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 Dectin-1-Mediated Production of Pro-Inflammatory Cytokines Induced by Yeast β-Glucans in Bovine Monocytes

2021 ◽  
Vol 12 ◽  
Author(s):  
Ana R. V. Pedro ◽  
Tânia Lima ◽  
Ricardo Fróis-Martins ◽  
Bárbara Leal ◽  
Isabel C. Ramos ◽  
...  
Keyword(s):  
Gene Expression ◽  
Cell Surface ◽  
Inflammatory Cytokines ◽  
Surface Expression ◽  
Cell Surface Receptor ◽  
Dependent Manner ◽  
Feed Supplements ◽  
Surface Receptor ◽  
Dose Dependent ◽  
Pro Inflammatory Cytokines

Yeast-derived products containing β-glucans have long been used as feed supplements in domesticated animals in an attempt to increase immunity. β-glucans are mainly recognized by the cell surface receptor CLEC7A, also designated Dectin-1. Although the immune mechanisms elicited through Dectin-1 activation have been studied in detail in mice and humans, they are poorly understood in other species. Here, we evaluated the response of bovine monocytes to soluble and particulate purified β-glucans, and also to Zymosan. Our results show that particulate, but not soluble β-glucans, can upregulate the surface expression of costimulatory molecules CD80 and CD86 on bovine monocytes. In addition, stimulated cells increased production of IL-8 and of TNF, IL1B, and IL6 mRNA expression, in a dose-dependent manner, which correlated positively with CLEC7A gene expression. Production of IL-8 and TNF expression decreased significantly after CLEC7A knockdown using two different pairs of siRNAs. Overall, we demonstrated here that bovine monocytes respond to particulate β-glucans, through Dectin-1, by increasing the expression of pro-inflammatory cytokines. Our data support further studies in cattle on the induction of trained immunity using dietary β-glucans.

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 Role of Mycoplasma penetransEndonuclease P40 as a Potential Pathogenic Determinant

1999 ◽  
Vol 67 (9) ◽  
pp. 4456-4462 ◽  
Author(s):  
Mourad Bendjennat ◽  
Alain Blanchard ◽  
Mohammed Loutfi ◽  
Luc Montagnier ◽  
Elmostafa Bahraoui
Keyword(s):  
Mononuclear Cells ◽  
Morphological Changes ◽  
Fluorescein Isothiocyanate ◽  
Host Cells ◽  
Cell Surface Receptor ◽  
Dependent Manner ◽  
Peripheral Blood Mononuclear ◽  
Surface Receptor

ABSTRACT Recently, we reported the purification to homogeneity and characterization of Ca2+- and Mg2+-dependent endonuclease P40 produced by Mycoplasma penetrans (M. Bendjennat, A. Blanchard, M. Loutfi, L. Montagnier, and E. Bahraoui, J. Bacteriol. 179; 2210–2220, 1997), a mycoplasma which was isolated for the first time from the urine of human immunodeficiency virus-infected patients. To evaluate how this nuclease could interact with host cells, we tested its effect on CEM and Molt-4 lymphocytic cell lines and on peripheral blood mononuclear cells. We observed that 10−7to 10−9 M P40 is able to mediate a cytotoxic effect. We found that 100% of cells were killed after 24 h of incubation with 10−7 M P40 while only 40% cytotoxicity was obtained after 72 h of incubation with 10−9 M P40. Phase-contrast microscopy observations of P40-treated cells revealed morphological changes, including pronounced blebbing of the plasma membrane and cytoplasmic shrinkage characteristic of programmed cell death, which is in agreement with the internucleosomal fragmentation of P40-treated cell DNA as shown by agarose gel electrophoresis. We showed that 125I-radiolabeled or fluorescein isothiocyanate-labeled P40 was able to bind specifically in a dose-dependent manner to the cell membrane of CEM cells, which suggested that the cytotoxicity of P40 endonuclease was mediated by its interaction with the cell surface receptor(s). The concentration of unlabeled P40 required to inhibit by 50% the formation of125I-P40-CEM complexes was about 3 × 10−9 M, indicating a high-affinity interaction. Both P40 interaction and cytotoxicity are Ca2+ dependent. Our results suggest that the cytotoxicity of M. penetransobserved in vitro is mediated at least partially by secreted P40, which, after interaction with host cells, can induce an apoptosis-like death. These results strongly suggest a major role of mycoplasmal nucleases as potential pathogenic determinants.

