Poly-L-Lysine Induces Fibrosis on Alginate Microcapsules via the Induction of Cytokines

2001 ◽  
Vol 10 (3) ◽  
pp. 263-275 ◽  
Author(s):  
Berit L. Strand ◽  
Liv Ryan ◽  
Peter In't Veld ◽  
Bård Kulseng ◽  
Anne Mari Rokstad ◽  
...  
Keyword(s):  
Lipid A ◽  
Kinase Inhibitor ◽  
Inflammatory Responses ◽  
Type I Diabetes ◽  
Annexin V ◽  
Cell Types ◽  
P38 Map Kinase ◽  
Common Element ◽  
Type I ◽  
Inflammatory Reactions

Alginate – poly-l-lysine (PLL) microcapsules can be used for transplantation of insulin-producing cells for treatment of type I diabetes. In this work we wanted to study the inflammatory reactions against implanted microcapsules due to PLL. We have seen that by reducing the PLL layer, less overgrowth of the capsule is obtained. By incubating different cell types with PLL and afterwards measuring cell viability with MTT, we found massive cell death at concentrations of PLL higher than 10 μg/ml. Staining with annexin V and propidium iodide showed that PLL induced necrosis but not apoptosis. The proinflammatory cytokine, tumor necrosis factor (TNF), was detected in supernatants from monocytes stimulated with PLL. The TNF response was partly inhibited with antibodies against CD14, which is a well-known receptor for lipopolysaccharide (LPS). Bactericidal permeability increasing protein (BPI) and a lipid A analogue (B-975), which both inhibit LPS, did not inhibit PLL from stimulating monocytes to TNF production. This indicates that PLL and LPS bind to different sites on monocytes, but because they both are inhibited by a p38 MAP kinase inhibitor, they seem to have a common element in the signal transducing pathway. These results suggest that PLL may provoke inflammatory responses either directly or indirectly through its necrosis-inducing abilities. By combining soluble PLL and alginate both the toxic and TNF-inducing effects of PLL were reduced. The implications of these data are to use alginate microcapsules with low amounts of PLL for transplantation purposes.

Inhibition of monocyte-derived inflammatory cytokines by IL-25 occurs via p38 Map kinase–dependent induction of Socs-3

Blood ◽  
2009 ◽  
Vol 113 (15) ◽  
pp. 3512-3519 ◽  
Author(s):  
Roberta Caruso ◽  
Carmine Stolfi ◽  
Massimiliano Sarra ◽  
Angelamaria Rizzo ◽  
Massimo C. Fantini ◽  
...  
Keyword(s):  
Map Kinase ◽  
Inflammatory Cytokines ◽  
Inflammatory Responses ◽  
Human Peripheral Blood ◽  
Serum Levels ◽  
Cell Types ◽  
P38 Map Kinase ◽  
Negative Regulator ◽  
Therapeutic Implications

Abstract IL-25, a member of the IL-17 cytokine family, is known to enhance Th2-like responses associated with increased serum levels of IgE, IgG1, IgA, blood eosinophilia, and eosinophilic infiltrates in various tissues. However, IL-25 also abrogates inflammatory responses driven by Th17 cells. However, the cell types that respond to IL-25 and the mechanisms by which IL-25 differentially regulates immune reactions are not well explored. To identify potential targets of IL-25, we initially examined IL-25 receptor (IL-25R) in human peripheral blood cells. IL-25R was predominantly expressed by CD14+ cells. We next assessed the functional role of IL-25 in modulating the response of CD14+ cells to various inflammatory signals. CD14+ cells responded to IL-25 by down-regulating the synthesis of inflammatory cytokines induced by toll-like receptor (TLR) ligands and inflammatory cytokines. Inhibition of cytokine response by IL-25 occurred via a p38 Map kinase–driven Socs-3–dependent mechanism. In vivo, IL-25 inhibited monocyte-derived cytokines and protected against LPS-induced lethal endotoxemia in mice. These data indicate that IL-25 is a negative regulator of monocyte proinflammatory cytokine responses, which may have therapeutic implications.

