scholarly journals Lymphatic-specific intracellular modulation of receptor tyrosine kinase signaling improves lymphatic growth and function

2021 ◽  
Vol 14 (695) ◽  
pp. eabc0836
Author(s):  
Raghu P. Kataru ◽  
Jung Eun Baik ◽  
Hyeung Ju Park ◽  
Catherine L. Ly ◽  
Jinyeon Shin ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Intact Cell ◽  
Cell Junctions ◽  
Tyrosine Kinase Signaling ◽  
Adult Mice ◽  
Lipid Phosphatase ◽  
Downstream Effects ◽  
Lymphatic Network ◽  
Growth Factor Production ◽  
And Function

Exogenous administration of lymphangiogenic growth factors is widely used to study changes in lymphatic function in pathophysiology. However, this approach can result in off-target effects, thereby generating conflicting data. To circumvent this issue, we modulated intracellular VEGF-C signaling by conditionally knocking out the lipid phosphatase PTEN using the Vegfr3 promoter to drive the expression of Cre-lox in lymphatic endothelial cells (LECs). PTEN is an intracellular brake that inhibits the downstream effects of the activation of VEGFR3 by VEGF-C. Activation of Cre-lox recombination in adult mice resulted in an expanded functional lymphatic network due to LEC proliferation that was independent of lymphangiogenic growth factor production. Furthermore, compared with lymphangiogenesis induced by VEGF-C injection, LECPTEN animals had mature, nonleaky lymphatics with intact cell-cell junctions and reduced local tissue inflammation. Last, compared with wild-type or VEGF-C–injected mice, LECPTEN animals had an improved capacity to resolve inflammatory responses. Our findings indicate that intracellular modulation of lymphangiogenesis is effective in inducing functional lymphatic networks and has no off-target inflammatory effects.

scholarly journals Midbrain microglia exhibit early proliferative and inflammatory responses during aging that are modulated by CX3CR1 and microglial ablation and repopulation

2021 ◽  
Author(s):  
EN Moca ◽  
D Lecca ◽  
KT Hope ◽  
D Tweedie ◽  
S Sidhu ◽  
...  
Keyword(s):  
Basal Ganglia ◽  
Inflammatory Responses ◽  
Functional Decline ◽  
Neuronal Loss ◽  
Brain Regions ◽  
Dopamine Neurons ◽  
Substantia Nigra Pars Compacta ◽  
Inflammatory Factors ◽  
Adult Mice ◽  
And Function

ABSTRACTMicroglia maintain tissue health and can critically influence synaptic connectivity and function. During aging, microglia produce inflammatory factors, show reduced tissue surveillance, altered interactions with synapses, and prolonged responses to insults. In addition, risk genes for neurodegenerative disease are highly expressed by microglia. These findings argue that microglial function is likely to critically shape vulnerability or resilience of neurons during aging. We recently discovered that microglia in the ventral tegmental area (VTA) of young adult mice differ markedly from their counterparts in other brain regions. Whether this regional variation in microglia persists, diminishes, or increases during aging has not been determined. Here, we analyze microglia in several nuclei of the basal ganglia throughout the lifespan in mice and find that VTA microglia exhibit increased proliferation and production of inflammatory factors months prior to microglia in other basal ganglia nuclei. Comparable early proliferative responses were observed in the substantia nigra pars compacta where disease-vulnerable dopamine neurons reside. These proliferative and inflammatory responses of VTA microglia began as early at 13 months of age in mice and were not accompanied by substantial neuronal loss or changes in local astrocyte number. Finally, these region-specific responses of microglia to aging were enhanced by knockout of the fractalkine receptor (CX3CR1) and reduced by microglial ablation and repopulation, identifying two signaling axes by which region-specific responses of microglia to aging can be modulated. Collectively, these findings indicate that VTA and SNc microglia continue to differ from their counterparts in other basal ganglia nuclei during aging. Moreover, the early phenotypic changes in these cells result in “pockets” of inflammation near dopamine neurons beginning in middle age, which may be linked to enhanced vulnerability of these neurons to functional decline and degenerative disease.

scholarly journals Cutaneous Effects of In Utero and Lactational Exposure of C57BL/6J Mice to 2,3,7,8-Tetrachlorodibenzo-p-dioxin

