bluuebunny/crossref_metadata_2025_split huggingface dataset:
Independent production of distinct monocyte subsets by granulocyte-monocyte progenitors (GMPs) and monocyte-dendritic cell progenitors (MDPs)
Authors: Boyer Alberto Yanez , Goodridge Helen 
Published: January 2023

Abstract
Myeloid cells – neutrophils, monocytes and dendritic cells (DCs) – play key roles in inflammation, immune defense against pathogens, and tissue repair and remodeling. Myelopoiesis, the production of myeloid cells by hematopoietic stem and progenitor cells, must be carefully regulated to support immune surveillance in the steady-state and meet the additional demands of emergency conditions such as infections. The current widely-accepted model of myelopoiesis describes the production of neutrophils by granulocyte-monocyte progenitors (GMPs), which also yield monocytes and DCs via monocyte-DC progenitors (MDPs). However, our data show that murine GMPs do not give rise to MDPs and that conventional and plasmacytoid DCs (cDCs and pDCs) are produced by MDPs but not GMPs. Thus GMPs and MDPs arise separately but both yield monocytes. Our in vitro and in vivo studies of the pathways and mechanisms of monocyte production have revealed that both GMPs and MDPs yield Ly6C+ inflammatory monocytes and Ly6C− CD43+ monocytes, but that GMP-derived and MDP-derived Ly6C+ inflammatory monocytes exhibit distinct patterns of gene expression. In ongoing studies we are comparing the phenotype and function of GMP- and MDP-derived monocytes, and determining the relative contributions of GMPs and MDPs to the monocyte and tissue macrophage pools under steady-state and emergency conditions.
In vitro immunosuppressive effects of mesenchymal stem cells on allergic asthma
Authors: Liou Yih-Mei , Chuang Ya-Hui 
Published: January 2023

Abstract
Allergic asthma is an airway inflammation in the present of high serum IgE and large numbers of eosinophils which mediated by an imbalanced type II helper T cell (Th2) immune response. Mesenchymal stem cell (MSC) is a multipotent progenitor which shows immunomodulatory ability and thought to be a potential immunotherapy. In this study, we evaluated whether allogenic MSC suppress immune cells from allergic asthma patients and whether Th2 microenvironment cytokine affect the immunomodulatory properties of MSCs. To this end, peripheral blood mononuclear cells (PBMCs) from allergic asthma patients were cocultured with MSC and proliferation and cytokine production of PBMCs were assayed. In addition, MSCs were treated with Th2 cytokine IL-4 and immunosuppressive properties of MSCs were examined. Our results showed that MSC suppressed proliferation and the expression of activation marker CD25 of both CD4+ and CD8+ T cells form allergic asthma patients. Otherwise, Th2 cytokine production was also reduced. However, IL-4 did not affect the immunosuppressive properties of MSCs. It seems that MSCs did not response to IL-4 since the immunosuppression related genes COX2, IDO, IL6 and IL8 did not increase. In conclusion, MSC is able to reduce Th2 response in allergic disease and Th2 environment might not affect their immunosuppressive function.
Direct aeroallergen exposure disrupts the oxidant and antioxidant balance in human bronchial epithelial cells
Authors: Wong W.S. Fred , Chan Tze Khee , Tan W.S. Daniel , Peh Hong Yong , Engelward Bevin P. 
Published: January 2023

Abstract
Exposure to aeroallergens is a major risk factor for asthma development. Allergen possessing proteolytic activity is capable of disrupting airway epithelium. Increasing evidence pointing to asthma as an epithelial disease, however, the underlying mechanisms that drive asthma are not fully elucidated. Here, we investigated the DNA damage potential of aeroallergens on human bronchial epithelial cells BEAS-2B, and elucidated the damaging mechanisms. We exposed BEAS-2B cells to house dust mite (HDM), and measured DNA damage by CometChip and DNA double strand breaks (DSBs) by γH2AX staining. Intracellular oxidative stress was evaluated by staining cells with CellROS and MitoTracker. Antioxidant genes expression were determined using RT-PCR. Cell viability was determined by XTT assay. Cell death was studied using flow cytometry. To elucidate the underlying mechanism, cells were treated with Toll-like receptor 4 (TLR4) agonist or antagonist, or antioxidants glutathione or catalase. BEAS-2B cells exposed to HDM showed enhanced DNA damage, elevated ROS production, and increased mitochondrial oxidative stress and nitrite level. Expression of Nrf2-dependent antioxidant genes was reduced by HDM exposure. HDM also reduced cell viability and induced cell death. Importantly, HDM-induced DNA damage could be prevented by antioxidants. Our results suggest that direct HDM exposure to bronchial epithelial cells leads to production of RONS that damage DNA and induce cytotoxicity. Antioxidants can prevent HDM-induced DNA damage, revealing a novel role for antioxidants in preventing genotoxicity. [This study was partially supported by NMRC/CBRG/0027/2012, NUHS Seed Grant R-184-000-238-112, NRF, NIEHS R44-ES0211116 and Trevigen Inc.]
Effects of immunomodulatory supplementation with pre and probiotic on Th2-mediated airway inflammation in A/J and C57BL/6 mice
Authors: Ferreira Caroline Marcantonio , Casaro Mateus , Fukumori Claudio , Câmara Niels Olsen Saraiva , Curi Rui , Vieira Angelica Thomaz , martins Flaviano S 
Published: January 2023