scholarly journals Triggering of Suicidal Erythrocyte Death by Ruxolitinib

2015 ◽  
Vol 37 (2) ◽  
pp. 768-778 ◽  
Author(s):  
Marilena Briglia ◽  
Antonella Fazio ◽  
Caterina Faggio ◽  
Stefan Laufer ◽  
Kousi Alzoubi ◽  
...  
Keyword(s):  
Cell Membrane ◽  
Map Kinase ◽  
Kinase Inhibitor ◽  
Myeloproliferative Neoplasm ◽  
Annexin V ◽  
P38 Map Kinase ◽  
Cell Shrinkage ◽  
Forward Scatter ◽  
Mitogen Activated Protein ◽  
Suicidal Death

Background/Aims: The JAK1/JAK2 tyrosine kinase inhibitor ruxolitinib is widely used for the treatment of myeloproliferative neoplasm-associated myelofibrosis and other malignancies. Most important side effects include anemia. A common cause of anemia is accelerated suicidal death of erythrocytes or eryptosis, which is characterized by cell shrinkage and cell membrane scrambling with phosphatidylserine translocation to the erythrocyte surface. Mechanisms contributing to the triggering of eryptosis include oxidative stress, Ca2+ entry with increase of cytosolic Ca2+ activity ([Ca2+]i), and activation of distinct kinases, such as p38 mitogen activated protein (MAP) kinase. The present study explored whether and how ruxolitinib induces eryptosis. Methods: Phosphatidylserine exposure at the cell surface was estimated from annexin-V-binding, cell volume from forward scatter, hemolysis from hemoglobin release, [Ca2+]i from Fluo3-fluorescence, and ROS formation from DCFDA dependent fluorescence. Results: A 48 hours exposure of human erythrocytes to ruxolitinib (25 µM) significantly increased the percentage of annexin-V-binding cells and significantly decreased forward scatter. Ruxolitinib did not significantly modify Fluo3-fluorescence and DCFDA fluorescence and the effect of ruxolitinib on annexin-V-binding was not significantly modified by removal of extracellular Ca2+. The effect of ruxolitinib on annexin-V-binding was, however, significantly blunted by the p38 MAP kinase inhibitor SB203580 and virtually abolished by the p38 MAP kinase inhibitor skepinone. Conclusion: Ruxolitinib triggers cell shrinkage and phospholipid scrambling of the erythrocyte cell membrane, an effect in part requiring p38 MAP kinase activity.

scholarly journals The transcription factor NFAT5 limits infection-induced type I interferon responses

2019 ◽  
Vol 217 (3) ◽  
Author(s):  
Hector Huerga Encabo ◽  
Laia Traveset ◽  
Jordi Argilaguet ◽  
Ana Angulo ◽  
Estanislao Nistal-Villán ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Type I Interferon ◽  
Poly I:C ◽  
Type I ◽  
Hematopoietic Stem ◽  
Inflammatory Reactions ◽  
Conserved Sequence ◽  
Evolutionarily Conserved ◽  
And Function ◽  
Interferon Responses

Type I interferon (IFN-I) provides effective antiviral immunity but can exacerbate harmful inflammatory reactions and cause hematopoietic stem cell (HSC) exhaustion; therefore, IFN-I expression must be tightly controlled. While signaling mechanisms that limit IFN-I induction and function have been extensively studied, less is known about transcriptional repressors acting directly on IFN-I regulatory regions. We show that NFAT5, an activator of macrophage pro-inflammatory responses, represses Toll-like receptor 3 and virus-induced expression of IFN-I in macrophages and dendritic cells. Mice lacking NFAT5 exhibit increased IFN-I production and better control of viral burden upon LCMV infection but show exacerbated HSC activation under systemic poly(I:C)-induced inflammation. We identify IFNβ as a primary target repressed by NFAT5, which opposes the master IFN-I inducer IRF3 by binding to an evolutionarily conserved sequence in the IFNB1 enhanceosome that overlaps a key IRF site. These findings illustrate how IFN-I responses are balanced by simultaneously opposing transcription factors.

scholarly journals CD200/CD200R Paired Potent Inhibitory Molecules Regulating Immune and Inflammatory Responses; part I: CD200/CD200R Structure, Activation, and Function

2012 ◽  
Vol 55 (1) ◽  
pp. 12-17 ◽  
Author(s):  
Drahomíra Holmannová ◽  
Martina Koláčková ◽  
Kateřina Kondělková ◽  
Pavel Kuneš ◽  
Jan Krejsek ◽  
...  
Keyword(s):  
Inflammatory Responses ◽  
Fetal Loss ◽  
Cell Types ◽  
Lymphoid Cells ◽  
Type I ◽  
Membrane Glycoproteins ◽  
Treg Subset ◽  
And Function ◽  
Inhibitory Molecules ◽  
Domain V

