scholarly journals Sustained TREM2 stabilization accelerates microglia heterogeneity and Abeta pathology in a mouse model of Alzheimer s disease

2021 ◽  
Author(s):  
Rahul Dhandapani ◽  
Marilisa Neri ◽  
Mario Bernhard ◽  
Irena Brzak ◽  
Tatjana Schweizer ◽  
...  
Keyword(s):  
Mouse Model ◽  
Inflammatory Responses ◽  
Transmembrane Protein ◽  
Proteolytic Cleavage ◽  
Cell Surface Receptor ◽  
Pathological Conditions ◽  
Mouse Cortex ◽  
Surface Receptor ◽  
And Function ◽  
The Brain

TREM2 is a transmembrane protein expressed exclusively in microglia in the brain that regulates inflammatory responses to pathological conditions. Proteolytic cleavage of membrane TREM2 affects microglial function and is associated with Alzheimer s disease, but the consequence of reduced TREM2 proteolytic cleavage has not been determined. We generated a transgenic mouse model of reduced TREM2 shedding (Trem2-IPD) through amino acid substitution of ADAM-protease recognition site. We found that Trem2-IPD mice displayed increased TREM2 cell surface receptor load, survival and function in myeloid cells. Using single cell transcriptomic profiling of mouse cortex we show that sustained TREM2 stabilization induces a shift of fate in microglial maturation and accelerates microglial responses to Abeta pathology in a mouse model of Alzheimer s disease. Our data indicate that reduction of TREM2 proteolytic cleavage aggravates neuroinflammation during the course of AD pathology suggesting that TREM2 shedding is a critical regulator of microglial activity in pathological states.

scholarly journals Soluble TREM2 induces inflammatory responses and enhances microglial survival

2017 ◽  
Vol 214 (3) ◽  
pp. 597-607 ◽  
Author(s):  
Li Zhong ◽  
Xiao-Fen Chen ◽  
Tingting Wang ◽  
Zhe Wang ◽  
Chunyan Liao ◽  
...  
Keyword(s):  
Inflammatory Cytokines ◽  
Inflammatory Responses ◽  
Morphological Changes ◽  
Cell Surface Receptor ◽  
Soluble Form ◽  
Dependent Manner ◽  
Soluble Trem2 ◽  
Surface Receptor ◽  
The Brain ◽  
Ad Therapy

Triggering receptor expressed on myeloid cells 2 (TREM2) is an innate immune receptor expressed in microglia in the brain. A soluble form of TREM2 (sTREM2) derived from proteolytic cleavage of the cell surface receptor is increased in the preclinical stages of AD and positively correlates with the amounts of total and phosphorylated tau in the cerebrospinal fluid. However, the physiological and pathological functions of sTREM2 remain unknown. Here, we show that sTREM2 promotes microglial survival in a PI3K/Akt-dependent manner and stimulates the production of inflammatory cytokines depending on NF-κB. Variants of sTREM2 carrying AD risk-associated mutations were less potent in both suppressing apoptosis and triggering inflammatory responses. Importantly, sTREM2 delivered to the hippocampi of both wild-type and Trem2-knockout mice elevated the expression of inflammatory cytokines and induced morphological changes of microglia. Collectively, these data indicate that sTREM2 triggers microglial activation inducing inflammatory responses and promoting survival. This study has implications for the pathogenesis of AD and provides insights into targeting sTREM2 pathway for AD therapy.

scholarly journals Computational Characterization of the mtORF of Pocilloporid Corals: Insights into Differences in Protein Structure and Function among Stylophora Lineages from Contrasting Environments

2019 ◽  
Author(s):  
Eulalia Banguera-Hinestroza ◽  
Yvonne Sawall ◽  
Jean-François Flot
Keyword(s):  
Stress Response ◽  
Transmembrane Protein ◽  
Thermal Adaptation ◽  
Cell Surface Receptor ◽  
Reading Frame ◽  
Intrinsically Disordered ◽  
Protein Functions ◽  
Surface Receptor ◽  
Environmental Variations ◽  
And Function