Toxics ◽  
2021 ◽  
Vol 9 (8) ◽  
pp. 192
Author(s):  
Jyoti Bhuju ◽  
Kristin M. Olesen ◽  
Clarisse S. Muenyi ◽  
Tejesh S. Patel ◽  
Robert W. Read ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Cyst Formation ◽  
In Utero ◽  
Lactational Exposure ◽  
Adult Mice ◽  
Transient Activation ◽  
Barrier Formation ◽  
Tetrachlorodibenzo P Dioxin ◽  
Cell Niche ◽  
And Function

To determine the cutaneous effects of in utero and lactational exposure to the AHR ligand 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD), pregnant C57BL/6J mice were exposed by gavage to a vehicle or 5 μg TCDD/kg body weight at embryonic day 12 and epidermal barrier formation and function were studied in their offspring from postnatal day 1 (P1) through adulthood. TCDD-exposed pups were born with acanthosis. This effect was AHR-dependent and subsided by P6 with no evidence of subsequent inflammatory dermatitis. The challenge of adult mice with MC903 showed similar inflammatory responses in control and treated animals, indicating no long-term immunosuppression to this chemical. Chloracne-like sebaceous gland hypoplasia and cyst formation were observed in TCDD-exposed P21 mice, with concomitant microbiome dysbiosis. These effects were reversed by P35. CYP1A1 and CYP1B1 expression in the skin was increased in the exposed mice until P21, then declined. Both CYP proteins co-localized with LRIG1-expressing progenitor cells at the infundibulum. CYP1B1 protein also co-localized with a second stem cell niche in the isthmus. These results indicate that this exposure to TCDD causes a chloracne-like effect without inflammation. Transient activation of the AhR, due to the shorter half-life of TCDD in mice, likely contributes to the reversibility of these effects.

scholarly journals Molecular and phenotypic analysis of rodent models reveals conserved and species-specific modulators of human sarcopenia

2021 ◽  
Vol 4 (1) ◽  
Author(s):  
Anastasiya Börsch ◽  
Daniel J. Ham ◽  
Nitish Mittal ◽  
Lionel A. Tintignac ◽  
Eugenia Migliavacca ◽  
...  
Keyword(s):  
Muscle Mass ◽  
Inflammatory Responses ◽  
Molecular Data ◽  
Model Organisms ◽  
Sequencing Data ◽  
Phenotypic Analysis ◽  
Age Related ◽  
Analogous Data ◽  
Species Specific ◽  
And Function

AbstractSarcopenia, the age-related loss of skeletal muscle mass and function, affects 5–13% of individuals aged over 60 years. While rodents are widely-used model organisms, which aspects of sarcopenia are recapitulated in different animal models is unknown. Here we generated a time series of phenotypic measurements and RNA sequencing data in mouse gastrocnemius muscle and analyzed them alongside analogous data from rats and humans. We found that rodents recapitulate mitochondrial changes observed in human sarcopenia, while inflammatory responses are conserved at pathway but not gene level. Perturbations in the extracellular matrix are shared by rats, while mice recapitulate changes in RNA processing and autophagy. We inferred transcription regulators of early and late transcriptome changes, which could be targeted therapeutically. Our study demonstrates that phenotypic measurements, such as muscle mass, are better indicators of muscle health than chronological age and should be considered when analyzing aging-related molecular data.

scholarly journals New Tricks for an Old (Hedge)Hog: Sonic Hedgehog Regulation of Astrocyte Function

Cells ◽  
2021 ◽  
Vol 10 (6) ◽  
pp. 1353
Author(s):  
A. Denise R. Garcia
Keyword(s):  
Signaling Pathway ◽  
Sonic Hedgehog ◽  
Synapse Formation ◽  
Inflammatory Responses ◽  
Molecular Signaling ◽  
Synaptic Organization ◽  
Shh Signaling ◽  
Broad Array ◽  
And Function ◽  
Molecular Signaling Pathway

The Sonic hedgehog (Shh) molecular signaling pathway is well established as a key regulator of neurodevelopment. It regulates diverse cellular behaviors, and its functions vary with respect to cell type, region, and developmental stage, reflecting the incredible pleiotropy of this molecular signaling pathway. Although it is best understood for its roles in development, Shh signaling persists into adulthood and is emerging as an important regulator of astrocyte function. Astrocytes play central roles in a broad array of nervous system functions, including synapse formation and function as well as coordination and orchestration of CNS inflammatory responses in pathological states. Neurons are the source of Shh in the adult, suggesting that Shh signaling mediates neuron–astrocyte communication, a novel role for this multifaceted pathway. Multiple roles for Shh signaling in astrocytes are increasingly being identified, including regulation of astrocyte identity, modulation of synaptic organization, and limitation of inflammation. This review discusses these novel roles for Shh signaling in regulating diverse astrocyte functions in the healthy brain and in pathology.