CD200/CD200R are highly conserved type I paired membrane glycoproteins that belong to the Ig superfamily containing a two immunoglobulin‑like domain (V, C). CD200 is broadly distributed in a variety of cell types, whereas CD200R is primarily expressed in myeloid and lymphoid cells. They fulfill multiple functions in regulating inflammation. The interaction between CD200/CD200R results in activation of the intracellular inhibitory pathway with RasGAP recruitment and thus contributes to effector cell inhibition. It was confirmed that the CD200R activation stimulates the differentiation of T cells to the Treg subset, upregulates indoleamine 2,3‑dioxygenase activity, modulates cytokine environment from a Th1 to a Th2 pattern, and facilitates an antiinflammatory IL‑10 and TGF‑β synthesis. CD200/CD200R are required for maintaining self‑tolerance. Many studies have demonstrated the importance of CD200 in controlling autoimmunity, inflammation, the development and spread of cancer, hypersensitivity, and spontaneous fetal loss.

scholarly journals Sulfatides are endogenous ligands for the TLR4–MD-2 complex

2021 ◽  
Vol 118 (30) ◽  
pp. e2105316118
Author(s):  
Lijing Su ◽  
Muhammad Athamna ◽  
Ying Wang ◽  
Junmei Wang ◽  
Marina Freudenberg ◽  
...  
Keyword(s):  
Lipid A ◽  
Inflammatory Responses ◽  
Receptor Activation ◽  
Sterile Inflammation ◽  
Human Macrophage ◽  
Type I ◽  
Endogenous Ligands ◽  
Limited Length ◽  
Factor Α ◽  
Myeloid Differentiation Factor

Many endogenous molecules, mostly proteins, purportedly activate the Toll-like receptor 4 (TLR4)–myeloid differentiation factor-2 (MD-2) complex, the innate immune receptor for lipopolysaccharide (LPS) derived from gram-negative bacteria. However, there is no structural evidence supporting direct TLR4–MD-2 activation by endogenous ligands. Sulfatides (3-O-sulfogalactosylceramides) are natural, abundant sulfated glycolipids that have variously been shown to initiate or suppress inflammatory responses. We show here that short fatty acid (FA) chain sulfatides directly activate mouse TLR4–MD-2 independent of CD14, trigger MyD88- and TRIF-dependent signaling, and stimulate tumor necrosis factor α (TNFα) and type I interferon (IFN) production in mouse macrophages. In contrast to the agonist activity toward the mouse receptor, the tested sulfatides antagonize TLR4–MD-2 activation by LPS in human macrophage-like cells. The agonistic and antagonistic activities of sulfatides require the presence of the sulfate group and are inversely related to the FA chain length. The crystal structure of mouse TLR4–MD-2 in complex with C16-sulfatide revealed that three C16-sulfatide molecules bound to the MD-2 hydrophobic pocket and induced an active dimer conformation of the receptor complex similar to that induced by LPS or lipid A. The three C16-sulfatide molecules partially mimicked the detailed interactions of lipid A to achieve receptor activation. Our results suggest that sulfatides may mediate sterile inflammation or suppress LPS-stimulated inflammation, and that additional endogenous negatively charged lipids with up to six lipid chains of limited length might also bind to TLR4–MD-2 and activate or inhibit this complex.

scholarly journals Natural Killer Cells as Key Mediators in Type I Diabetes Immunopathology

2021 ◽  
Vol 12 ◽  
Author(s):  
Graeme Gardner ◽  
Christopher A. Fraker
Keyword(s):  
Immune System ◽  
Viral Infection ◽  
Natural Killer ◽  
Immune Cell ◽  
Nk Cell ◽  
Type I Diabetes ◽  
Adaptive Immune System ◽  
Cell Types ◽  
Underlying Mechanism ◽  
Type I