Abstract
Studies have demonstrated that some probiotics and prebiotics could improve Th2 airway inflammation, such as asthma disease. However, it is unclear if a specific probiotic and prebiotic could regulate asthma disease independent of genetic host and gut microbiota composition. Our objective is to elucidate if the habitual probiotic and prebiotic consumption can affect Th2-mediated airway inflammation in two inbred mice, A/J and C57BL/6 (B6). It is known that A/J have a greater Th2 airway inflammation predisposition than B6 and this fact was attributed to genetic difference. The purpose of this study is to examine the role of gut microbiota composition on Th2 inflammation predisposition and the effects of the probiotic (Bifidobacterium longum) and the prebiotic (pectin fiber) on experimental asthma on both mouse strains. Before treatment, an Ion-Torrent 16S rRNA gene-based amplification and sequencing protocol was used to determine the fecal microbiota profile. Ten days before sensitization, they were treated with probiotic or prebiotic. Experimental asthma was performed by sensitization and challenges with ovalbumin. Twenty-four hours after the last challenge, pulmonary inflammation and lung function were analyzed. Our results show that A/J mice have lower microbiota diversity than B6. Interestingly, probiotic and prebiotic treatment reduced lung inflammation and airway hyperresponsiveness, only on A/J mice. The results suggest that low microbiota diversity and genetic background can predispose Th2 airway inflammation. Moreover, high gut microbiota diversity can to strengthen the barrier function of the mucous membrane and to interfere with the effects of pre and probiotics, such as we observed in B6 mice.
Dipeptidyl peptidase-4 promotes T cell migration
Authors: Zhong Jixin , Rao Xiaoquan , Braunstein Zachary , Bromberg Jonathan S , Rajagopalan Sanjay 
Published: January 2023

Abstract
Dipeptidyl peptidase-4 (DPP4) is well known as a post-prandial blood glucose regulating protein by inactivation of incretin hormones. DPP4 also regulates T cell activation by interacting with adenosine deaminase. We investigated the role of hematopoietic DPP4 in T cell-mediated vascular inflammation and atherosclerosis. DPP4 highly expressed on the plasma membrane of T cells especially CD4+ T cells. DPP4 expression increased on circulating T cells in atherosclerotic patients (% DPP4+ CD4+ T cells: 27.46 ± 2.67 vs. 48.06 ± 1.96 for healthy control vs. atherosclerotic patients, p&lt;0.0001). Deficiency of DPP4 on hematopoietic cells protected Ldlr−/− mice from high fat diet-induced atherosclerosis progression and reduced T cell infiltration in aortic plaque. Aorta from Ldlr−/− mice with Dpp4−/− bone marrows showed a much less DPP4 expression, suggesting bone marrow derived cells are the major sources of DPP4 within the aorta. Transwell® migration assay showed T cells with high migratory activity had higher levels of DPP4 expression. Both in vitro and in vivo migration assays suggest T cells deficient for DPP4 displayed a reduced migratory ability. Futher investigation suggests both enzymatic and non-enzymatic actions of DPP4 are involved in the regulation of T cell migration. Taken together, DPP4 increased on T cells in atherosclerosis and is important for T cell migratory activity, which promotes T cell-mediated vascular inflammation and atherosclerotic progression. Our results suggest an essential role for DPP4 in regulating T cell migration.
Anti-inflammaging effect of human alpha 1 antitrypsin
Authors: Yuan Ye , Li Ying , Titov Denis , Brenner Brian , Seifer Lee , El Shikha Ahmed , Akbar Mohammad , Zhou Lei , Song Sihong 
Published: January 2023