More than a decade ago, a new mitochondrial Open Reading Frame (mtORF) was discovered in corals of the family Pocilloporidae, which turn out to be an effective barcode gene for these corals. However, its function remains unknown. Recently, this gene revealed the existence of a hybrid Stylophora lineage (RS_LinA) inhabiting in sympatry along the environmental gradient of the Red Sea (18.5°C to 33.9°C) with its parental species (RS_LinB). Furthermore, in RS_LinB, the mtORF uncovered phylogeographic patterns that were strongly correlated with environmental variations. This was similar to the patterns unraveled by hsp70, suggesting that mtORF too might be involved in thermal adaptation. Here we used computational approaches to characterize the mtORF and to identify its potential role. Results showed that this gene encodes a transmembrane protein (0.97<P< 1.00) involved in transport (0.80<P< 0.87), regulation of metabolic processes (0.70<P<0.85), and likely in the cell-surface receptor signaling pathway (0.56<P<0.80). Predicted protein functions differed among Stylophora lineages and interestingly, in RS_LinB only, the protein was intrinsically disordered and displayed domains involved in cellular complexes and stress response (0.0001< P <0.001). These characteristics, exclusive of an endemic lineage adapted to extreme environmental fluctuations, support a role of the mtORF in stress response, speciation and adaptation.

scholarly journals Breeder Diet Strategies for Generating Ttpa-Null and Wild-Type Mice with Low Vitamin E Status to Assess Neurological Outcomes

2020 ◽  
Vol 4 (11) ◽  
Author(s):  
Katherine M Ranard ◽  
Matthew J Kuchan ◽  
John W Erdman
Keyword(s):  
Animal Model ◽  
Vitamin E ◽  
Mouse Model ◽  
Wild Type ◽  
Future Studies ◽  
Neurological Outcomes ◽  
Transfer Protein ◽  
And Function ◽  
The Brain ◽  
Vitamin E Status

ABSTRACT Studying vitamin E [α-tocopherol (α-T)] metabolism and function in the brain and other tissues requires an animal model with low α-T status, such as the transgenic α-T transfer protein (Ttpa)–null (Ttpa−/−) mouse model. Ttpa+/− dams can be used to produce Ttpa−/− and Ttpa+/+mice for these studies. However, the α-T content in Ttpa+/− dams’ diet requires optimization; diets must provide sufficient α-T for reproduction, while minimizing the transfer of α-T to the offspring destined for future studies that require low baseline α-T status. The goal of this work was to assess the effectiveness and feasibility of 2 breeding diet strategies on reproduction outcomes and offspring brain α-T concentrations. These findings will help standardize the breeding methodology used to generate the Ttpa−/− mice for neurological studies.

scholarly journals Correlated STORM-homoFRET Imaging: Applications to the Study of Membrane Receptor Self-Association and Clustering

2021 ◽  
Author(s):  
Amine Driouchi ◽  
Scott Gray-Owen ◽  
Christopher M Yip
Keyword(s):  
Spatial Distribution ◽  
Membrane Proteins ◽  
Complex Mixture ◽  
Cell Surface Receptor ◽  
Oligomeric State ◽  
Imaging Approach ◽  
Surface Receptor ◽  
A Cell ◽  
Self Association ◽  
And Function

Mapping the self-organization and spatial distribution of membrane proteins is key to understanding their function. We report here on a correlated STORM/homoFRET imaging approach for resolving the nanoscale distribution and oligomeric state of membrane proteins. Live cell homoFRET imaging of CEACAM1, a cell-surface receptor known to exist in a complex equilibrium between monomer and dimer/oligomer states, revealed highly heterogenous diffraction-limited structures on the surface of HeLa cells. Correlated super-resolved STORM imaging revealed that these structures comprised a complex mixture and spatial distribution of self-associated CEACAM1 molecules. This correlated approach provides a compelling strategy for addressing challenging questions about the interplay between membrane protein concentration, distribution, interaction, clustering, and function.

scholarly journals The mouse pulvinar nucleus: Organization of the tectorecipient zones

2017 ◽  
Vol 34 ◽  
Author(s):  
NA ZHOU ◽  
PHILLIP S. MAIRE ◽  
SEAN P. MASTERSON ◽  
MARTHA E. BICKFORD
Keyword(s):  
Mouse Model ◽  
Superior Colliculus ◽  
Comparative Studies ◽  
Visual Pathways ◽  
Comparative Approach ◽  
Open Questions ◽  
Human Thalamus ◽  
And Function ◽  
The Brain