The immunopathology of type I diabetes (T1D) presents a complicated case in part because of the multifactorial origin of this disease. Typically, T1D is thought to occur as a result of autoimmunity toward islets of Langerhans, resulting in the destruction of insulin-producing cells (β cells) and thus lifelong reliance on exogenous insulin. However, that explanation obscures much of the underlying mechanism, and the actual precipitating events along with the associated actors (latent viral infection, diverse immune cell types and their roles) are not completely understood. Notably, there is a malfunctioning in the regulation of cytotoxic CD8+ T cells that target endocrine cells through antigen-mediated attack. Further examination has revealed the likelihood of an imbalance in distinct subpopulations of tolerogenic and cytotoxic natural killer (NK) cells that may be the catalyst of adaptive immune system malfunction. The contributions of components outside the immune system, including environmental factors such as chronic viral infection also need more consideration, and much of the recent literature investigating the origins of this disease have focused on these factors. In this review, the details of the immunopathology of T1D regarding NK cell disfunction is discussed, along with how those mechanisms stand within the context of general autoimmune disorders. Finally, the rarer cases of latent autoimmune, COVID-19 (viral), and immune checkpoint inhibitor (ICI) induced diabetes are discussed as their exceptional pathology offers insight into the evolution of the disease as a whole.

Single-Cell Sequencing Reveals the Relationship between Phenotypes and Genotypes of Klinefelter Syndrome

2019 ◽  
Vol 159 (2) ◽  
pp. 55-65 ◽  
Author(s):  
Xiaohui Liu ◽  
Donge Tang ◽  
Fengping Zheng ◽  
Yong Xu ◽  
Hui Guo ◽  
...  
Keyword(s):  
Single Cell ◽  
Klinefelter Syndrome ◽  
Type I Diabetes ◽  
Expression Patterns ◽  
Cell Types ◽  
Marker Genes ◽  
Type I ◽  
Single Cell Sequencing ◽  
The Relationship ◽  
Chinese Male

Klinefelter syndrome (KS) is one of the most common congenital disorders of male infertility. Given its high heterogeneity in clinical and genetic presentation, the relationship between transcriptome, clinical phenotype, and associated co-morbidities seen in KS has not been fully clarified. Here, we report a 47,XXY Chinese male with infertility and analyzed the differences in gene expression patterns of peripheral blood mononuclear cells (PBMCs) with regard to a Chinese male and a female control with normal karyotype by single-cell sequencing. A total of 24,439 cells were analyzed and divided into 5 immune cell types (including B cells, T cells, macrophage cells, dendritic cells, and natural killer cells) according to marker genes. Using unsupervised dimensionality reduction and clustering algorithms, we identified molecularly distinct subpopulations of cells between the KS patient and both controls. Gene ontology enrichment analyses yielded terms associated with well-known comorbidities seen in KS as well as an affected immune system and type I diabetes mellitus. Based on our data, we identified several candidate genes which may be implicated in regulating the phenotype of KS. Overall, this analysis provides a comprehensive map of the cell types of PBMCs in a KS patient at the single-cell level, which will contribute to the prevention of comorbidity and improvement of the life quality of KS patients.

scholarly journals Fish Paralog Proteins RNASEK-a and -b Enhance Type I Interferon Secretion and Promote Apoptosis

2021 ◽  
Vol 12 ◽  
Author(s):  
Zhi-Chao Sun ◽  
Zeyin Jiang ◽  
Xiaowen Xu ◽  
Meifeng Li ◽  
Qing Zeng ◽  
...  
Keyword(s):  
Grass Carp ◽  
Viral Infections ◽  
Type I Interferon ◽  
Annexin V ◽  
Cell Types ◽  
Ctenopharyngodon Idella ◽  
Poly I:C ◽  
Immunofluorescent Staining ◽  
Type I ◽  
Multiple Cell

Type I interferon and apoptosis elicit multifaceted effects on host defense and various diseases, such as viral infections and cancers. However, the gene/protein network regulating type I interferon and apoptosis has not been elucidated completely. In this study, we selected grass carp (Ctenopharyngodon idella) as an experimental model to investigate the modulation of RNASEK on the secretion of type I interferon and apoptosis. We first cloned two paralogs RNASEK-a and -b in grass carp, defined three exons in each gene, and found the length of both coding regions is 306 bp with 73.27% of protein homology. The protein sequences of the two paralogs are highly conserved across species. Two proteins were mainly localized in early and late endosomes and endoplasmic reticulum. Further, quantitative real-time PCR demonstrated that dsRNA poly I:C and grass carp reovirus upregulated RNASEK-a and -b in grass carp cells and tissues. Overexpression of RNASEK-a and -b individually induced type I interferon expression and the phosphorylation of IRF3/IRF7 shown by Western blot and immunofluorescent staining, increased Bax/Bcl-2 mRNA ratio, DNA fragmentations, TUNEL-positive cells, and the proportion of Annexin V-positive signals in flow cytometry, and activated eIF2α, opposite to that observed when RNASEK-a and -b were knocked down in multiple cell types. Taken together, we claim for the first time that fish paralog proteins RNASEK-a and -b enhance type I interferon secretion and promote apoptosis, which may be involved in the phosphorylation of IRF3/IRF7 and eIF2α, respectively. Our study reveals a previously unrecognized role of RNASEK as a new positive regulator of type I interferon and apoptosis.