scholarly journals The long noncoding RNA Synage regulates synapse stability and neuronal function in the cerebellum

2021 ◽  
Author(s):  
Fei Wang ◽  
Qianqian Wang ◽  
Baowei Liu ◽  
Lisheng Mei ◽  
Sisi Ma ◽  
...  
Keyword(s):  
Noncoding Rna ◽  
Cerebellar Atrophy ◽  
Synaptic Activity ◽  
Motor Dysfunction ◽  
Cerebellar Development ◽  
Full Spectrum ◽  
Density Reduction ◽  
Adult Mice ◽  
Synapse Density ◽  
And Function

AbstractThe brain is known to express many long noncoding RNAs (lncRNAs); however, whether and how these lncRNAs function in modulating synaptic stability remains unclear. Here, we report a cerebellum highly expressed lncRNA, Synage, regulating synaptic stability via at least two mechanisms. One is through the function of Synage as a sponge for the microRNA miR-325-3p, to regulate expression of the known cerebellar synapse organizer Cbln1. The other function is to serve as a scaffold for organizing the assembly of the LRP1-HSP90AA1-PSD-95 complex in PF-PC synapses. Although somewhat divergent in its mature mRNA sequence, the locus encoding Synage is positioned adjacent to the Cbln1 loci in mouse, rhesus macaque, and human, and Synage is highly expressed in the cerebella of all three species. Synage deletion causes a full-spectrum cerebellar ablation phenotype that proceeds from cerebellar atrophy, through neuron loss, on to synapse density reduction, synaptic vesicle loss, and finally to a reduction in synaptic activity during cerebellar development; these deficits are accompanied by motor dysfunction in adult mice, which can be rescued by AAV-mediated Synage overexpression from birth. Thus, our study demonstrates roles for the lncRNA Synage in regulating synaptic stability and function during cerebellar development.

scholarly journals Adult medial habenula neurons require GDNF receptor GFRα1 for synaptic stability and function

PLoS Biology ◽  
2021 ◽  
Vol 19 (11) ◽  
pp. e3001350
Author(s):  
Diana Fernández-Suárez ◽  
Favio A. Krapacher ◽  
Katarzyna Pietrajtis ◽  
Annika Andersson ◽  
Lilian Kisiswa ◽  
...  
Keyword(s):  
Synaptic Plasticity ◽  
Proximity Ligation Assay ◽  
Glutamatergic Synapses ◽  
Proximity Ligation ◽  
Postsynaptic Currents ◽  
Adult Mice ◽  
Medial Habenula ◽  
Factor Receptor Alpha ◽  
And Function ◽  
Anxiety And Fear

The medial habenula (mHb) is an understudied small brain nucleus linking forebrain and midbrain structures controlling anxiety and fear behaviors. The mechanisms that maintain the structural and functional integrity of mHb neurons and their synapses remain unknown. Using spatiotemporally controlled Cre-mediated recombination in adult mice, we found that the glial cell–derived neurotrophic factor receptor alpha 1 (GFRα1) is required in adult mHb neurons for synaptic stability and function. mHb neurons express some of the highest levels of GFRα1 in the mouse brain, and acute ablation of GFRα1 results in loss of septohabenular and habenulointerpeduncular glutamatergic synapses, with the remaining synapses displaying reduced numbers of presynaptic vesicles. Chemo- and optogenetic studies in mice lacking GFRα1 revealed impaired circuit connectivity, reduced AMPA receptor postsynaptic currents, and abnormally low rectification index (R.I.) of AMPARs, suggesting reduced Ca2+ permeability. Further biochemical and proximity ligation assay (PLA) studies defined the presence of GluA1/GluA2 (Ca2+ impermeable) as well as GluA1/GluA4 (Ca2+ permeable) AMPAR complexes in mHb neurons, as well as clear differences in the levels and association of AMPAR subunits with mHb neurons lacking GFRα1. Finally, acute loss of GFRα1 in adult mHb neurons reduced anxiety-like behavior and potentiated context-based fear responses, phenocopying the effects of lesions to septal projections to the mHb. These results uncover an unexpected function for GFRα1 in the maintenance and function of adult glutamatergic synapses and reveal a potential new mechanism for regulating synaptic plasticity in the septohabenulointerpeduncular pathway and attuning of anxiety and fear behaviors.

