Development of an ex vivo cellular model of rheumatoid arthritis: Critical role of cd14-positive monocyte/macrophages in the development of pannus tissue

2007 ◽  
Vol 56 (9) ◽  
pp. 2875-2885 ◽  
Author(s):  
Toshiko Nozaki ◽  
Kyoko Takahashi ◽  
Osamu Ishii ◽  
Sachio Endo ◽  
Kyoji Hioki ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Ex Vivo ◽  
Critical Role ◽  
Cellular Model ◽  
Pannus Tissue

scholarly journals Critical Role of Glucose Metabolism in Rheumatoid Arthritis Fibroblast-like Synoviocytes

2016 ◽  
Vol 68 (7) ◽  
pp. 1614-1626 ◽  
Author(s):  
Ricard Garcia-Carbonell ◽  
Ajit S. Divakaruni ◽  
Alessia Lodi ◽  
Ildefonso Vicente-Suarez ◽  
Arindam Saha ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Glucose Metabolism ◽  
Critical Role ◽  
Fibroblast Like Synoviocytes

scholarly journals The Pivotal Role of TBK1 in Inflammatory Responses Mediated by Macrophages

2012 ◽  
Vol 2012 ◽  
pp. 1-8 ◽  
Author(s):  
Tao Yu ◽  
Young-Su Yi ◽  
Yanyan Yang ◽  
Jueun Oh ◽  
Deok Jeong ◽  
...  
Keyword(s):  
Rheumatoid Arthritis ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Cell Damage ◽  
Critical Role ◽  
Biological Response ◽  
Antiviral Defense ◽  
Functional Roles ◽  
Virus Interaction

Inflammation is a complex biological response of tissues to harmful stimuli such as pathogens, cell damage, or irritants. Inflammation is considered to be a major cause of most chronic diseases, especially in more than 100 types of inflammatory diseases which include Alzheimer's disease, rheumatoid arthritis, asthma, atherosclerosis, Crohn's disease, colitis, dermatitis, hepatitis, and Parkinson's disease. Recently, an increasing number of studies have focused on inflammatory diseases. TBK1 is a serine/threonine-protein kinase which regulates antiviral defense, host-virus interaction, and immunity. It is ubiquitously expressed in mouse stomach, colon, thymus, and liver. Interestingly, high levels of active TBK1 have also been found to be associated with inflammatory diseases, indicating that TBK1 is closely related to inflammatory responses. Even though relatively few studies have addressed the functional roles of TBK1 relating to inflammation, this paper discusses some recent findings that support the critical role of TBK1 in inflammatory diseases and underlie the necessity of trials to develop useful remedies or therapeutics that target TBK1 for the treatment of inflammatory diseases.

The Role of Microtubule Regulatory Protein Stathmin (STMN1) in Megakaryopoiesis.

Blood ◽  
2009 ◽  
Vol 114 (22) ◽  
pp. 4591-4591
Author(s):  
Camelia Iancu-Rubin ◽  
Joseph Tripodi ◽  
Vesna Najfeld ◽  
George F. Atweh
Keyword(s):  
Flow Cytometry ◽  
Conflicts Of Interest ◽  
Ex Vivo ◽  
Critical Role ◽  
Regulatory Protein ◽  
Active Form ◽  
Fish Analysis ◽  
Ploidy Levels ◽  
Significant Difference

