Diversity and Function of Glial Cell Types in Multiple Sclerosis

Schirmer, Lucas; Schafer, Dorothy P.; Bartels, Theresa; Rowitch, David H.; Calabresi, Peter A.

doi:10.1016/j.it.2021.01.005

Cited by 59 publications

(45 citation statements)

References 184 publications

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“…LncRNA-H19 facilitated PDCD4 expression via sponging miR-21 and regulated the ischemia and reperfusion (I/R)-induced sterile in ammation and neuronal lesion in mice retinas [25]. Oxidative stress, de ned as excess production of reactive oxygen species (ROS), is a typical feature of neuroin ammation, and directly leads to subsequent neuronal damage [4]. In the present study, a persistent elevation of PDCD4 expression was detected in the H2O2-induced neuron oxidative damage model.…”

Section: Discussionmentioning

confidence: 99%

“…Neuroin ammation, an in ammatory reaction occurring within the central nervous system (CNS), extensively participates in CNS pathological processes [1][2][3]. Microglia, the principal resident immune cells in CNS, accounting for approximately 10% of brain parenchymal cells, act as the main executor of neuroin ammation [4][5][6]. Under physiological conditions, microglia secrete multiple neurotrophic factors, dynamically monitor synaptic functions and clear dead cell debris to maintain brain homeostasis.…”

Section: Introductionmentioning

confidence: 99%

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PDCD4-MAPKs-NF-κB positive loop simultaneously promotes microglia activation and neuron apoptosis during neuroinflammation

Chen

Lü

Duan

et al. 2021

Preprint

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Neuroinflammation and neuron injury are common features of the central nervous system (CNS) diseases. It will be of great significance to identify their shared regulatory mechanisms and explore the potential therapeutic targets. Programmed cell death factor 4 (PDCD4), an apoptosis-related molecule, extensively participates in tumorigenesis and inflammatory diseases, but its expression and biological function during CNS neuroinflammation remain unclear. In the present study, utilizing the lipopolysaccharide (LPS)-induced neuroinflammation model on mice, we first reported an elevated expression of PDCD4 in both injured neurons and activated microglia of the inflamed mice brain. A similar change of PDCD4 expression was observed in the in vitro microglial activation model. Silencing PDCD4 by shRNA significantly inhibited the phosphorylation of MAPKs (p38, ERK, and JNK), prevented the phosphorylation and nuclear transportation of NF-κB p65, and thus attenuated the LPS-induced microglial inflammatory activation. Interestingly, LPS also required the MAPKs/NF-κB signaling activation to boost PDCD4 expression in microglia, and thus form a positive loop. Moreover, a persistent elevation of PDCD4 expression was detected in the H2O2-induced neuronal oxidative damage model. Knocking down PDCD4 significantly inhibited the expression of pro-apoptotic protein BAX, suggesting the pro-apoptotic activity of PDCD4 in the neuron. Taken together, our data indicated that PDCD4 may serve as a hub regulatory molecule that simultaneously promotes both the microglial inflammatory activation and the oxidative stress-induced neuronal apoptosis within CNS. The microglial PDCD4/MAPKs/NF-κB positive feedback loop may exaggerate the vicious cycle of neuroinflammation and neuronal injury, and thus may become potential therapeutic targets for neuroinflammatory diseases.

show abstract

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

PDCD4-MAPKs-NF-κB positive loop simultaneously promotes microglia activation and neuron apoptosis during neuroinflammation

Chen

Lü

Duan

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…LncRNA-H19 facilitated PDCD4 expression via sponging miR-21 and regulated the ischemia and reperfusion (I/R)induced sterile in ammation and neuronal lesion in mice retinas [25]. Oxidative stress, de ned as excess production of reactive oxygen species (ROS), is a typical feature of neuroin ammation, and directly leads to subsequent neuronal damage [4]. In the present study, a persistent elevation of PDCD4 expression was detected in the H 2 O 2 -induced neuron oxidative damage model.…”

Section: Discussionmentioning

confidence: 99%

“…Neuroin ammation, an in ammatory reaction occurring within the central nervous system (CNS), extensively participates in pathological processes in the CNS [1][2][3]. Microglia, the principal resident immune cells in CNS that account for approximately 10% of brain parenchymal cells, act as the main executor of neuroin ammation [4][5][6]. Under physiological conditions, microglia secrete multiple neurotrophic factors, dynamically monitor synaptic functions, and clear dead cell debris to maintain brain homeostasis.…”

Section: Introductionmentioning

confidence: 99%

PDCD4–MAPK–NF-κB Positive Loop Simultaneously Promotes Microglia Activation and Neuron Apoptosis During Neuroinflammation

