scholarly journals Immunoglobulin kappa light chain produced by cardiomyocytes and participates in maintaining intercalated disc integrity

2020 ◽  
Author(s):  
Xiaoyan Qiu ◽  
Zhu Zhu ◽  
Zhan Shi ◽  
Meng Zhang ◽  
Wenjing Zhou ◽  
...  
Keyword(s):  
B Cells ◽  
Light Chain ◽  
Cardiac Contractility ◽  
Conditional Knockout ◽  
Human Cardiomyocytes ◽  
Intercalated Discs ◽  
Mechanistic Investigation ◽  
And Migration ◽  
Almost All ◽  
And Function

Abstract It is widely accepted that immunoglobulins (Igs) are produced only by B cells and function as antibodies. However, growing evidence has proven that almost all non-B cells also produce Igs with nonconventional roles, such as promotion of cell survival, proliferation and migration. In this study, we identified Ig light chain (κ chain) expression in mouse and human cardiomyocytes, especially on intercalated discs (ICDs). Unexpectedly, conditional knockout (cKO) of Igκ in adult cardiomyocytes in mice resulted in significant hypotension, a rapid decrease in cardiac contractility and conduction defects. Histologically, Igκ knockout in mouse cardiomyocytes led to structural disruption of intercalated discs (ICDs) and loss of localization of adhesion-related N-cadherin and CX43 on ICDs. Mechanistic investigation indicated that Igκ can bind with plectin/desmoplakin, a complex that connects desmin and desmosomes and enhances the protein stability of plectin. In conclusion, Our findings identify Igκ expressed by cardiomyocytes as a new ICD-related molecule that participates in cardiomyocyte contraction and conduction by stabilizing plectin.

scholarly journals MiR 208a Regulates Mitochondrial Biogenesis in Metabolically Challenged Cardiomyocytes

Cells ◽  
2021 ◽  
Vol 10 (11) ◽  
pp. 3152
Author(s):  
Naveen Mekala ◽  
Jacob Kurdys ◽  
Alexis Paige Vicenze ◽  
Leana Rose Weiler ◽  
Carmen Avramut ◽  
...  
Keyword(s):  
Mitochondrial Biogenesis ◽  
Protein Trafficking ◽  
Cardiac Contractility ◽  
Metabolic Stress ◽  
Mitochondrial Translation ◽  
Human Cardiomyocytes ◽  
Bioenergetic Metabolism ◽  
Mitochondrial Defects ◽  
And Function ◽  
High Albumin

Metabolic syndrome increases the risk for cardiovascular disease including metabolic cardiomyopathy that may progress to heart failure. The decline in mitochondrial metabolism is considered a critical pathogenic mechanism that drives this progression. Considering its cardiac specificity, we hypothesized that miR 208a regulates the bioenergetic metabolism in human cardiomyocytes exposed to metabolic challenges. We screened in silico for potential miR 208a targets focusing on mitochondrial outcomes, and we found that mRNA species for mediator complex subunit 7, mitochondrial ribosomal protein 28, stanniocalcin 1, and Sortin nexin 10 are rescued by the CRISPR deletion of miR 208a in human SV40 cardiomyocytes exposed to metabolic challenges (high glucose and high albumin-bound palmitate). These mRNAs translate into proteins that are involved in nuclear transcription, mitochondrial translation, mitochondrial integrity, and protein trafficking. MiR 208a suppression prevented the decrease in myosin heavy chain α isoform induced by the metabolic stress suggesting protection against a decrease in cardiac contractility. MiR 208a deficiency opposed the decrease in the mitochondrial biogenesis signaling pathway, mtDNA, mitochondrial markers, and respiratory properties induced by metabolic challenges. The benefit of miR 208a suppression on mitochondrial function was canceled by the reinsertion of miR 208a. In summary, miR 208a regulates mitochondrial biogenesis and function in cardiomyocytes exposed to diabetic conditions. MiR 208a may be a therapeutic target to promote mitochondrial biogenesis in chronic diseases associated with mitochondrial defects.

scholarly journals Cochaperone Mzb1 is a key effector of Blimp1 in plasma cell differentiation and β1-integrin function