Abstract Abstract 4591 Megakaryopoiesis is a complex process in which hematopoietic progenitor cells proliferate and acquire megakaryocyte (MK)-specific markers then undergo polyploidization (i.e. acquisition of DNA content >2n) and cytoplasmic maturation, and start producing platelets. Polyploidization and platelet formation are highly dependent on microtubule (MT) function. To become polyploid, MK undergo abortive mitosis that is mediated by a mitotic spindle that consists of MT. Mature polyploid MK extend cytoplasmic extensions (i.e. proplatelets) into the vascular space and release platelets into the circulation. MT provide the structural scaffold for the proplatelets and mediate the transport of organelles and specific granules into nascent platelets. Despite the critical role of MT in MK biology, the regulation of MT in MK is poorly defined. Stathmin (STMN1) is a cytosolic phosphoprotein whose major function is to regulate MT function by promoting their depolymerization. We had previously shown that STMN1 is expressed at high levels early during megakaryopoiesis and is downregulated later during MK maturation. We also showed that inhibition of STMN1 expression increased ploidy while its overexpression decreased ploidy of MK-like cell lines. Thus, we hypothesized that the dynamic regulation of STMN1 expression may be necessary for megakaryopoiesis and that perturbing its expression may impair MK polyploidization and platelet production. To test this hypothesis, we developed feline immunodeficiency virus (FIV)-based lentiviruses that express STMN1 to investigate the effects of overexpression in primary MK. Since the depolymerizing activity of STMN1 can be inactivated by a variety of cellular kinases, we generated a STMN1 vectors that expresses wild-type (WT) and another that expresses a contitutively active phosphorylation-deficient mutant of STMN1 (MT). We also developed a vector that expresses GFP as a negative control. Human MK generated ex vivo in liquid culture from CD34+ cells were infected with these different lentiviruses. After ectopic STMN1 expression by RT-PCR and flow cytometry was confirmed, MK differentiation was assessed in the presence or absence of STMN1 overexpression. Uninfected MK and MK infected with GFP lentiviruses differentiated and matured into large, easily recognizable cells with typical nuclear morphology and expressed similar levels of CD41 and CD42b by flow cytometry. The numbers of MK generated in the presence of WT-STMN1 expressing lentiviruses was similar to that generated in the cultures infected with control lentiviruses, while the number of MK generated in the presence of phosphorylation-deficient MT-STMN1 was drasticaly reduced. Similarly, the numbers of CD41+ and CD42b+ MK generated in the presence of MT-STMN1 was reduced two and three times, respectively, suggesting that overexpression of a contitutively active form of STMN1 prevents MK differentiation and maturation. We then evaluated the effects of STMN1 overexpression on MK polyploidization by determining the number X and Y chromosomes by FISH analysis. While a normal diploid cell has one copy of each chromosome, cells with ploidy levels of 4N, 8N and 16N will have 2, 4 and 8 copies, respectively. There was no significant difference between the fraction of polyploid MK infected with control-GFP and those infected with WT-STMN1 lentiviruses. In contrast, the fraction of polyploid MK infected with MT-STMN1 lentiviruses was reduced by approximately 50%, suggesting that STMN1 overexpression impairs the ability of MK to become polyploid. In conclusion, we demonstrated that perturbing the normal downregulation of STMN1 in primary human MK impairs differentiation and polyploidization. Since STMN1 is expressesd at extremely high levels in a variety of human leukemias, we have started assessing STMN1 expression expression in patients with hematological malignancies characterized by striking abnormalities in their MK lineage. Such studies might validate the role of MT regulation in MK biology in vivo and support the development of potential therapeutic strategies to target MT and/or STMN1 function in MK and platelet disorders. Disclosures: No relevant conflicts of interest to declare.

Restoration of Barrier Function in Injured Intestinal Mucosa

2007 ◽  
Vol 87 (2) ◽  
pp. 545-564 ◽  
Author(s):  
Anthony T. Blikslager ◽  
Adam J. Moeser ◽  
Jody L. Gookin ◽  
Samuel L. Jones ◽  
Jack Odle
Keyword(s):  
Small Intestine ◽  
Basement Membrane ◽  
Barrier Function ◽  
Ex Vivo ◽  
Critical Role ◽  
Acute Injury ◽  
Epithelial Basement Membrane ◽  
Mammalian Tissues ◽  
Epithelial Basement

Mucosal repair is a complex event that immediately follows acute injury induced by ischemia and noxious luminal contents such as bile. In the small intestine, villous contraction is the initial phase of repair and is initiated by myofibroblasts that reside immediately beneath the epithelial basement membrane. Subsequent events include crawling of healthy epithelium adjacent to the wound, referred to as restitution. This is a highly regulated event involving signaling via basement membrane integrins by molecules such as focal adhesion kinase and growth factors. Interestingly, however, ex vivo studies of mammalian small intestine have revealed the importance of closure of the interepithelial tight junctions and the paracellular space. The critical role of tight junction closure is underscored by the prominent contribution of the paracellular space to measures of barrier function such as transepithelial electrical resistance. Additional roles are played by subepithelial cell populations, including neutrophils, related to their role in innate immunity. The net result of reparative mechanisms is remarkably rapid closure of mucosal wounds in mammalian tissues to prevent the onset of sepsis.

scholarly journals Adrenergic/Cholinergic Immunomodulation in the Rat Model—In VivoVeritas?

1998 ◽  
Vol 6 (3-4) ◽  
pp. 245-252 ◽  
Author(s):  
I. Rinner ◽  
P. Felsner ◽  
P. M. Liebmann ◽  
D. Hofer ◽  
A. Wölfler ◽  
...  
Keyword(s):  
Rat Model ◽  
Ex Vivo ◽  
Critical Role ◽  
Thymic Epithelial Cells ◽  
Cholinergic Pathways ◽  
Culture Supernatants ◽  
T Cell Maturation ◽  
The Brain