Chen

Lü

Duan

et al. 2021

Preprint

View full text Add to dashboard Cite

Neuroinflammation and neuron injury are common features of the central nervous system (CNS) diseases. It is of great significance to identify their shared regulatory mechanisms and explore the potential therapeutic targets. Programmed cell death factor 4 (PDCD4), an apoptosis-related molecule, extensively participates in tumorigenesis and inflammatory diseases, but its expression and biological function during CNS neuroinflammation remain unclear. In the present study, utilizing the lipopolysaccharide (LPS)-induced neuroinflammation model in mice, we reported an elevated expression of PDCD4 both in injured neurons and activated microglia of the inflamed brain. A similar change in PDCD4 expression was observed in vitro in the microglial activation model. Silencing PDCD4 by shRNA significantly inhibited the phosphorylation of MAPKs (p38, ERK, and JNK), prevented the phosphorylation and nuclear translocation of NF-κB p65, and thus attenuated the LPS-induced microglial inflammatory activation. Interestingly, LPS also required the MAPK/NF-κB signaling activation to boost PDCD4 expression in microglia, indicating the presence of a positive loop. Moreover, a persistent elevation of PDCD4 expression was detected in the H2O2-induced neuronal oxidative damage model. Knocking down PDCD4 significantly inhibited the expression of proapoptotic protein BAX, suggesting the proapoptotic activity of PDCD4 in neurons. Taken together, our data indicated that PDCD4 may serve as a hub regulatory molecule that simultaneously promotes the microglial inflammatory activation and the oxidative stress-induced neuronal apoptosis within CNS. The microglial PDCD4–MAPK–NF-κB positive feedback loop may exaggerate the vicious cycle of neuroinflammation and neuronal injury and thus may become a potential therapeutic target for neuroinflammatory diseases.

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“…In particular, activated B cells mature into plasma cells and produce antibodies, maintaining and reactivating CD4 + T cells that produce proinflammatory cytokines. In the later stages of the disease, the inflammatory response is supported by the activation and polarization of microglia, leading to chronic neurodegeneration [1,13,14].…”

Section: Introductionmentioning

confidence: 99%

Host Genetics and Gut Microbiome: Perspectives for Multiple Sclerosis

Maglione

Zuccalà

Tosi

et al. 2021

Genes

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As a complex disease, Multiple Sclerosis (MS)’s etiology is determined by both genetic and environmental factors. In the last decade, the gut microbiome has emerged as an important environmental factor, but its interaction with host genetics is still unknown. In this review, we focus on these dual aspects of MS pathogenesis: we describe the current knowledge on genetic factors related to MS, based on genome-wide association studies, and then illustrate the interactions between the immune system, gut microbiome and central nervous system in MS, summarizing the evidence available from Experimental Autoimmune Encephalomyelitis mouse models and studies in patients. Finally, as the understanding of influence of host genetics on the gut microbiome composition in MS is in its infancy, we explore this issue based on the evidence currently available from other autoimmune diseases that share with MS the interplay of genetic with environmental factors (Inflammatory Bowel Disease, Rheumatoid Arthritis and Systemic Lupus Erythematosus), and discuss avenues for future research.

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Diversity and Function of Glial Cell Types in Multiple Sclerosis

Cited by 59 publications

References 184 publications

PDCD4-MAPKs-NF-κB positive loop simultaneously promotes microglia activation and neuron apoptosis during neuroinflammation

PDCD4-MAPKs-NF-κB positive loop simultaneously promotes microglia activation and neuron apoptosis during neuroinflammation

PDCD4–MAPK–NF-κB Positive Loop Simultaneously Promotes Microglia Activation and Neuron Apoptosis During Neuroinflammation

Host Genetics and Gut Microbiome: Perspectives for Multiple Sclerosis

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Diversity and Function of Glial Cell Types in Multiple Sclerosis

Cited by 59 publications

References 184 publications

PDCD4-MAPKs-NF-κB positive loop&nbsp;simultaneously&nbsp;promotes&nbsp;microglia activation and neuron apoptosis&nbsp;during&nbsp;neuroinflammation

PDCD4-MAPKs-NF-κB positive loop&nbsp;simultaneously&nbsp;promotes&nbsp;microglia activation and neuron apoptosis&nbsp;during&nbsp;neuroinflammation

PDCD4–MAPK–NF-κB Positive Loop Simultaneously Promotes Microglia Activation and Neuron Apoptosis During Neuroinflammation

Host Genetics and Gut Microbiome: Perspectives for Multiple Sclerosis

Contact Info

Product

Resources

About

PDCD4-MAPKs-NF-κB positive loop simultaneously promotes microglia activation and neuron apoptosis during neuroinflammation

PDCD4-MAPKs-NF-κB positive loop simultaneously promotes microglia activation and neuron apoptosis during neuroinflammation