2018 ◽  
Vol 115 (41) ◽  
pp. E9630-E9639 ◽  
Author(s):  
Virginia Andreani ◽  
Senthilkumar Ramamoorthy ◽  
Abhinav Pandey ◽  
Ekaterina Lupar ◽  
Stephen L. Nutt ◽  
...  
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
Plasma Cell ◽  
Target Genes ◽  
Β1 Integrin ◽  
Plasma Cell Differentiation ◽  
And Migration ◽  
And Function ◽  
Antibody Secreting Cells

Plasma cell differentiation involves coordinated changes in gene expression and functional properties of B cells. Here, we study the role of Mzb1, a Grp94 cochaperone that is expressed in marginal zone (MZ) B cells and during the terminal differentiation of B cells to antibody-secreting cells. By analyzing Mzb1−/−Prdm1+/gfp mice, we find that Mzb1 is specifically required for the differentiation and function of antibody-secreting cells in a T cell-independent immune response. We find that Mzb1-deficiency mimics, in part, the phenotype of Blimp1 deficiency, including the impaired secretion of IgM and the deregulation of Blimp1 target genes. In addition, we find that Mzb1−/− plasmablasts show a reduced activation of β1-integrin, which contributes to the impaired plasmablast differentiation and migration of antibody-secreting cells to the bone marrow. Thus, Mzb1 function is required for multiple aspects of plasma cell differentiation.

SDF-1 Responsiveness Does Not Correlate With CXCR4 Expression Levels of Developing Human Bone Marrow B Cells

Blood ◽  
1999 ◽  
Vol 94 (9) ◽  
pp. 2990-2998 ◽  
Author(s):  
Marek Honczarenko ◽  
Raymond S. Douglas ◽  
Clarissa Mathias ◽  
Benhur Lee ◽  
Mariusz Z. Ratajczak ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Cxcr4 Expression ◽  
B Lymphopoiesis ◽  
Cell Stage ◽  
Immature B Cells ◽  
Stromal Cell Derived Factor ◽  
And Migration ◽  
And Function

Abstract Chemokines and their receptors are broadly expressed in different tissues and are involved in diverse biologic processes. Gene inactivation studies have shown that both stromal cell derived factor-1 (SDF-1) and chemokine receptor 4 (CXCR4) are essential for B lymphopoiesis. However, it is not yet clear by which mechanisms B lymphopoiesis is affected. In the present study, we have examined CXCR4 expression and function on primary B cells representing sequential stages of development (eg, pro-B, pre-B, immature, and mature B cells) in fetal and adult bone marrow. The expression of CXCR4 was observed to be sinusoidal. Expression was highest on pre-B cells, decreased as cells developed into immature B cells, and then increased again upon transition to the mature B-cell stage. The corresponding ligand SDF-1 was shown to trigger vigorous cell signaling and migration responses, which are restricted to early lineage B cells. The responsiveness to SDF-1 was markedly decreased for immature and mature B cells despite relatively high levels of CXCR4 expression. Thus, the diminished responsiveness to SDF-1 by more mature B cells was determined to be disproportionate to the level of CXCR4 expression. These findings raise the possibility that CXCR4 function is differentially controlled during B lymphopoiesis and may be relevant to the compartmentalization of B-cell precursors in the bone marrow.

scholarly journals Ikaros is absolutely required for pre-B cell differentiation by attenuating IL-7 signals

2013 ◽  
Vol 210 (13) ◽  
pp. 2823-2832 ◽  
Author(s):  
Beate Heizmann ◽  
Philippe Kastner ◽  
Susan Chan
Keyword(s):  
Cell Differentiation ◽  
B Cells ◽  
B Cell ◽  
Cell Receptor ◽  
B Cell Differentiation ◽  
B Cell Signaling ◽  
And Migration ◽  
And Function

Pre-B cell receptor (pre-BCR) signaling and migration from IL-7–rich environments cooperate to drive pre-B cell differentiation via transcriptional programs that remain unclear. We show that the Ikaros transcription factor is required for the differentiation of large pre-B to small pre-B cells. Mice deleted for Ikaros in pro/pre-B cells show a complete block of differentiation at the fraction C′ stage, and Ikaros-null pre-B cells cannot differentiate upon withdrawal of IL-7 in vitro. Restoration of Ikaros function rescues pre-B cell differentiation in vitro and in vivo and depends on DNA binding. Ikaros is required for the down-regulation of the pre-BCR, Igκ germline transcription, and Ig L chain recombination. Furthermore, Ikaros antagonizes the IL-7–dependent regulation of >3,000 genes, many of which are up- or down-regulated between fractions C′ and D. Affected genes include those important for survival, metabolism, B cell signaling, and function, as well as transcriptional regulators like Ebf1, Pax5, and the Foxo1 family. Our data thus identify Ikaros as a central regulator of IL-7 signaling and pre-B cell development.