scholarly journals Immunosuppressive Mechanisms of Regulatory B Cells

2021 ◽  
Vol 12 ◽  
Author(s):  
Diego Catalán ◽  
Miguel Andrés Mansilla ◽  
Ashley Ferrier ◽  
Lilian Soto ◽  
Kristine Oleinika ◽  
...  
Keyword(s):  
B Cells ◽  
Immune Responses ◽  
Metabolic Diseases ◽  
Inflammatory Responses ◽  
Surface Proteins ◽  
Regulatory B Cells ◽  
Cell Surface Proteins ◽  
The Past ◽  
And Function

Regulatory B cells (Bregs) is a term that encompasses all B cells that act to suppress immune responses. Bregs contribute to the maintenance of tolerance, limiting ongoing immune responses and reestablishing immune homeostasis. The important role of Bregs in restraining the pathology associated with exacerbated inflammatory responses in autoimmunity and graft rejection has been consistently demonstrated, while more recent studies have suggested a role for this population in other immune-related conditions, such as infections, allergy, cancer, and chronic metabolic diseases. Initial studies identified IL-10 as the hallmark of Breg function; nevertheless, the past decade has seen the discovery of other molecules utilized by human and murine B cells to regulate immune responses. This new arsenal includes other anti-inflammatory cytokines such IL-35 and TGF-β, as well as cell surface proteins like CD1d and PD-L1. In this review, we examine the main suppressive mechanisms employed by these novel Breg populations. We also discuss recent evidence that helps to unravel previously unknown aspects of the phenotype, development, activation, and function of IL-10-producing Bregs, incorporating an overview on those questions that remain obscure.

Perinatal Inflammation Negatively Impacts Lung Structure And Function In Adult Mice

2012 ◽  
Author(s):  
Markus Velten ◽  
Rodney D. Britt ◽  
Kathryn M. Heyob ◽  
Trent E. Tipple ◽  
Lynette K. Rogers
Keyword(s):  
Structure And Function ◽  
Adult Mice ◽  
Lung Structure ◽  
And Function

scholarly journals Lipopolysaccharide induces neuroglia activation and NF-κB activation in cerebral cortex of adult mice

2019 ◽  
Vol 35 (1) ◽  
Author(s):  
Ju-Bin Kang ◽  
Dong-Ju Park ◽  
Murad-Ali Shah ◽  
Myeong-Ok Kim ◽  
Phil-Ok Koh
Keyword(s):  
Oxidative Stress ◽  
Cerebral Cortex ◽  
Calcium Binding ◽  
Inflammatory Responses ◽  
Inflammatory Factors ◽  
Adult Mice ◽  
Tnf Α ◽  
Factor Α ◽  
And Oxidative Stress ◽  
Necrosis Factor

Abstract Lipopolysaccharide (LPS) acts as an endotoxin, releases inflammatory cytokines, and promotes an inflammatory response in various tissues. This study investigated whether LPS modulates neuroglia activation and nuclear factor kappa B (NF-κB)-mediated inflammatory factors in the cerebral cortex. Adult male mice were divided into control animals and LPS-treated animals. The mice received LPS (250 μg/kg) or vehicle via an intraperitoneal injection for 5 days. We confirmed a reduction of body weight in LPS-treated animals and observed severe histopathological changes in the cerebral cortex. Moreover, we elucidated increases of reactive oxygen species and oxidative stress levels in LPS-treated animals. LPS administration led to increases of ionized calcium-binding adaptor molecule-1 (Iba-1) and glial fibrillary acidic protein (GFAP) expression. Iba-1 and GFAP are well accepted as markers of activated microglia and astrocytes, respectively. Moreover, LPS exposure induced increases of NF-κB and pro-inflammatory factors, such as interleukin-1β (IL-1β) and tumor necrosis factor-α (TNF-α). Increases of these inflammatory mediators by LPS exposure indicate that LPS leads to inflammatory responses and tissue damage. These results demonstrated that LPS activates neuroglial cells and increases NF-κB-mediated inflammatory factors in the cerebral cortex. Thus, these findings suggest that LPS induces neurotoxicity by increasing oxidative stress and activating neuroglia and inflammatory factors in the cerebral cortex.

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