AbstractComparative studies have greatly contributed to our understanding of the organization and function of visual pathways of the brain, including that of humans. This comparative approach is a particularly useful tactic for studying the pulvinar nucleus, an enigmatic structure which comprises the largest territory of the human thalamus. This review focuses on the regions of the mouse pulvinar that receive input from the superior colliculus, and highlights similarities of the tectorecipient pulvinar identified across species. Open questions are discussed, as well as the potential contributions of the mouse model for endeavors to elucidate the function of the pulvinar nucleus.

scholarly journals Stimulatory Effects of Peroxisome Proliferator-Activated Receptor-γon FcγReceptor-Mediated Phagocytosis by Alveolar Macrophages

PPAR Research ◽  
2007 ◽  
Vol 2007 ◽  
pp. 1-8 ◽  
Author(s):  
David M. Aronoff ◽  
Carlos H. Serezani ◽  
Jennifer K. Carstens ◽  
Teresa Marshall ◽  
Srinivasa R. Gangireddy ◽  
...  
Keyword(s):  
Alveolar Macrophages ◽  
Peritoneal Macrophages ◽  
Receptor Expression ◽  
Cell Surface Receptor ◽  
Peroxisome Proliferator ◽  
Quiescent State ◽  
Peroxisome Proliferator Activated Receptor ◽  
Downstream Signaling ◽  
Surface Receptor ◽  
And Function

Alveolar macrophages abundantly express PPAR-γ, with both natural and synthetic agonists maintaining the cell in a quiescent state hyporesponsive to antigen stimulation. Conversely, agonists upregulate expression and function of the cell-surface receptor CD36, which mediates phagocytosis of lipids, apoptotic neutrophils, and other unopsonized materials. These effects led us to investigate the actions of PPAR-γagonists on the Fcγreceptor, which mediates phagocytosis of particles opsonized by binding of immunoglobulin G antibodies. We found that troglitazone, rosiglitazone, and 15-deoxy-Δ12,14-prostaglandinJ2increase the ability of alveolar, but not peritoneal, macrophages to carry out phagocytosis mediated by the Fcγreceptor. Receptor expression was not altered but activation of the downstream signaling proteins Syk, ERK-1, and ERK-2 was observed. Although it was previously known that PPAR-γligands stimulate phagocytosis of unopsonized materials, this is the first demonstration that they stimulate phagocytosis of opsonized materials as well.

scholarly journals Autophagy Inhibitors Treatment Alleviates Degree of Infection and Cerebral Inflammatory Responses in Mouse Model of Japanese Encephalitis

2021 ◽  
Author(s):  
Jinhua Zhang ◽  
Wei Han ◽  
changqing xie ◽  
mingxing Gao ◽  
Xugang Wang ◽  
...  
Keyword(s):  
Mouse Model ◽  
Viral Infection ◽  
Japanese Encephalitis ◽  
Host Response ◽  
Inflammatory Responses ◽  
Heart Diseases ◽  
Brain Inflammation ◽  
Specific Mechanism ◽  
Epidemic Disease ◽  
The Brain

Abstract Background: Japanese Encephalitis (JE) is a zoonotic natural epidemic disease caused by Japanese Encephalitis Virus (JEV) infection. Currently, there is no specific medicine for Japanese encephalitis. At present, autophagy regulating drugs have played an important role in the treatment of tumors, heart diseases and other diseases. We hope that by studying the effects of autophagy-regulating drugs on JEV infection and host response in mice, will provide effective clinical trials for autophagy-regulating drugs in the treatment of Japanese encephalitis and other viral infectious diseases. Methods: After establishing appropriate animal model. We observed the neurological symptoms of the mice and counted their survival rate. We compared the degree of viral infection in the brain of mice infected with JE virus. We compared the extent of neuroinflammatory responses in the brain of mice and explored the signaling processes involved in neuroinflammation.Results: We found autophagy inhibitors wortmannin (Wort) and chloroquine (CQ) alleviate degree of viral infection in the brain of JEV-infected mice. Autophagy inhibitors reduced the neuroinflammation in Mouse Model of Japanese encephalitis. We speculated that autophagy inhibitors may attenuate the activation of the PI3K/AKT/NF-kB pathway, thereby reducing the brain inflammation in mice, thereby protecting mice from JEV-induced death. This result is not significant enough, the specific mechanism still needs further study.Conclusions: Our study suggests that autophagy inhibitors wortmannin and chloroquine could reduce the degree of viral infection and inflammatory response in the brain of JEV infected mice, providing a clinical basis for the treatment of Japanese encephalitis.

