bluuebunny/crossref_metadata_2025_split huggingface dataset:
REV-ERB mediated regulation of dendritic cell maturation and function
Authors: Amir Mohammed , Campbell Sean , Kamenecka Theodore , Solt Laura A 
Published: January 2023

Abstract
The REV-ERBs (REV-ERBα and REV-ERBβ) are members of the nuclear receptor superfamily of ligand-regulated transcription factors and owing to their ability to recruit corepressor, act as transcriptional repressors. The REV-ERBs have well-established roles in regulating various physiological functions, including metabolism and the circadian rhythm. However, little is known about their roles in the immune system. While some evidence exists suggesting the REV-ERBs, particularly REV-ERBα, regulates macrophage inflammatory responses, the REV-ERB’s role in regulating other cells of myeloid origin remains largely unknown.
Dendritic cells (DCs), like macrophages, are of myeloid origin and serve as the master regulator of immune responses by connecting microbial sensing and innate immunity to adaptive immune responses. Given the central role of DCs in regulating immune responses, we investigated if the REV-ERBs regulate DC maturation and function. We found that both REV-ERBα and REV-ERBβ expression is upregulated during the course of bone marrow derived dendritic cell (BMDCs) differentiation. BMDCs from REV-ERBα and REV-ERBβ deficient mice showed enhanced expression of maturation markers like CD86, MHCII, CD83 and proinflammatory cytokines. In contrast, treatment of BMDCs with a REV-ERB-specific agonist, SR9009, inhibited the expression of these maturation markers and proinflammatory cytokines. Our study suggests the REV-ERBs act as negative regulators of dendritic cell maturation and function thus pharmacological modulation of REV-ERB activity could be an attractive strategy in treating inflammatory diseases.
Method development for the analysis of PBMC-mediated killing of K562 cells by bovine colostrum and various fractions
Authors: Vieira-Brock Paula d , Andersen Anna , Vaughan Brent , Vollmer David 
Published: January 2023

Abstract

Background
Colostrum is the first milk that supplies newborns with immune supporting peptides. Due to its heterogeneous and variable characteristic, standardized assays for assessment of its biological activities are a challenge. Current set of studies were aimed to investigate the immune activity of bovine colostrum blends and different fractions as well as validate a method to assess variability across different lots.

Methods
Immune activity of a bovine colostrum blend and different fractions was evaluated by their ability to enhance PBMC-mediated killing of K562 cells. K562 cell killing was assessed by flow cytometry using DAPI. PBMCs derived from multiple healthy donors were initially investigated. Sample from the highest responder was used for subsequent studies. Different lots of product were assessed.

Results
Bovine colostrum blend and different fractions similarly reduced K562 cells number and these effects were generally greater than IL-2 control. Despite consistently effective at enhancing PBMCs-mediated K562 killing, the degree of the effect was significantly variable across different lots. These biological effects were dependable on the solubility of the product.

Conclusion
Assessment of PBMC-mediated killing of K562 cells by flow cytometry using DAPI is a reliable method for measuring immune activity of bovine colostrum and different fractions as long as product is well dissolved into solution and the same biological sample from a single donor is used for investigation of batch-to-batch variability.
Histamine-releasing factor (HRF) is a novel alarmin
Authors: Kasakura Kazumi , Kawakami Yu , Kawakami Yuko , Kawakami Toshiaki 
Published: January 2023

Abstract

Objective
We are investigating how HRF secretion is regulated during allergic conditions.

Results
HRF interacts with a subset of IgE molecules. HRF dimer and oligomers, but not monomer, enhance the antigen sensitivity and magnitude of IgE-dependent mast cell activation. We found that BEAS-2B human bronchial epithelial cells constitutively secrete various forms of HRF (monomer, disulfide-linked dimer/oligomers). Secretion of these forms of HRF was enhanced by allergens such as house dust mites (HDM). HDM-mediated HRF secretion was dramatically enhanced by epithelial-derived cytokines (IL-25, IL-33, TSLP), Th2 cytokines (IL-4, IL-5, IL-13), and proinflammatory cytokines (IL-1b, IL-6, TNF), although the cytokines alone had much less effects. Mechanical injury of BEAS-2B cells and its byproducts (i.e., adenosine and ATP) also enhanced HRF secretion. In contrast, papain and bromelain (occupational allergens) as well as uric acid (NLRP3 inflammasome activator) exhibited limited effects on HRF secretion. Several high-molecular-weight forms (≥150 kDa) of HRF were found in body fluids. Interestingly, rhinovirus infection in humans and nasal instillation of HDM in mice, conditions predisposing asthma exacerbation, induced secretion of these HRF forms into airways. These results suggest that disulfide-linked HRF dimer/oligomers are involved in asthma exacerbation.