scholarly journals Geongangbuja-Tang Decoction and Its Active Ingredient, Aconiti Lateralis Radix Preparata, Exerts Inhibitory Effects on Heat Stress-Induced Inflammation in Mice

2021 ◽  
Vol 11 (15) ◽  
pp. 6902
Author(s):  
Eugene Huh ◽  
Wonil Lee ◽  
Yujin Choi ◽  
Tae Hee Lee ◽  
Myung Sook Oh
Keyword(s):  
Heat Stress ◽  
Energy Metabolism ◽  
Inflammatory Cytokines ◽  
Hpa Axis ◽  
Inflammatory Responses ◽  
Heat Exposure ◽  
Mouse Serum ◽  
Dependent Manner ◽  
Active Constituent ◽  
Pro Inflammatory Cytokines

Heat stress induces the hypothalamic-pituitary-adrenal (HPA) axis activation, influences biological responses, and reduces energy metabolism. Geongangbuja-tang (GBT) and its components, Zingiberis Rhizoma (ZOR) and Aconiti Lateralis Radix Preparata (ALRP) have been used to induce energy metabolism; however, the effects of GBT and its ingredients on heat-induced inflammatory responses have not yet been investigated. In this study, we performed an open-field test to evaluate locomotor activity in mice. To assess the effects of GBT and its ingredients on inflammation, the protein levels of c-fos, pro-inflammatory cytokines, and cortisol were measured in the mouse hypothalamus and serum. The results showed that GBT alleviated locomotive activity and reduced c-fos levels in a dose-dependent manner under the heat exposure. After investigating the active constituent of GBT, we found that compared to GBT and ZOR, ALRP significantly suppressed c-fos expression under heat stress. Subsequently, ALRP decreased the expression of pro-inflammatory cytokines, such as interleukin-9 and -13 and prostaglandin, under the heat stress in the mouse hypothalamus. Moreover, treatment with ALRP inhibited cortisol secretion in the mouse serum following heat exposure. These results indicate that GBT and its active component, ALRP, could be the thermoregulatory agents that regulate the HPA axis.

scholarly journals Senescent Accelerated Prone 8 (SAMP8) Mice as A Model of Age Dependent Neuroinflammation

2020 ◽  
Author(s):  
Andrés Fernández ◽  
Elena Quintana ◽  
Patricia Velasco ◽  
Belén de Andrés ◽  
Maria Luisa Gaspar ◽  
...  
Keyword(s):  
Choroid Plexus ◽  
Inflammatory Cytokines ◽  
Hippocampal Formation ◽  
Morphological Changes ◽  
Interleukin 1 ◽  
Brain Parenchyma ◽  
Age Related ◽  
Inflammatory Changes ◽  
Samp8 Mice ◽  
The Brain