SDF-1 Responsiveness Does Not Correlate With CXCR4 Expression Levels of Developing Human Bone Marrow B Cells

Blood ◽  
1999 ◽  
Vol 94 (9) ◽  
pp. 2990-2998 ◽  
Author(s):  
Marek Honczarenko ◽  
Raymond S. Douglas ◽  
Clarissa Mathias ◽  
Benhur Lee ◽  
Mariusz Z. Ratajczak ◽  
...  
Keyword(s):  
Bone Marrow ◽  
B Cells ◽  
B Cell ◽  
Cxcr4 Expression ◽  
B Lymphopoiesis ◽  
Cell Stage ◽  
Immature B Cells ◽  
Stromal Cell Derived Factor ◽  
And Migration ◽  
And Function

Chemokines and their receptors are broadly expressed in different tissues and are involved in diverse biologic processes. Gene inactivation studies have shown that both stromal cell derived factor-1 (SDF-1) and chemokine receptor 4 (CXCR4) are essential for B lymphopoiesis. However, it is not yet clear by which mechanisms B lymphopoiesis is affected. In the present study, we have examined CXCR4 expression and function on primary B cells representing sequential stages of development (eg, pro-B, pre-B, immature, and mature B cells) in fetal and adult bone marrow. The expression of CXCR4 was observed to be sinusoidal. Expression was highest on pre-B cells, decreased as cells developed into immature B cells, and then increased again upon transition to the mature B-cell stage. The corresponding ligand SDF-1 was shown to trigger vigorous cell signaling and migration responses, which are restricted to early lineage B cells. The responsiveness to SDF-1 was markedly decreased for immature and mature B cells despite relatively high levels of CXCR4 expression. Thus, the diminished responsiveness to SDF-1 by more mature B cells was determined to be disproportionate to the level of CXCR4 expression. These findings raise the possibility that CXCR4 function is differentially controlled during B lymphopoiesis and may be relevant to the compartmentalization of B-cell precursors in the bone marrow.

Stratigraphic Intervals for Oil and Tar Sand Deposits in the Uinta Basin, Utah

2017 ◽  
Vol 54 (4) ◽  
pp. 227-264
Author(s):  
Ronald Johnson ◽  
Justin Birdwell ◽  
Paul Lillis
Keyword(s):  
Brackish Water ◽  
Source Rocks ◽  
Uinta Basin ◽  
Green River ◽  
Reservoir Rocks ◽  
Stratigraphic Framework ◽  
Two Samples ◽  
The Rich ◽  
And Migration ◽  
Almost All

To better understand oil and bitumen generation and migration in the Paleogene lacustrine source rocks of the Uinta Basin, Utah, analyses of 182 oil samples and tar-impregnated intervals from 82 core holes were incorporated into a well-established stratigraphic framework for the basin. The oil samples are from the U.S. Geological Survey Energy Resources Program Geochemistry Laboratory Database; the tar-impregnated intervals are from core holes drilled at the Sunnyside and P.R. Spring-Hill Creek tar sands deposits. The stratigraphic framework includes transgressive and regressive phases of the early freshwater to near freshwater lacustrine interval of Lake Uinta and the rich and lean zone architecture developed for the later brackish-to-hypersaline stages of the lake. Two types of lacustrine-sourced oil are currently recognized in the Uinta Basin: (1) Green River A oils, with high wax and low β-carotane contents thought to be generated by source rocks in the fresh-to-brackish water lacustrine interval, and (2) much less common Green River B oils, an immature asphaltic oil with high β-carotane content thought to be generated by marginally mature to mature source rocks in the hypersaline lacustrine interval. Almost all oil samples from reservoir rocks in the fresh-to-brackish water interval are Green River A oils; however four samples of Green River A oils were present in the hypersaline interval, which likely indicates vertical migration. In addition, two samples of Green River B oil are from intervals that were assumed to contain only Green River A oil. Tar sand at the P.R. Spring-Hill Creek deposit are restricted to marginal lacustrine and fluvial sandstones deposited during the hypersaline phase of Lake Uinta, suggesting a genetic relationship to Green River B oils. Tar sand at the Sunnyside deposit, in contrast, occur in marginal lacustrine and alluvial sandstones deposited from the early fresh to nearly freshwater phase of Lake Uinta through the hypersaline phase. The Sunnyside deposit occurs in an area with structural dips that range from 7 to 14 degrees, and it is possible that some tar migrated stratigraphically down section.