Conclusion
HRF dimer/oligomers secreted by epithelial and other cells enhance allergic inflammation as a novel alarmin.
RNA-binding protein EWS, a novel modulator of LTβR signaling
Authors: Virgen-Slane Richard , Correa Ricardo G , Ramezani-Rad Parham , Rosa-Campos Alexandre , Li Jun , Ware Carl F. 
Published: January 2023

Abstract
Efficient immune responses depend on signaling networks coordinated by dynamic protein-protein interactions. Adaptor proteins, like TRAF3, participates in distinct signaling pathways critical for immune development and host defense. To identify distinct complexes of TRAF3 that may serve as important modulators, we carried out Affinity-Purification-Mass Spectrometry from different human immune cell lines. We identified a core group of cell line-independent protein-protein interactions and then used machine learning to infer distinct functional complexes. Our analysis revealed a unique, switch-like relationship between TRAF3, signaling molecule TRAF2, and RNA-binding protein EWS. With protein-binding experiments, we found that EWS associates with TRAF3 in the absence of TRAF2. Given that formation of the TRAF3:TRAF2 complex is a regulatory mechanism for some Tumor Necrosis Factor Receptor Superfamily members, we hypothesized that EWS may have a novel function downstream of these pathways. To test our hypothesis, we used LTβR as a prototype given its well-studied signaling through the TRAF3:TRAF2 complex. With endogenous proteins, we found that EWS associates with TRAF3 in unstimulated cells; however, dissociation occurs following LTβR stimulation. To infer a potential function of EWS for LTβR signaling, we carried out machine learning analysis of RNAseq expression data generated from unmodified fibroblasts, following LTβR stimulation. Our unsupervised analysis predicts a critical function for EWS in mRNA transport and expression of several NF-κB regulatory molecules. With RNAi, transcriptomics, and a NF-κB reporter system, we show that EWS is required for optimal activation of LTβR signaling.
Genomic Analysis Of Bone Marrow Progenitors During Viral Infection Reveals Novel Dendritic Cell Regulators
Authors: Jo Yeara , Zhang Kai , Wang Wei , Zuniga Elina 
Published: January 2023

Abstract
Dendritic cells (DC) play a central role in immune responses and can broadly subdivided into conventional (c) and plasmacytoid (p) DCs. We and others have described several adaptations of DCs and their progenitors during acute and chronic infections, including impaired DC development, maturation and altered cytokine production. To understand the underlying mechanisms we determined the transcriptional and chromatin landscapes of bone marrow (BM) DC progenitors from lymphocytic choriomeningitis virus (LCMV) infected mice, via RNA-Seq and ATAC-Seq, respectively. Initial analysis indicated that infection induced multiple alterations in gene signatures, including type-I-interferon signaling and metabolic pathways, as well as changes in chromatin accessibility, which were more enriched within intergenic regions. We next used the Taiji algorithm, which integrates chromatin accessibility and gene expression to assess the global importance of transcription factors (TFs) at the systems level. This analysis identified 11 known DC regulators and 24 TFs with no previous connection to DC biology. Knock-down experiments revealed that Glucocorticoid Modulatory Element Binding Protein 1 (Gmeb1), which was predicted to exhibit increased activity in progenitors from LCMV-infected mice, suppressed DC development and maturation. On the other hand, Zinc Finger Protein 524 (Zfp524), whose activity was predicted to be reduced in progenitors from LCMV-infected mice, promoted pDC cytokine production while inhibiting the same function in cDCs. These results highlight two novel TFs that regulate DC development and/or function, deepening our understanding of DC biology and providing potential new targets for DC-based immunotherapies.
Elucidation of long non-coding RNA Snhg7 functions in T Cells
Authors: Varney Melinda , McCall Jamie , Westfall Sydney , Blethen Kathryn , Martinez Ivan , Barnett John B 
Published: January 2023