For several years, our group has been studying thein vivorole of adrenergic and cholinergic mechanisms in the immune-neuroendocrine dialogue in the rat model. The main results of these studies can be summarized as follows: (1) exogenous or endogenous catecholamines suppress PBL functions through alpha-2-receptor-mediated mechanisms, lymphocytes of the spleen are resistant to adrenergicin vivostimulation, (2) direct or indirect cholinergic treatment leads to enhancedex vivofunctions of splenic and thymic lymphocytes leaving PBL unaffected, (3) cholinergic pathways play a critical role in the “talking back” of the immune system to the brain, (4) acetylcholine inhibits apoptosis of thymocytes possibly via direct effects on thymic epithelial cells, and may thereby influence T-cell maturation, (5) lymphocytes of the various immunological compartments were found to be equipped with the key enzymes for the synthesis of both acetylcholine and norepinephrine, and to secrete these neurotransmitters in culture supernatants

scholarly journals High-Intensity Exercise Training Protects the Brain Against Autoimmune Neuroinflammation: Regulation of Microglial Redox and Pro-inflammatory Functions

2021 ◽  
Vol 15 ◽  
Author(s):  
Yifat Zaychik ◽  
Nina Fainstein ◽  
Olga Touloumi ◽  
Yehuda Goldberg ◽  
Liel Hamdi ◽  
...  
Keyword(s):  
T Cells ◽  
Exercise Training ◽  
High Intensity ◽  
Inflammatory Responses ◽  
Ex Vivo ◽  
Critical Role ◽  
Treadmill Running ◽  
Clinical Severity ◽  
Ros Formation

Background: Exercise training induces beneficial effects on neurodegenerative diseases, and specifically on multiple sclerosis (MS) and it’s model experimental autoimmune encephalomyelitis (EAE). However, it is unclear whether exercise training exerts direct protective effects on the central nervous system (CNS), nor are the mechanisms of neuroprotection fully understood. In this study, we investigated the direct neuroprotective effects of high-intensity continuous training (HICT) against the development of autoimmune neuroinflammation and the role of resident microglia.Methods: We used the transfer EAE model to examine the direct effects of training on the CNS. Healthy mice performed HICT by treadmill running, followed by injection of encephalitogenic proteolipid (PLP)-reactive T-cells to induce EAE. EAE severity was assessed clinically and pathologically. Brain microglia from sedentary (SED) and HICT healthy mice, as well as 5-days post EAE induction (before the onset of disease), were analyzed ex vivo for reactive oxygen species (ROS) and nitric oxide (NO) formation, mRNA expression of M1/M2 markers and neurotrophic factors, and secretion of cytokines and chemokines.Results: Transfer of encephalitogenic T-cells into HICT mice resulted in milder EAE, compared to sedentary mice, as indicated by reduced clinical severity, attenuated T-cell, and neurotoxic macrophage/microglial infiltration, and reduced loss of myelin and axons. In healthy mice, HICT reduced the number of resident microglia without affecting their profile. Isolated microglia from HICT mice after transfer of encephalitogenic T-cells exhibited reduced ROS formation and released less IL-6 and monocyte chemoattractant protein (MCP) in response to PLP-stimulation.Conclusions: These findings point to the critical role of training intensity in neuroprotection. HICT protects the CNS against autoimmune neuroinflammation by reducing microglial-derived ROS formation, neurotoxicity, and pro-inflammatory responses involved in the propagation of autoimmune neuroinflammation.

scholarly journals Complementary roles for parvalbumin and somatostatin interneurons in the generation of hippocampal gamma oscillations

2019 ◽  
Author(s):  
Pantelis Antonoudiou ◽  
Yu Lin Tan ◽  
Georgina Kontou ◽  
A. Louise Upton ◽  
Edward O. Mann
Keyword(s):  
Information Transfer ◽  
Ex Vivo ◽  
Critical Role ◽  
Gamma Oscillations ◽  
Synaptic Excitation ◽  
Gamma Frequency ◽  
Hippocampal Ca3 ◽  
Neuronal Encoding ◽  
Interneuron Activity

AbstractGamma-frequency oscillations (30-120 Hz) can be separated into fast (>60 Hz) and slow oscillations, with different roles in neuronal encoding and information transfer. While synaptic inhibition is important for synchronization across the gamma-frequency range, the role of distinct interneuronal subtypes in fast and slow gamma states remains unclear. Here, we used optogenetics to examine the involvement of parvalbumin (PV+) and somatostatin (SST+) expressing interneurons in gamma oscillations in the mouse hippocampal CA3 ex vivo. Disrupting either PV+ or STT+ interneuron activity, via either photo-inhibition or photo-excitation, led to a decrease in the power of cholinergically-induced slow gamma oscillations. Furthermore, photo-excitation of SST+ interneurons induced fast gamma oscillations, which depended on both synaptic excitation and inhibition. Our findings support a critical role for both PV+ and SST+ interneurons in slow hippocampal gamma oscillations, and further suggest that STT+ interneurons are capable of switching the network between slow and fast gamma states.

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