scholarly journals Neutrophil and monocyte dysfunctional effector response towards bacterial challenge in critically-ill COVID-19 patients

2020 ◽  
Author(s):  
Srikanth Mairpady Shambat ◽  
Alejandro Gómez-Mejia ◽  
Tiziano A. Schweizer ◽  
Markus Huemer ◽  
Chun-Chi Chang ◽  
...  
Keyword(s):  
Bacterial Infections ◽  
Distinct Pattern ◽  
Innate Immune ◽  
Receptor Expression ◽  
Cell Surface Receptor ◽  
Functional Responses ◽  
Innate Immune Signaling ◽  
Surface Receptor ◽  
And Function ◽  
Effector Response

AbstractCOVID-19 displays diverse disease severities and symptoms. Elevated inflammation mediated by hypercytokinemia induces a detrimental dysregulation of immune cells. However, there is limited understanding of how SARS-CoV-2 pathogenesis impedes innate immune signaling and function against secondary bacterial infections. We assessed the influence of COVID-19 hypercytokinemia on the functional responses of neutrophils and monocytes upon bacterial challenges from acute and corresponding recovery COVID-19 ICU patients. We show that severe hypercytokinemia in COVID-19 patients correlated with bacterial superinfections. Neutrophils and monocytes from acute COVID-19 patients showed severely impaired microbicidal capacity, reflected by abrogated ROS and MPO production as well as reduced NETs upon bacterial challenges. We observed a distinct pattern of cell surface receptor expression on both neutrophils and monocytes leading to a suppressive autocrine and paracrine signaling during bacterial challenges. Our data provide insights into the innate immune status of COVID-19 patients mediated by their hypercytokinemia and its transient effect on immune dysregulation upon subsequent bacterial infections

scholarly journals Programmed Cell Death-1 Receptor (PD-1)-Mediated Regulation of Innate Lymphoid Cells

2019 ◽  
Vol 20 (11) ◽  
pp. 2836 ◽  
Author(s):  
Grace Mallett ◽  
Arian Laurence ◽  
Shoba Amarnath
Keyword(s):  
Cell Death ◽  
Programmed Cell Death ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
Cell Surface Receptor ◽  
Programmed Cell Death 1 ◽  
Surface Receptor ◽  
A Cell ◽  
And Function

Programmed cell death-1 (PD-1) is a cell surface receptor that dampens adaptive immune responses. PD-1 is activated by the engagement of its ligands PDL-1 or PDL-2. This results in the inhibition of T cell proliferation, differentiation, cytokine secretion, and cytolytic function. Although a great deal is known about PD-1 mediated regulation of CD4+ and CD8+ T cells, its expression and function in innate lymphoid cells (ILCs) are yet to be fully deciphered. This review summarizes the role of PD-1 in (1) modulating ILC development, (2) ILC function, and (3) PD-1 signaling in ILC. Finally, we explore how PD-1 based immunotherapies may be beneficial in boosting ILC responses in cancer, infections, and other immune-related disorders.

scholarly journals The Role of Hyaluronan and CD44 in the Pathogenesis of Lupus Nephritis

2012 ◽  
Vol 2012 ◽  
pp. 1-9 ◽  
Author(s):  
Susan Yung ◽  
Tak Mao Chan
Keyword(s):  
Lupus Nephritis ◽  
Lupus Erythematosus ◽  
Inflammatory Responses ◽  
Tissue Injury ◽  
Cell Surface Receptor ◽  
Systemic Lupus ◽  
Permanent Damage ◽  
Immune Mediated ◽  
Surface Receptor

Systemic lupus erythematosus (SLE) is a prototype autoimmune disease that affects multiorgan systems. Lupus nephritis is one of the most severe manifestations of SLE whereby immune-mediated inflammation can lead to permanent damage within the glomerular, tubulo-interstitial, and vascular compartments of the kidney, resulting in acute or chronic renal failure. The mechanisms that regulate host inflammatory responses and tissue injury are incompletely understood. Accumulating evidence suggests that hyaluronan and its interaction with its cell surface receptor CD44 plays an important role in mediating pathogenic mechanisms in SLE. This paper discusses the putative mechanisms through which hyaluronan and CD44 contribute to the pathogenesis of SLE, with particular emphasis on lupus nephritis.

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