Accumulation of Cytoplasmic DNA Due to ATM Deficiency Activates the Microglial Viral Response System with Neurotoxic Consequences

Song, Xuan; Ma, Fulin; Herrup, Karl

doi:10.1523/jneurosci.0774-19.2019

Cited by 108 publications

(128 citation statements)

References 86 publications

(91 reference statements)

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“…Additionally, caspase-1 can cleave gasdermin D to initiate pyroptotic cell death, characterized by the formation of pores in the plasma membrane and the release of cellular contents into the extracellular environment (Kayagaki et al, 2015;Shi et al, 2015). The AIM2 inflammasome has been shown to form following infection with either DNA or RNA viruses in peripheral myeloid and lymphoid immune celltypes, such as bone marrow derived dendritic cells (BMDCs), bone marrow derived macrophages (BMDM), monocytes, and fibroblasts (Rathinam et al, 2010;Ekchariyawat et al, 2015;Schattgen et al, 2016;Huang et al, 2017;Zhang et al, 2017), and the role of this and other inflammasomes during viral infection is discussed extensively elsewhere (Chen and Ichinohe, 2015;Lupfer et al, 2015;Man et al, 2016;Shrivastava et al, 2016;Lugrin and Martinon, 2018;Zhu et al, 2019).…”

Section: Aim2mentioning

confidence: 99%

Cytosolic DNA Sensors and CNS Responses to Viral Pathogens

Jeffries

Marriott

2020

Front. Cell. Infect. Microbiol.

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Viral central nervous system (CNS) infections can lead to life threatening encephalitis and long-term neurological deficits in survivors. Resident CNS cell types, such as astrocytes and microglia, are known to produce key inflammatory and antiviral mediators following infection with neurotropic DNA viruses. However, the mechanisms by which glia mediate such responses remain poorly understood. Recently, a class of intracellular pattern recognition receptors (PRRs), collectively known as DNA sensors, have been identified in both leukocytic and non-leukocytic cell types. The ability of such DNA sensors to initiate immune mediator production and contribute to infection resolution in the periphery is increasingly recognized, but our understanding of their role in the CNS remains limited at best. In this review, we describe the evidence for the expression and functionality of DNA sensors in resident brain cells, with a focus on their role in neurotropic virus infections. The available data indicate that glia and neurons can constitutively express, and/or can be induced to express, various disparate DNA sensing molecules previously described in peripheral cell types. Furthermore, multiple lines of investigation suggest that these sensors are functional in resident CNS cells and are required for innate immune responses to viral infections. However, it is less clear whether DNA sensormediated glial responses are beneficial or detrimental, and the answer to this question appears to dependent on the context of the infection with regard to the identity of the pathogen, host cell type, and host species. Defining such parameters will be essential if we are to successfully target these molecules to limit damaging inflammation while allowing beneficial host responses to improve patient outcomes.

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Section: Aim2mentioning

confidence: 99%

Cytosolic DNA Sensors and CNS Responses to Viral Pathogens

Jeffries

Marriott

2020

Front. Cell. Infect. Microbiol.

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“…In fact, a series of elegant studies provided evidence for replication stress-induced inflammation as a driver of neuronal degeneration in models of ataxia telangiectasia. Studies about the immune response in At −/− -mice revealed that the accumulation of cytoplasmic DNA in microglial cells triggered the release of neurotoxic cytokines, leading to chronic neuroinflammation and neurodegeneration [81,82]. Understanding the contributions of RSR to nervous system development, degeneration, and regeneration is of fundamental biomedical importance.…”

Section: Overview Of Dna Replication Stress: How Cells Prevent and Rementioning

confidence: 99%

“…A direct link of defective DDR, cGAS-STING pathway, inflammatory cytokines, and neurodegeneration was recently established. In Atm −/− mice: Atm-deficient microglia accumulate cytoplasmic DNA and trigger a STING-mediated proinflammatory response that secretes neurotoxic interleukins [81] (Figure 5). Consistent findings were also reported in a rat model of A-T [348].…”

Section: Non-cell-autonomous Rsr In the Cnsmentioning

confidence: 99%

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Protective Mechanisms Against DNA Replication Stress in the Nervous System

Charlier

Martins

2020

Genes

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The precise replication of DNA and the successful segregation of chromosomes are essential for the faithful transmission of genetic information during the cell cycle. Alterations in the dynamics of genome replication, also referred to as DNA replication stress, may lead to DNA damage and, consequently, mutations and chromosomal rearrangements. Extensive research has revealed that DNA replication stress drives genome instability during tumorigenesis. Over decades, genetic studies of inherited syndromes have established a connection between the mutations in genes required for proper DNA repair/DNA damage responses and neurological diseases. It is becoming clear that both the prevention and the responses to replication stress are particularly important for nervous system development and function. The accurate regulation of cell proliferation is key for the expansion of progenitor pools during central nervous system (CNS) development, adult neurogenesis, and regeneration. Moreover, DNA replication stress in glial cells regulates CNS tumorigenesis and plays a role in neurodegenerative diseases such as ataxia telangiectasia (A-T). Here, we review how replication stress generation and replication stress response (RSR) contribute to the CNS development, homeostasis, and disease. Both cell-autonomous mechanisms, as well as the evidence of RSR-mediated alterations of the cellular microenvironment in the nervous system, were discussed.

