scholarly journals Complement C3-dependent glutamatergic synapse elimination in the developing hippocampus is region- and synapse-specific

2020 ◽  
Author(s):  
Eric W. Salter ◽  
Gang Lei ◽  
Sun-Lim Choi ◽  
Liam T. Ralph ◽  
Lijia Zhang ◽  
...  
Keyword(s):  
Molecular Layer ◽  
Stratum Radiatum ◽  
Complement C3 ◽  
Inhibitory Synapses ◽  
Complement Cascade ◽  
Synapse Elimination ◽  
Immune Pathway ◽  
Innate Immune Pathway ◽  
Stratum Lacunosum Moleculare

SummaryThe complement cascade is an innate immune pathway that, in addition to host defense against pathogens, actively maintains tissue homeostasis. Complement is necessary for synaptic pruning during development and drives aberrant synapse loss in a number of neurodegenerative disorders that affect the hippocampus. However, the physiological function of complement in hippocampal synapse development is unknown. To address this, we investigated C3−/− mice at P16-18. We found that VGLUT2+ synapses were increased in the CA1 stratum lacunosum moleculare (SLM) and dentate gyrus molecular layer (DGML) of C3−/− mice compared to wildtype. Conversely, VGLUT1+ synapses, inhibitory synapses and myelin were not affected in the CA1 stratum radiatum (SR), SLM or DGML of C3−/− mice. Finally, we found that there was a decrease in microglial phagocytic activity only in VGLUT2+ regions and this correlated with the amount of VGLUT2+ synapses. Our study elucidates a role of the complement cascade in regulating hippocampus synapse number with exceptional specificity for VGLUT2-containing synapses during development.

scholarly journals Role of the Inflammasome, IL-1β, and IL-18 in Bacterial Infections

2011 ◽  
Vol 11 ◽  
pp. 2037-2050 ◽  
Author(s):  
Manoranjan Sahoo ◽  
Ivonne Ceballos-Olvera ◽  
Laura del Barrio ◽  
Fabio Re
Keyword(s):  
Bacterial Infections ◽  
Innate Immune ◽  
Host Responses ◽  
Inflammasome Activation ◽  
Different Types ◽  
Molecular Aspects ◽  
Immune Pathway ◽  
Innate Immune Pathway ◽  
Receptor Family

The inflammasome is an important innate immune pathway that regulates at least two host responses protective against infections: (1) secretion of the proinflammatory cytokines IL-1βand IL-18 and (2) induction of pyroptosis, a form of cell death. Inflammasomes, of which different types have been identified, are multiprotein complexes containing pattern recognition receptors belonging to the Nod-like receptor family or the PYHIN family and the protease caspase-1. The molecular aspects involved in the activation of different inflammasomes by various pathogens are being rapidly elucidated, and their role during infections is being characterized. Production of IL-1βand IL-18 and induction of pyroptosis of the infected cell have been shown to be protective against many infectious agents. Here, we review the recent literature concerning inflammasome activation in the context of bacterial infections and identify important questions to be answered in the future.

scholarly journals Targeting macrophage priming by polyphyllin VII triggers anti-tumor immunity via STING-governed cytotoxic T-cell infiltration in lung cancer

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Jinglu Yu ◽  
Haibin Deng ◽  
Zhenye Xu
Keyword(s):  
Immune Cells ◽  
Expression Patterns ◽  
Immune Checkpoint Blockade ◽  
Innate Immune ◽  
Cytotoxic T Cell ◽  
T Cell Infiltration ◽  
Immune Pathway ◽  
Innate Immune Pathway ◽  
Pathogenic Infection

AbstractStimulator of interferon genes (STING) controlled innate immune pathway is essential for host defense against pathogenic infection and effective anti-tumor adaptive immunity initiation. Although macrophages transformed across diverse phenotypes play crucial roles in anti-tumor immune response, events determining this transformation and the host-intrinsic role of STING in this process remain controversial. Here we report how STING signaling acts as a key switch to dominate the gene expression patterns of macrophage transformation for promoting priming and releasing immunosuppression. Furthermore, polyphyllin VII, a potential STING agonist, exerts anti-tumor efficacy upon macrophages priming and subsequent cytotoxic T lymphocytes intratumoral infiltration. Meanwhile, the simultaneous PD-L1 amplification on macrophages in response to PP VII is also ruled by STING, thus PP VII may benefit immune-checkpoint blockade therapy for combining. Moreover, PP VII suppresses carcinogenesis upon restraining the immunosuppressed macrophage transformation. This is due to the boosted STING that negatively regulates a STAT3 propagated crosstalk between immune cells and tumor cells. Overall, PP VII-stimulated STING in macrophages provides a paradigm for anti-tumor, and if possible, anti-infection immunotherapy.

scholarly journals Physical Forces and Transient Nuclear Envelope Rupture during Metastasis: The Key for Success?

