appears to be an important general mechanism of infection control in the CNS. There is agreement between studies, that microglia depletion by pharmacological inhibition of the CSF‐R1 exacerbates disease in diverse models of virus infection of the brain (Sanchez et al, ; Seitz, Clarke, & Tyler, ; Waltl et al, ; Wheeler & Quintana, ). This may be due to a role of microglia in the local restimulation of CD8 + T‐cells (Funk & Klein, ).…”

Section: Microglia and Macrophages In Inflammatory Diseases In Humansmentioning

confidence: 80%

Pathology of inflammatory diseases of the nervous system: Human disease versus animal models

Lassmann

2019

Glia

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Numerous recent studies have been performed to elucidate the function of microglia, macrophages, and astrocytes in inflammatory diseases of the central nervous system. Regarding myeloid cells a core pattern of activation has been identified, starting with the activation of resident homeostatic microglia followed by recruitment of blood borne myeloid cells. An initial state of proinflammatory activation is at later stages followed by a shift toward an‐anti‐inflammatory and repair promoting phenotype. Although this core pattern is similar between experimental models and inflammatory conditions in the human brain, there are important differences. Even in the normal human brain a preactivated microglia phenotype is evident, and there are disease specific and lesion stage specific differences in the contribution between resident and recruited myeloid cells and their lesion state specific activation profiles. Reasons for these findings reside in species related differences and in differential exposure to different environmental cues. Most importantly, however, experimental rodent studies on brain inflammation are mainly focused on autoimmune encephalomyelitis, while there is a very broad spectrum of human inflammatory diseases of the central nervous system, triggered and propagated by a variety of different immune mechanisms.

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Section: Microglia and Macrophages In Inflammatory Diseases In Humansmentioning

confidence: 80%

Pathology of inflammatory diseases of the nervous system: Human disease versus animal models

Lassmann

2019

Glia

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“…6,43 Because mTOR is ubiquitously expressed in neurons and microglia, recent studies have specifically targeted mTOR hyperactivation in microglia 44 as well as CSF1R signaling. [45][46][47] A microglia-specific TSC1 KO mouse model produced an mTOR hyperactivation phenotype that resulted in an increase in the number of microglia with enhanced phagocytic activity in the hippocampus. 44 In these mice, the altered microglial properties correlated with reduced densities of excitatory and inhibitory synapses, and with the development of SRS.…”

Section: Microglial Proliferationmentioning

confidence: 99%

“…46 Similarly, treatment with the CSF1R inhibitor PLX3397 decreased both the number of IBA1-positive microglial cells in the hippocampus and seizure frequency in a mouse model of pilocarpine-induced SE. 45 Although these studies suggest that suppressing microgliosis during epileptogenesis is beneficial, recent studies also showed that total ablation is detrimental, 47,50 thereby suggesting that microglia have multiple roles. Ablation of microglia with the CSF1R inhibitor PLX5622 exacerbated the seizure phenotype and the mortality rate in epileptic mice induced with the Theiler murine encephalomyelitis virus.…”

Section: Microglial Proliferationmentioning

confidence: 99%

“…Ablation of microglia with the CSF1R inhibitor PLX5622 exacerbated the seizure phenotype and the mortality rate in epileptic mice induced with the Theiler murine encephalomyelitis virus. 47 Moreover, homozygous mutations in the human CSF1R gene are associated with a drastic loss of microglia and brain structural malformations. 50 Of two patients described in this study, one died prematurely at age one and the other presented with developmental delay and epilepsy.…”

Section: Microglial Proliferationmentioning

confidence: 99%

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Emerging Roles for Microglial Phagocytic Signaling in Epilepsy

Wyatt-Johnson

Brewster

2019

Epilepsy Curr

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Microglia are the resident immune cells and professional phagocytes of the central nervous system. However, little is known about the contribution of their phagocytic signaling to the neuropathology and pathophysiology of epilepsy. Here, we summarize and discuss the implications of recent evidence supporting that aberrant microglia phagocytic activity and alterations in phagocytosis signaling molecules occur in association with microglia–neuronal contacts, neuronal/synaptic loss, and spontaneous recurrent seizures in human and preclinical models of epilepsy. This body of evidence provides strong support that the microglial contribution to epileptogenic networks goes beyond inflammation, and suggests that phagocytic signaling molecules may be novel therapeutic targets for epilepsy.

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“…We have previously determined that macrophage infiltration, more specifically IL-6-producing macrophages [15,22,35,36], but not T cell or neutrophil infiltration, is important for seizure development [22]. Recently, we and others have also demonstrated that macrophages and microglia have unique roles in controlling viral infection in the brain [37][38][39].…”

Section: Introductionmentioning

confidence: 99%

Differential transcriptional profiles identify microglial- and macrophage-specific gene markers expressed during virus-induced neuroinflammation

DePaula-Silva

Gorbea

Doty

et al. 2019

J Neuroinflammation

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107

113

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Background In the healthy central nervous system (CNS), microglia are found in a homeostatic state and peripheral macrophages are absent from the brain. Microglia play key roles in maintaining CNS homeostasis and acting as first responders to infection and inflammation, and peripheral macrophages infiltrate the CNS during neuroinflammation. Due to their distinct origins and functions, discrimination between these cell populations is essential to the comprehension of neuroinflammatory disorders. Studies comparing the gene profiles of microglia and peripheral macrophages, or macrophages in vitro-derived from bone marrow, under non-infectious conditions of the CNS, have revealed valuable microglial-specific genes. However, studies comparing gene profiles between CNS-infiltrating macrophages and microglia, when both are isolated from the CNS during viral-induced neuroinflammation, are lacking. Methods We isolated, via flow cytometry, microglia and infiltrating macrophages from the brains of Theiler’s murine encephalomyelitis virus-infected C57BL/6 J mice and used RNA-Seq, followed by validation with qPCR, to examine the differential transcriptional profiles of these cells. We utilized primary literature defining subcellular localization to determine whether or not particular proteins extracted from the transcriptional profiles were expressed at the cell surface. The surface expression and cellular specificity of triggering receptor expressed on myeloid cells 1 (TREM-1) protein were examined via flow cytometry. We also examined the immune response gene profile within the transcriptional profiles of these isolated microglia and infiltrating macrophages. Results We have identified and validated new microglial- and macrophage-specific genes, encoding cell surface proteins, expressed at the peak of neuroinflammation. TREM-1 protein was confirmed to be expressed by infiltrating macrophages, not microglia, at the peak of neuroinflammation. We also identified both unique and redundant immune functions, through examination of the immune response gene profiles, of microglia and infiltrating macrophages during neurotropic viral infection. Conclusions The differential expression of cell surface-specific genes during neuroinflammation can potentially be used to discriminate between microglia and macrophages as well as provide a resource that can be further utilized to target and manipulate specific cell responses during neuroinflammation. Electronic supplementary material The online version of this article (10.1186/s12974-019-1545-x) contains supplementary material, which is available to authorized users.

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Microglial cell depletion is fatal with low level picornavirus infection of the central nervous system

Cited by 40 publications

References 14 publications

Pathology of inflammatory diseases of the nervous system: Human disease versus animal models

Pathology of inflammatory diseases of the nervous system: Human disease versus animal models

Emerging Roles for Microglial Phagocytic Signaling in Epilepsy

Differential transcriptional profiles identify microglial- and macrophage-specific gene markers expressed during virus-induced neuroinflammation

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