Inactivation of Nf-κb Pathway by Taxifolin Attenuates Sepsis-Induced Acute Lung Injury

2019 ◽  
Vol 18 (2) ◽  
pp. 176-182
Author(s):  
Chen Weiyan ◽  
Deng Wujian ◽  
Chen Songwei
Keyword(s):  
Acute Lung Injury ◽  
B Cells ◽  
Lung Injury ◽  
Signaling Pathway ◽  
Light Chain ◽  
Cecal Ligation ◽  
Nuclear Factor ◽  
Kappa Light Chain ◽  
Cecal Ligation And Puncture ◽  
Light Chain Enhancer

Acute lung injury is a clinical syndrome consisting of a wide range of acute hypoxemic respiratory failure disorders. Sepsis is a serious complication caused by an excessive immune response to pathogen-induced infections, which has become a major predisposing factor for acute lung injury. Taxifolin is a natural flavonoid that shows diverse therapeutic benefits in inflammation- and oxidative stress-related diseases. In this study, we investigated the role of taxifolin in a mouse model of cecal ligation and puncture-induced sepsis. Cecal ligation and puncture-operated mice presented damaged alveolar structures, thickened alveolar walls, edematous septa, and hemorrhage compared to sham-treated controls. Cecal ligation and puncture mice also showed increased wet-to-dry (W/D) lung weight ratio and elevated total protein concentration and lactate dehydrogenase level in bronchoalveolar lavage fluid. Taxifolin treatment protected animals against sepsis-induced pulmonary damage and edema. Septic mice presented compromised antioxidant capacity, whereas the administration of taxifolin prior to cecal ligation and puncture surgery decreased malondialdehyde concentration and enhanced the levels of reduced glutathione and superoxide dismutase in mice with sepsis-induced acute lung injury. Moreover, cecal ligation and puncture-operated mice showed markedly higher levels of proinflammatory cytokines relative to sham-operated group, while taxifolin treatment effectively mitigated sepsis-induced inflammation in mouse lungs. Further investigation revealed that taxifolin suppressed the activation of the nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathway in cecal ligation and puncture-challenged mice by regulating the phosphorylation of p65 and IκBα. In conclusion, our study showed that taxifolin alleviated sepsis-induced acute lung injury via the inhibition of nuclear factor kappa-light-chain-enhancer of activated B cells signaling pathway, suggesting the therapeutic potential of taxifolin in the treatment sepsis-induced acute lung injury.

scholarly journals Hide and seek: interplay between influenza viruses and B cells

2020 ◽  
Vol 32 (9) ◽  
pp. 605-611 ◽  
Author(s):  
Masayuki Kuraoka ◽  
Yu Adachi ◽  
Yoshimasa Takahashi
Keyword(s):  
B Cells ◽  
B Cell ◽  
Surface Protein ◽  
Influenza Viruses ◽  
Influenza Vaccines ◽  
Native Structure ◽  
Humoral Immune ◽  
Protective Antibodies ◽  
Major Surface ◽  
And Function

Abstract Influenza virus constantly acquires genetic mutations/reassortment in the major surface protein, hemagglutinin (HA), resulting in the generation of strains with antigenic variations. There are, however, HA epitopes that are conserved across influenza viruses and are targeted by broadly protective antibodies. A goal for the next-generation influenza vaccines is to stimulate B-cell responses against such conserved epitopes in order to provide broad protection against divergent influenza viruses. Broadly protective B cells, however, are not easily activated by HA antigens with native structure, because the virus has multiple strategies to escape from the humoral immune responses directed to the conserved epitopes. One such strategy is to hide the conserved epitopes from the B-cell surveillance by steric hindrance. Technical advancement in the analysis of the human B-cell antigen receptor (BCR) repertoire has dissected the BCRs to HA epitopes that are hidden in the native structure but are targeted by broadly protective antibodies. We describe here the characterization and function of broadly protective antibodies and strategies that enable B cells to seek these hidden epitopes, with potential implications for the development of universal influenza vaccines.

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