Abstract Background: Aging and age related diseases are strong risk factors for the development of neurodegenerative diseases. Neuroinflammation (NIF), as the brain's immune response, plays an important role in aged associated degeneration of central nervous system (CNS). The need of animal models that will allow us to understand and modulate this process is required for the scientific community. Methods: We have analyzed aging-phenotypical and inflammatory changes of brain myeloid cells (bMyC) in a senescent accelerated prone aged (SAMP8) mouse model, and compared with their resistant to senescence control (SAMR1). We have performed morphometric methods to evaluate the architecture of cellular prolongations and analyzed Iba1+ clustered cells with aging. To analyse specific constant brain areas we have performed stereology measurements of Iba1+ cells in the hippocampal formation. We have isolated bMyC from brain parenchyma (BP) and choroid plexus and meningeal membranes (m/Ch), and analyzed their response to systemic LPS- driven inflammation.Results: Aged 10 month old SAMP8 mice presents many of the hallmarks of aging-dependent neuroinflammation when compared with their senescence resistant control (SAMR1); ie, increase of protein aggregates, presence of Iba1+ clusters, but not increase in the number of Iba1+ cells. We have further observed and increased of main inflammatory mediator IL-1β, and augment of border MHCII+Iba1+ cells. Isolated CD45+ bMyC from brain parenchyma (BP) and choroid plexus and meningeal membranes (m/Ch) have been analyzed showing that there is not significant increase of CD45+ from the periphery. Our data support that aged-driven pro-inflammatory cytokine interleukin 1 beta (IL1β) transcription is mainly enhanced in CD45+BP cells. Furthermore, we are showing that LPS-driven systemic inflammation produces inflammatory cytokines mainly in the border bMyC, sensed to a lesser extent by the BP bMyC, and is enhanced in aged SAMP8 compared to control SAMR1.Conclusion: Our data validate the SAMP8 model to study age-associated neuroinflammatory events, but careful controls for age and strain are required. These animals show morphological changes in their bMyC cell repertoires associated to age, corresponding to an increase in the production of main pro inflammatory cytokines such as IL-1β, which predispose the brain to an enhanced inflammatory response after LPS-systemic challenge.

scholarly journals Leptospiral Endostatin-Like Protein A Is a Bacterial Cell Surface Receptor for Human Plasminogen

2010 ◽  
Vol 78 (5) ◽  
pp. 2053-2059 ◽  
Author(s):  
Ashutosh Verma ◽  
Catherine A. Brissette ◽  
Amy A. Bowman ◽  
Samir T. Shah ◽  
Peter F. Zipfel ◽  
...  
Keyword(s):  
Binding Sites ◽  
Protein A ◽  
Aminocaproic Acid ◽  
Factor H ◽  
Cell Surface Receptor ◽  
Dependent Manner ◽  
Public Health Importance ◽  
Amino Terminal ◽  
Surface Receptor ◽  
Human Plasminogen

ABSTRACT The spirochete Leptospira interrogans is a highly invasive pathogen of worldwide public health importance. Studies from our laboratories and another have demonstrated that L. interrogans can acquire host plasminogen on its surface. Exogenous plasminogen activators can then convert bound plasminogen into the functionally active protease plasmin. In this study, we extend upon those observations and report that leptospiral endostatin-like protein A (LenA) binds human plasminogen in a dose-dependent manner. LenA-plasminogen interactions were significantly inhibited by the lysine analog ξ-aminocaproic acid, suggesting that the lysine-binding sites on the amino-terminal kringle portion of the plasminogen molecule play a role in the binding. Previous studies have shown that LenA also binds complement regulator factor H and the extracellular matrix component laminin. Plasminogen competed with both factor H and laminin for binding to LenA, which suggests overlapping ligand-binding sites on the bacterial receptor. Finally, LenA-bound plasminogen could be converted to plasmin, which in turn degraded fibrinogen, suggesting that acquisition of host-derived plasmin by LenA may aid bacterial dissemination throughout host tissues.

Regulation of c-ret expression by retinoic acid in rat metanephros: implication in nephron mass control

1998 ◽  
Vol 275 (6) ◽  
pp. F938-F945 ◽  
Author(s):  
Evelyne Moreau ◽  
José Vilar ◽  
Martine Lelièvre-Pégorier ◽  
Claudie Merlet-Bénichou ◽  
Thierry Gilbert
Keyword(s):  
Retinoic Acid ◽  
Molecular Mechanisms ◽  
Kidney Development ◽  
Mrna Level ◽  
Cell Surface Receptor ◽  
Dependent Manner ◽  
All Trans Retinoic Acid ◽  
Surface Receptor ◽  
Dose Dependent