Cancers ◽  
2021 ◽  
Vol 14 (1) ◽  
pp. 83
Author(s):  
Benoit R. Gauthier ◽  
Petra I. Lorenzo ◽  
Valentine Comaills
Keyword(s):  
Nuclear Envelope ◽  
Tumor Progression ◽  
Tumor Cells ◽  
Innate Immune ◽  
Genomic Aberration ◽  
Key Driver ◽  
Immune Pathway ◽  
Sting Pathway ◽  
Innate Immune Pathway

During metastasis, invading tumor cells and circulating tumor cells (CTC) face multiple mechanical challenges during migration through narrow pores and cell squeezing. However, little is known on the importance and consequences of mechanical stress for tumor progression and success in invading a new organ. Recently, several studies have shown that cell constriction can lead to nuclear envelope rupture (NER) during interphase. This loss of proper nuclear compartmentalization has a profound effect on the genome, being a key driver for the genome evolution needed for tumor progression. More than just being a source of genomic alterations, the transient nuclear envelope collapse can also support metastatic growth by several mechanisms involving the innate immune response cGAS/STING pathway. In this review we will describe the importance of the underestimated role of cellular squeezing in the progression of tumorigenesis. We will describe the complexity and difficulty for tumor cells to reach the metastatic site, detail the genomic aberration diversity due to NER, and highlight the importance of the activation of the innate immune pathway on cell survival. Cellular adaptation and nuclear deformation can be the key to the metastasis success in many unsuspected aspects.

scholarly journals Crosstalk Between Apoptosis and Autophagy: Environmental Genotoxins, Infection, and Innate Immunity

2017 ◽  
Vol 10 ◽  
pp. 117967071668508 ◽  
Author(s):  
Michael G Kemp
Keyword(s):  
Type I Interferons ◽  
Health Concern ◽  
Type I ◽  
Environmental Carcinogens ◽  
Disease Symptoms ◽  
Cyclic Dinucleotides ◽  
Genetic And Environmental Factors ◽  
Immune Pathway ◽  
Innate Immune Pathway

Autoimmune disorders constitute a major and growing health concern. However, the genetic and environmental factors that contribute to or exacerbate disease symptoms remain unclear. Type I interferons (IFNs) are known to break immune tolerance and be elevated in the serum of patients with autoimmune diseases such as lupus. Extensive work over the past decade has characterized the role of a protein termed stimulator of interferon genes, or STING, in mediating IFN expression and activation in response to cytosolic DNA and cyclic dinucleotides. Interestingly, this STING-dependent innate immune pathway both utilizes and is targeted by the cell’s autophagic machinery. Given that aberrant interplay between the apoptotic and autophagic machineries contributes to deregulation of the STING-dependent pathway, IFN-regulated autoimmune phenotypes may be influenced by the combined exposure to environmental carcinogens and pathogenic microorganisms and viruses. This review therefore summarizes recent data regarding these important issues in the field of autoimmunity.

scholarly journals The role of innate immune pathway in repeated social defeat stress-induced behavioral changes in mice

2018 ◽  
Vol WCP2018 (0) ◽  
pp. PO3-1-20
Author(s):  
Shiho Kitaoka ◽  
Xiang Nie ◽  
Kohei Tanaka ◽  
Atsubumi Ogawa ◽  
Fumitake Nakano ◽  
...  
Keyword(s):  
Social Defeat ◽  
Innate Immune ◽  
Behavioral Changes ◽  
Social Defeat Stress ◽  
Immune Pathway ◽  
Innate Immune Pathway

scholarly journals Dendritic GABAergic inhibition controlled by Shh signaling-dependent stellate cell pool is critical for motor learning

2021 ◽  
Author(s):  
Wen Li ◽  
Lei Chen ◽  
Jonathan T Fleming ◽  
Emily Y Brignola ◽  
Kirill Zavalin ◽  
...  
Keyword(s):  
Motor Learning ◽  
Neural Circuit ◽  
Stellate Cell ◽  
Eyeblink Conditioning ◽  
Molecular Layer ◽  
Inhibitory Synapses ◽  
Shh Signaling ◽  
Shh Pathway ◽  
Pathway Activation

Cerebellar inhibitory interneurons are important regulators of neural circuit activity for diverse motor and non-motor functions. The molecular layer interneurons (MLI), consisting of basket cells (BCs) and stellate cells (SCs), are generated sequentially from Pax2+ immature interneurons which migrate from the prospective white matter to the ML of the cortex. However, little is known as to how MLI subtype identities and pool sizes are determined, nor are their contributions to motor learning well-understood. Here, we show that GABAergic progenitors fated to generate BCs and SCs transiently respond to the Shh signal. Conditional abrogation of Shh signaling reduced the number of Pax2+ cells, whereas persistent Shh pathway activation increased their numbers. These changes did not affect BC numbers but selectively altered the SC pool size. Moreover, genetic depletion of GABAergic progenitors when BCs are generated resulted in a specific reduction of SCs, suggesting that the specification of MLI subtypes is independent of their birth order and occurs after Pax2+ cells settle into their final laminar positions. Mutant mice with reduced SC numbers displayed decreased dendritic inhibitory synapses and neurotransmission onto Purkinje cells, resulting in an impaired acquisition of eyeblink conditioning. These findings reveal an essential role of Shh signaling-dependent SCs in regulating inhibitory dendritic synapses and motor learning.