scholarly journals NOD Mice Are Defective in Proteasome Production and Activation of NF-κB

1999 ◽  
Vol 19 (12) ◽  
pp. 8646-8659 ◽  
Author(s):  
Takuma Hayashi ◽  
Denise Faustman
Keyword(s):  
Transcription Factor ◽  
Inflammatory Responses ◽  
Type I Diabetes ◽  
Nod Mice ◽  
Nod Mouse ◽  
Proteolytic Processing ◽  
Type I ◽  
Inhibitory Protein ◽  
Necrosis Factor Alpha ◽  
Mouse Splenocytes

ABSTRACT The nonobese diabetic (NOD) mouse is an animal model of human type I diabetes with a strong genetic component that maps to the major histocompatibility complex (MHC) of the genome. We have identified in NOD lymphocytes a specific proteasome defect that results from the lack of the LMP2 subunit. The pronounced proteasome defect results in defective production and activation of the transcription factor NF-κB, which plays an important role in immune and inflammatory responses as well as in preventing apoptosis induced by tumor necrosis factor alpha. The defect in proteasome function in NOD mouse splenocytes was evident from impaired NF-κB subunit p50 and p52 generation by proteolytic processing and impaired degradation of the NF-κB-inhibitory protein IκBα. An obligatory role of MHC-linked proteasome subunits in transcription factor processing and activation has been established in a spontaneous-disease model and mutant cells similarly lacking the MHC-encoded subunit. These data suggest that NOD proteasome dysfunction is due to a tissue- and developmental-stage-specific defect in expression of the MHC-linkedLmp2 gene, resulting in altered transcription factor NF-κB activity, and that this defect contributes to pathogenesis in NOD mice. These observations are consistent with the diverse symptomatology of type I diabetes and demonstrate clear sex-, tissue-, and age-specific differences in the expression of this error which parallel the initiation and disease course of insulin-dependent (type I) diabetes mellitus.

Intraperitoneal influx of neutrophils in response to IL-33 is mast cell–dependent

Blood ◽  
2013 ◽  
Vol 121 (3) ◽  
pp. 530-536 ◽  
Author(s):  
Mattias Enoksson ◽  
Christine Möller-Westerberg ◽  
Grzegorz Wicher ◽  
Padraic G. Fallon ◽  
Karin Forsberg-Nilsson ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Mast Cell ◽  
Mast Cells ◽  
Inflammatory Responses ◽  
Neutrophil Infiltration ◽  
Cell Types ◽  
Wild Type ◽  
Inflammatory Reactions ◽  
Neutrophil Response

Abstract IL-33 is a recently discovered cytokine involved in induction of Th2 responses and functions as an alarmin. Despite numerous recent studies targeting IL-33, its role in vivo is incompletely understood. Here we investigated inflammatory responses to intraperitoneal IL-33 injections in wild-type and mast cell–deficient mice. We found that wild-type mice, but not mast cell–deficient Wsh/Wsh mice, respond to IL-33 treatment with neutrophil infiltration to the peritoneum, whereas other investigated cell types remained unchanged. In Wsh/Wsh mice, the IL-33–induced innate neutrophil response could be rescued by local reconstitution with wild-type but not with T1/ST2−/− mast cells, demonstrating a mast cell–dependent mechanism. Furthermore, we found this mechanism to be partially dependent on mast cell–derived TNF, as we observed reduced neutrophil infiltration in Wsh/Wsh mice reconstituted with TNF−/− bone marrow–derived mast cells compared with those reconstituted with wild-type bone marrow–derived mast cells. In agreement with our in vivo findings, we demonstrate that humanneutrophils migrate toward the supernatant of IL-33–treated human mast cells. Taken together, our findings reveal that IL-33 activates mast cells in vivo to recruit neutrophils, a mechanism dependent on IL-33R expression on peritoneal mast cells. Mast cells activated in vivo by IL-33 probably play an important role in inflammatory reactions.

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