Vitamin A and its derivatives have been shown to promote kidney development in vitro in a dose-dependent fashion. To address the molecular mechanisms by which all- trans-retinoic acid (RA) may regulate the nephron mass, rat kidneys were removed on embryonic day 14( E14) and grown in organ culture under standard or RA-stimulated conditions. By using RT-PCR, we studied the expression of the glial cell line-derived neurotrophic factor (GDNF), its cell surface receptor-α (GDNFR-α), and the receptor tyrosine kinase c-ret, known to play a major role in renal organogenesis. Expression of GDNF and GDNFR-α transcripts was high at the time of explantation and remained unaffected in culture with or without RA. In contrast, c-ret mRNA level, which was low in E14 metanephros and dropped rapidly in vitro, was increased by RA in a dose-dependent manner. The same is true at the protein level. Exogenous GDNF barely promotes additional nephron formation in vitro. Thus the present data establish c-ret as a key target of retinoids during kidney organogenesis.

Abstract T P239: Therapeutic Efficacy and Pharmacological Mechanisms of SP-8203 for Treatment of Cerebral Ischemia

Stroke ◽  
2015 ◽  
Vol 46 (suppl_1) ◽  
Author(s):  
Won-Ki Kim ◽  
Chung Ju ◽  
Angela M. A. A Jalin ◽  
Jei-Man Ryu ◽  
Il-Hwan Cho ◽  
...  
Keyword(s):  
Oxidative Stress ◽  
Cerebral Ischemia ◽  
Inflammatory Cytokines ◽  
Inflammatory Responses ◽  
Time Window ◽  
Ischemic Injury ◽  
Blood Levels ◽  
Dependent Manner ◽  
Anti Oxidant ◽  
Therapeutic Time Window

In cerebral ischemia, neurons and glia are deteriorated by various mechanisms including excitotoxicity, oxidative stress and inflammatory responses. Thus, pharmacological blockade of multiple cytotoxic pathways would be a therapeutic strategy for the treatment of ischemic injury. We recently identified a novel multi-potent neuroprotectant SP-8203. Pharmacological efficacy and action mechanism of SP-8203 were evaluated in rat transient middle cerebral artery occlusion (MCAO). Post-ischemic treatment (i.v.) of SP-8203 reduced cerebral ischemic injury in a dose-dependent manner (0.03 ~ 10 mg/kg) and at clinically relevant therapeutic time window (up to 12 h after ischemia onset). Similar efficacy was also obtained in beagle dogs subjected to permanent MCAO. Although it did not ameliorate the excitotoxicity, SP-8203 markedly reduced ischemia-evoked oxidative stress via up-regulation of anti-oxidant enzymes, specifically Mn-SOD and Cu/Zn-SOD, but not catalase and glutathione reductase. SP-8203 also reduced the infiltration of ED-1-immunopositive monocytes and MPO-positive neutrophils into ischemic brain lesions of rats. Moreover, SP-8203 significantly reduced the release of pro-inflammatory cytokines/chemokines (e.g. IL-1beta, TNF-alpha, MCP-1) and also the expression of iNOS and resultant formation of nitrotyrosine. Early (3 h) thrombolysis with tPA restored perfusion and reduced infarction in embolic rat models. However, late 6-h tPA did not decrease infarction, but instead increased intracerebral hemorrhage and mortality. Interestingly, SP-8203 treatment at 1.5 h before late (6 h) tPA infusion markedly reduced tPA-evoked cerebral hemorrhage and mortality. Blood levels of MMPs were significantly correlated with the changes of hemorrhage and mortality. Taken together, SP-8203 has multiple neuroprotective activities in cerebral ischemia: up-regulation of anti-oxidant enzymes, reduction of inflammatory cells recruitment, and suppression of anti-inflammatory cytokines/chemokines and MMP expression. Thanks to the multiple neuroprotective mechanisms, SP-8203 could be a promising drug candidate for stroke treatment, especially in combination of tPA by extending therapeutic time window.

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.

Sign in / Sign up

Export Citation Format

Share Document