scholarly journals Chronic immune response dysregulation in MDS pathogenesis

Blood ◽  
2018 ◽  
Vol 132 (15) ◽  
pp. 1553-1560 ◽  
Author(s):  
Laura Barreyro ◽  
Timothy M. Chlon ◽  
Daniel T. Starczynowski
Keyword(s):  
Immune Response ◽  
Innate Immune ◽  
Direct Role ◽  
Immune Signaling ◽  
Innate Immune Signaling ◽  
Pathway Activation ◽  
Immune Pathway ◽  
Innate Immune Pathway ◽  
Inflammatory Component

Abstract Chronic innate immune signaling in hematopoietic cells is widely described in myelodysplastic syndromes (MDS), and innate immune pathway activation, predominantly via pattern recognition receptors, increases the risk of developing MDS. An inflammatory component to MDS has been reported for many years, but only recently has evidence supported a more direct role of chronic innate immune signaling and associated inflammatory pathways in the pathogenesis of MDS. Here we review recent findings and discuss relevant questions related to chronic immune response dysregulation in MDS.

scholarly journals Neuroprotective Metabolites of Hericium erinaceus Promote Neuro-Healthy Aging

2021 ◽  
Vol 22 (12) ◽  
pp. 6379
Author(s):  
Elisa Roda ◽  
Erica Cecilia Priori ◽  
Daniela Ratto ◽  
Fabrizio De Luca ◽  
Carmine Di Iorio ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Healthy Aging ◽  
Molecular Layer ◽  
Dietary Supplementation ◽  
Purkinje Neurons ◽  
Geriatric Syndrome ◽  
Oral Supplementation ◽  
Erinacine A ◽  
And Oxidative Stress

Frailty is a geriatric syndrome associated with both locomotor and cognitive decline, typically linked to chronic systemic inflammation, i.e., inflammaging. In the current study, we investigated the effect of a two-month oral supplementation with standardized extracts of H. erinaceus, containing a known amount of Erinacine A, Hericenone C, Hericenone D, and L-ergothioneine, on locomotor frailty and cerebellum of aged mice. Locomotor performances were monitored comparing healthy aging and frail mice. Cerebellar volume and cytoarchitecture, together with inflammatory and oxidative stress pathways, were assessed focusing on senescent frail animals. H. erinaceus partially recovered the aged-related decline of locomotor performances. Histopathological analyses paralleled by immunocytochemical evaluation of specific molecules strengthened the neuroprotective role of H. erinaceus able to ameliorate cerebellar alterations, i.e., milder volume reduction, slighter molecular layer thickness decrease and minor percentage of shrunken Purkinje neurons, also diminishing inflammation and oxidative stress in frail mice while increasing a key longevity regulator and a neuroprotective molecule. Thus, our present findings demonstrated the efficacy of a non-pharmacological approach, based on the dietary supplementation using H. erinaceus extract, which represent a promising adjuvant therapy to be associated with conventional geriatric treatments.

The role of GABAA receptor biogenesis, structure and function in epilepsy

2006 ◽  
Vol 34 (5) ◽  
pp. 863-867 ◽  
Author(s):  
S. Mizielinska ◽  
S. Greenwood ◽  
C.N. Connolly
Keyword(s):  
Gabaa Receptor ◽  
Structure And Function ◽  
Inhibitory Synapses ◽  
Normal Brain ◽  
Synaptic Targeting ◽  
Acid Type ◽  
Normal Brain Function ◽  
And Function ◽  
The Brain

Maintaining the correct balance in neuronal activation is of paramount importance to normal brain function. Imbalances due to changes in excitation or inhibition can lead to a variety of disorders ranging from the clinically extreme (e.g. epilepsy) to the more subtle (e.g. anxiety). In the brain, the most common inhibitory synapses are regulated by GABAA (γ-aminobutyric acid type A) receptors, a role commensurate with their importance as therapeutic targets. Remarkably, we still know relatively little about GABAA receptor biogenesis. Receptors are constructed as pentameric ion channels, with α and β subunits being the minimal requirement, and the incorporation of a γ subunit being necessary for benzodiazepine modulation and synaptic targeting. Insights have been provided by the discovery of several specific assembly signals within different GABAA receptor subunits. Moreover, a number of recent studies on GABAA receptor mutations associated with epilepsy have further enhanced our understanding of GABAA receptor biogenesis, structure and function.

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