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“…Applying this concept to an example such as stroke, cytotoxic microglia is observed in the striatum, whereas subventricular zone microglia promote neurogenesis [59]. Furthermore, mouse models for amyotrophic lateral sclerosis exhibit neuroprotective microglia at disease onset, which is gradually transformed into cells with a more neurotoxic phenotype at the end of the disease [94]. Therefore, therapeutic intervention at the right place and time is vital to achieving success.…”

Section: Communication Between Microglia and Mscsmentioning

confidence: 99%

Biomaterial-supported MSCs transplantation enhances cell-cell communication for spinal cord injury

Wang

yang

2020

Preprint

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The spinal cord is part of the central nervous system (CNS) and serves to connect the brain to the peripheral nervous system and peripheral tissues. The cell types that primarily comprise the spinal cord are neurons and several categories of glia, including astrocytes, oligodendrocytes, and microglia. Ependymal cells and small populations of endogenous stem cells, such as oligodendrocyte progenitor cells, also reside in the spinal cord [1]. Neurons are interconnected in circuits; those that process cutaneous sensory input are mainly located in the dorsal spinal cord, while those involved in proprioception and motor control are predominately located in the ventral spinal cord [2]. Due to the importance of the spinal cord, neurodegenerative disorders and traumatic injuries affecting the spinal cord will lead to motor deficits and loss of sensory inputs. Spinal cord injury (SCI), resulting in paraplegia and tetraplegia as a result of deleterious interconnected mechanisms encompassed by the primary and secondary injury, represents a heterogeneously behavioral and cognitive deficit that remains incurable. Following SCI, various barriers containing the neuroinflammation, neural tissue defect (neurons, microglia, astrocytes, and oligodendrocytes), cavity formation, loss of neuronal circuitry and function must be overcame[3]. Notably, the pro -inflammatory and anti-inflammatory effect s of cell-cell communication networks play critical roles in homeostatic, driving the pathophysiologic and consequent cognitive outcomes. In the spinal cord, astrocytes, oligodendrocytes and microglia are involved in not only development but also pathology. Glial cells play dual roles (negative vs. positive effects) in these processes. After SCI, detrimental effects usually dominate and significantly retard functional recovery, and curbing these effects is critical for promoting neurological improvement. Indeed, residential innate immune cells (microglia and astrocytes) and infiltrating leukocytes (macrophages and neutrophils), activated by SCI, give rise to full-blown inflammatory cascades. These inflammatory cells release neurotoxins (proinflammatory cytokines and chemokines, free radicals, excitotoxic amino acids, nitric oxide (NO)), all of which partake in axonal and neuronal deficit[4]. Given the various multifaceted obstacles in SCI treatment, a combinatorial therapy of cell transplantation and biomaterial implantation may be addressed in detail here. For the sake of preserving damaged tissue integrity and providing physical support and trophic supply for axon regeneration, MSCs transplantation has come to the front stage in therapy for SCI with the constant progress of stem cell engineering [5]. MSCs transplantation promotes scaffold integration and regenerative growth potential. Integrating into the implanted scaffold, MSCs influences implant integration by improving the healing process[6]. Conversely, biomaterial scaffolds offer MSCs with a sheltered microenvironment from the surrounding pathological changes, in addition to bridging connection spinal cord stump and offering physical and directional support for axonal regeneration. Besides, Biomaterial scaffolds mimic the extracellular matrix to suppress immune responses. Here, we review the advances in combinatorial biomaterial scaffolds and MSCs transplantation approach that targets certain aspects of various intercellular communications in the pathologic process following SCI. Finally, the challenges of biomaterial-supported MSCs transplantation and its future direction for neuronal regeneration will be presented.

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Accumulation of Cytoplasmic DNA Due to ATM Deficiency Activates the Microglial Viral Response System with Neurotoxic Consequences

Cited by 108 publications

References 86 publications

Cytosolic DNA Sensors and CNS Responses to Viral Pathogens

Cytosolic DNA Sensors and CNS Responses to Viral Pathogens

Protective Mechanisms Against DNA Replication Stress in the Nervous System

Biomaterial-supported MSCs transplantation enhances cell-cell communication for spinal cord injury

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