Abstract
Long non-coding RNAs (lncRNAs) have emerged as important molecules involved in a vast number of biological processes, including transcriptional, prost-transcriptional, and epigenetic regulation. The lncRNA Small Nucleolar RNA Host Gene 7 (Snhg7) has been shown to function as a competing endogenous RNA by sequestering several microRNAs (miRNAs) including miR-34a and miR-216b. Interestingly, these specific miRNAs have been shown to target GalNac transferases in many cancers. Given that O-linked glycosylation contributes to T-cell maturation, trafficking, and survival, the objective of this study was to determine the importance of Snhg7 in T cell maturation through the regulation of GALNAc transferases via miRNA sequestration. We tested the hypothesis that Snhg7 functions to sequester miR-34a and miR-216b, thereby controlling the production of Polypeptide N-acetylgalactosaminyltransferase proteins GALNT7 and GALNT1 in T cells. Our data demonstrate that siRNA knockdown of Snhg7 in T cells leads to miR-34a- and miR-216b-dependent decreases in GALNT7 and GALNT1 protein expression, respectively. Though Snhg7 knockdown has inhibited proliferation in cancer cells lines, it increased proliferation of T cells in a Jurkat cell line in a miR-34a- and miR-216- independent manner. Surprisingly, Jurkat cells produce truncated O-glycans. These data suggests that O-glycosylation contributes to Snhg7-induced cell proliferation. Taken together, our data support the hypothesis that Snhg7 influences critical processes in T cell function and should be considered in future biomarkers of disease or novel therapeutic strategies. Supported by NIH grant ES023845.
NF-κB-targeted intervention of acetaminophen-induced acute liver injury by benzyl indanone
Authors: Song Jin Yong , Jung Da-Eun , Jung Sang-Jun , Han Sang-Bae , Kim Youngsoo 
Published: January 2023

Abstract
Acetaminophen (APAP, Paracetamol) is a worldwide analgesic ingredient. Acetaminophen overdose accounts for 46% of acute liver failure. The toxic mechanism of acetaminophen-induced liver injury (AILI) consists of two phases: early phase by APAP and late phase by Kupffer cell-mediated inflammation. N-acetyl cysteine, the therapeutic drug of AILI, is effective in early phase but not in late phase. Here, we focus on the innate immunosuppressant to improve AILI and demonstrate protective effect of benzyl indanone derivative on AILI. The survival rate of AILI was increased from 12% to 91% and serum levels of ALT, AST and total bilirubin was decreased by benzyl indanone derivatives. It was associated with decreased hepatic necrosis, DNA fragmentation, neutrophil infiltration and expression levels of pro-inflammatory cytokines and chemokines. We isolated hepatocyte and kupffer cell to determine molecular target of benzyl indanone derivative. Benzyl indanone derivative did not affect primary hepatic damage such as ROS production, JNK phosphorylation, mitochondrial membrane potential and cell death. Benzyl indanone derivative reduced NO production and pro-inflammatory cytokine/chemokine expression in Kupffer cell. Benzyl indanone derivative reduced DNA binding affinity and transcriptional activity of NF-κB but did not affact NF-κB phosphorylation and nuclear import. This study suggest that inhibition of NF-κB activity by benzyl indanone derivative improves AILI.
The cholesterol transporter ABCG1 modulates macrophage polarization in human monocyte-derived macrophages
Authors: Sag Duygu , Purcu Duygu Unuvar , Altunay Meltem 
Published: January 2023

Abstract
The ATP-binding Cassette Transporter G1 (ABCG1) promotes cholesterol efflux from cells and regulates intracellular cholesterol homeostasis. Recent studies have shown that in mice in the absence of ABCG1, macrophages shift from a tumor-promoting M2 phenotype to a tumor-fighting M1 phenotype within the tumor and suppress bladder cancer growth in vivo. Two important aspects of this effect are still unknown: (1) whether ABCG1-would also impact polarization of human macrophages, and (2) the underlying molecular mechanism of this effect. Here, we show that in human monocyte-derived macrophages the inhibition of ABCG1 by siRNA significantly increased the expression of the M1 markers IDO1, CXCL10, CD64 and TNF after LPS/IFNγ (M1) stimulation. In contrast, after IL-4 (M2) stimulation the expression of the M2 markers MRC1, TGM2 and CD163 was significantly reduced. These data indicate that ABCG1-deficiency promotes the polarization of macrophage to an M1 phenotype in human macrophages. To address the molecular mechanism, we analysed cell signalling in bone marrow-derived macrophages from Abcg1−/− mice. These macrophages displayed reduced levels of Akt activation after stimulation with LPS/IFNγ or IL4. In addition, while Abcg1−/− macrophages stimulated with LPS/IFNγ produced more TNF compared to WT macrophages, after treatment with an Akt activator the TNF-production of Abcg1−/− and WT macrophages was comparable. These data suggest that the M1 bias of Abcg1−/− macrophages is mediated through the Akt signalling pathway. In summary, these findings deepen our mechanistic understanding of the M1/M2 switch in macrophages and suggest that ABCG1 could be a potential new target to modulate macrophage polarization for cancer immunotherapy.
Sargassum horneri inhibits particulate matter-induced apoptotic cell death in splenocytes
Authors: Jee Youngheun , Kim Areum , Herath K.H.I.N.M , Kim Hyo Jin , Mihindukulasooriya S.P. , Ko Mi-Ok , Jeon You-Jin 
Published: January 2023

Abstract
Recently, with rapid industrialization, air pollution is a significant public health hazard, and particulate matters (PM), solid or liquid particles small enough to remain airborne, have emerged as the main culprit of it. For instance, exposure to PM is known to induce ROS production, DNA damage, and apoptosis. Sargassum horneri (S. horneri), an brown algae distributed in Korea and Japan, is rich in amino acids, vitamins and polysaccharides. Also, it has been reported to present interesting biological and pharmacological properties including antioxidant, anti-allergic and anti-inflammatory efficacy. The aim of the present study is to examine the cytoprotective effects of S. horneri against PM-induced immune cell death in mice. To identity cytotoxicity of S. horneri, we treated splenocytes with S. horneri alone and could not observe cytotoxicity in the concentrations tested. When we exposed splenocytes to PM with or without S. horneri (62.5–125 μg/ml), we found that S. horneri reduced cytotoxicity due to PM (3.9–1,000 μg/ml). S. horneri treated splenocytes also displayed enhanced proliferation compared to untreated control group. We observed that S. horneri not only decreased oxidative stress due to its notable oxidant scavenging capacity but also reduced PM-induced apoptotic fragments of splenocytes. After S. horneri treatment, cell deaths of PM-challenged splenocytes were decreased. Our results suggest that S. horneri can protect immune cells from PM exposure-induced oxidative stress and cell death. This research is a part of a project titled ‘Development of functional food products with natural materials derived from marine resources’, funded by the Ministry of Oceans and Fisheries, Korea in 2017 (Project NO. 20170285).
Structure of human ferroportin (SLC40A1) inferred from mass spectrometry restraints
Authors: Parry Christian , Vazquez-meves Guelaguetza , Ivanov Andrey , Lin Xionghao , Kumari Namita , Nekhai Sergei 
Published: January 2023

Abstract
Nearly all organisms require iron for red blood cell manufacture, respiration, metabolism and immunity, and as cofactor in several enzymes. Paradoxically, free iron is toxic from the production of reactive oxygen species which induce cellular injury and damage to DNA. It is essential that iron is tightly regulated. Ferroportin is the only known exporter of cellular iron in mammals. Its function and expression are tightly regulated by hepcidin. Carriers of ferroportin mutation Q248H show reduced sensitivity to hepcidin, have elevated iron stores and high HIV-1 viral load. In HIV-1 infection, there is marked alteration in iron balance indicated by high ferritin levels. As well, iron-regulating peptide hepcidin is greatly elevated. High iron stores correlate with high morbidity, increased opportunistic infections and faster progression to AIDS: high iron content in bone marrow macrophage parallels greater infection, immune dysfunction and poor prognosis. By contrast, other studies show that patients who were being treated for iron overload with iron chelators had delayed AIDS progression and longer survival. In spite of its importance little structural information is available on human ferroportin, and how iron is transported through ferroportin is not understood. We have built the structure of ferroportin using hybrid methods with restraints from mass spectrometry. Our model comprises 12 transmembrane helices. The iron binding site matches what is seen in crystal structures of distant orthologs. We are using this structure along with functional data to answer outstanding questions about the mechanism of ferroportin, iron transport and the importance of the Q248H mutation found in African and black American populations.
Immune Complex (ICs) generate PD1int CD4+ T cells which are Bcl6+IFN-γ+ unlike exhausted PD1high cells
Authors: Chauhan Anil K 
Published: January 2023

Abstract
PD1 is targeted for cancer therapy, however the mechanisms that drive its expression are poorly recognized. Role for Fc-receptors in CD4+ T-cells responses has been ignored in the last decade. We and others have now shown the activation induced expression of CD16a (FcγRIIIa) and CD32 (FcγRIIa) (doi:10389/fimmu.2018.02814). Three groups have now shown that CD32 expression in CD4+ T cells mark HIV-1 provirus enrichment. Thus, we examined whether immune complexes (ICs) by engaging CD16a play a role in PD1 expression and Tfh cell development.
Using flow cytometry, biochemical techniques and RNA-seq, we establish a new subset of CD4+ PD1intCD16a+ Tcells. These cells are present in vivo and can be generated in vitro upon IC signaling. These cells express Bcl6+ and produce IFN-γ, IL-17A, and IL-21. A second population of terminally exhausted PD1highCD16a−Bcl6− do not produce cytokines also exist. CD16a ligation by ICs generates CD4+ T effector cells and relocate endosomal NATLRs to the cell surface for joint signaling with FcRs (JI, 198: 4596, 2017).
CD16a signaling up-regulate Tfh transcription factors c-Maf, FOXO, Bcl6, also lincRNA and microRNA associated with TFH/T cell differentiation i.e. miR155, 17HG, 22 and HOTIP. Upregulation of IL-27 and ICOS via CD16a could induce c-Maf expression. CD16a signal in CD4+ T cells showed up-regulation of ubiquitination, heat shock proteins, proteasome assembly, GPCR signaling genes and 1139 genes from GO: 007062 category of extracellular exosomes.
Our findings establish a new mechanism that drives PD1 expression. Tfh cells are enriched in HIV-1 provirus and expression of FcRs in such cells suggest their role in viral enrichment. Does CD16a+ mark non-exhausted CD4+ Tfh cells remains an open question.
Activation of aryl hydrocarbon receptor with structurally diverse ligands represses class switch to immunoglobulin A
Authors: Costa Alex B , Hirsch Aspen L , DeKrey Gregory K 
Published: January 2023

Abstract
Activation of the aryl hydrocarbon receptor (AhR) with its prototypical agonist 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) represses activation-induced cytidine deaminase expression and B cell class switch recombination (CSR). Structurally diverse AhR agonists have been shown to have differing impacts on T cell differentiation. We hypothesized that AhR activation with structurally diverse agonists would have differential impacts on CSR in B cells. The following agonists were tested: the endogenous ligands cinnabarinic acid (CA), 5,11-dihydroindolo[3,2-b]carbazole-6-carboxaldehyde (FICZ), and kynurenine (Kyn); the pharmaceuticals omeprazole (Omep) and tamoxifen (Tam); and the dietary component indole-3-carbanol (I3C). Mouse splenic CD19+ B cells were cultured with LPS, α-IgD-dextran, and TGF-β1 to stimulate CSR to IgA. IgA expression was measured by flow cytometry. Relative to control cells (10.84% IgA+), exposure to CA, FICZ, I3C, Kyn, Omep, Tam, or TCDD significantly decreased the proportion of IgA+ cells (P &lt; 0.05) to 4.48%, 2.48%, 2.25%, 4.39%, 0.79%, 6.95% and 3.93%, respectively. In contrast, CH-223191, an AhR antagonist, significantly increased the proportion of IgA+ cells to 16.19%. These results suggest that repression of CSR is a common effect of AhR agonists in activated mouse B cells.
E3 ubiquitin ligase Fbw7 regulates B cell survival and T cell-independent responses
Authors: Ramezani-Rad Parham , Leung Charlotte R , Apgar John R , Rickert Robert C 
Published: January 2023

Abstract
B cells continuously populate peripheral organs to maintain a large number of diverse mature B cell clones. These cells have controlled temporal boundaries and await their potential activation in a naïve resting state. Newly emerging B cells are maintained by survival signals while previous B cell generations die through apoptosis. During activation, B cells alter their metabolic machinery to enable categorical fate decisions. The E3 ubiquitin ligase, Fbw7, mandates proteasomal degradation of several oncogenes involved in cellular proliferation, growth, and survival. To elucidate the role of Fbw7 in B cells, we studied the function of Fbw7 in a conditional knockout mouse model. Ablation of Fbw7 during early B cell development diminished the mature recirculating B cell pool in the bone marrow and decreased the B cell population in the spleen. Further, we found a drastic reduction of the B1 cells in the peritoneal cavity. These unexpected results prompted us to generate a novel acute deletion model for Fbw7 to study mature B1 and B2 cells. Acute deletion of Fbw7 confirmed reduction of B cell population within a few weeks. When challenged with T cell-independent antigens the overall antibody responses were reduced. BCR-stimulation of B cells ex vivo showed reduced calcium signaling, poor proliferation potential and upregulation of apoptosis in knockout cells. Ectopic expression of BCL2 in B cells, partially rescued the apoptotic fate of these cells. Our results indicate for the first time that Fbw7 is a critical regulator in B cells, contributing to survival signaling and modulating B cell responses.