Abstract
An important feature of aging is a low grade, persistent, systemic inflammation without overt infection which is defined as “inflammaging”. Inflammaging plays an important role in both morbidity and mortality of most age-related diseases. However, the mechanism of inflammaging is largely unknown, and no treatment has been discovered. Human alpha-1 antitrypsin (hAAT), with anti-inflammatory properties, holds potential to decelerate the aging process. To test the anti-aging effect of hAAT, we generate hAAT transgenic Drosophila lines and showed that over-expression of hAAT in Drosophila fat body (liver) significantly extended the life span. Importantly, real-time PCR and RNA sequencing analyses showed that age-related inflammatory genes (Relish and Diptericin), and immune responsive genes were significantly inhibited in hAAT transgenic lines. To further investigate this anti-inflammaging effect in human cells, we employed a widely used irradiation-induced senescence cell model and tested the effect of hAAT treatment on Senescence-associated Secretory Phenotype (SASP). Our results from this study showed that hAAT treatments significantly decreased gene transcription and protein secretion of IL-6 and IL-8 (the 2 major SASP factors). In contrast, no effect from hAAT on senescence formation was detected. Intriguingly, it is strongly suggesting the epigenetic effect of hAAT since the inhibitory effect can last at least 7 days after withdraw of the treatment. In conclusion, our results have shown that hAAT has the anti-inflammaging effects and may extend life span by inhibiting transcription of inflammatory factors of SASP. Hence, as a FDA-approved drug, hAAT is a promising candidate to combat aging and aging-related diseases.
Systems analysis of microRNAs reveals a novel link between CD8 T cell dysfunction and TGF-β signaling in immune aging
Authors: Gustafson Claire Ellen , Cavanagh Mary , Hu Bin , Zhang David , Weyand Cornelia M , Goronzy Jorg J 
Published: January 2023

Abstract
MicroRNAs (miRNA) have been identified as important regulators of effector CD8 T cell responses and memory differentiation. Here, we examined whether miRNA expression is altered in CD8 T cells of older individuals and whether functional consequences of miRNA expression account for defective CD8 T cell responses with age. We characterized the expression of 44 immune-related miRNAs in CD8 T cells subsets in young and elderly adults using microfluidic qPCR. 32 out of the 44 miRNA investigated were expressed in CD8 T cells. Out of those expressed, 16 miRNAs had significantly altered expression between young and elderly adult CD8 T cells, with 11 of these being altered in naive CD8 T cells. These 11 miRNAs were not directly related to miRNA profiles seen with TCR-activation or T cell differentiation in CD8 T cells. Integrated pathway analysis of these miRNAs using the DIANA MirPath software identified the TGF-β receptor signaling pathway as a highly enriched (p=1.70E-08) target of the decreased miRNAs. Decreased expression of these five miRNAs suggested increased TGF-β receptors and/or signaling in naïve CD8 T cells during aging. Consistently, expression of TGFBR3 and PU.1, a TGF-β-induced transcription factor, was up-regulated in elderly naïve CD8 T cells compared with young. Moreover, overexpression of these miRNAs in elderly naïve CD8 T cells decreased TGFBR3 expression, demonstrating a direct effect of miRNAs on the TGF-β pathway. Thus, using a systems approach to interrogate the role of miRNAs, we identified TGF-β receptor signaling as a potential mediator of altered CD8 T cell responses during aging. Further studies into CD8 T cells and TGF-β signaling in the context of vaccination and aging are currently underway.
Retinoic acid-induced upregulation of αE integrin (CD103) is TGFβ-dependent in human dendritic cells
Authors: Roe Mandi M , Swain Steven D , Bimczok Diane 
Published: January 2023

Abstract
CD103 (αE integrin) is thought to mediate the cross-talk between dendritic and epithelial cells. Based on a recent study showing retinoic acid (RA) may enhance CD103 expression at high concentrations (Hartog, Allergy and Immunology. 2013), we examined monocyte-derived dendritic cell (MoDC) CD103 expression levels with physiological concentrations of RA (100nM) under serum-free conditions. FACS analysis revealed that RA induced a significant increase of MoDCs positive for both extracellular and intracellular CD103 expression. Gene expression analysis corroborated these results with a 57-fold increase in ITGAE upon RA culture. Moreover, expression of β7, which forms the αEβ7 integrin heterodimer with CD103, was similarly upregulated by RA. We next evaluated the TGFβ-dependence of RA-induced CD103 regulation based on a study showing that itgαE gene expression in mice is regulated by TGFβ in T-cells (Robinson, Immunology. 2001). MoDCs were cultured with RA and SB431542, a TGFβR inhibitor that blocks SMAD phosphorylation. When MoDCs were cultured with RA and SB431542, CD103 expression was significantly reduced when compared to MoDCs cultured with RA alone (p&lt;0.01). Similarly, qPCR analysis revealed RA-induced ITGAE gene expression was significantly decreased by 2.4-fold with SB431542 treatment. We also showed that TGFβ directly enhanced CD103 expression in human MoDCs. However, RA-treatment of the MoDCs did not result in enhanced secretion of TGFβ1/2/3 or enhanced expression of TGFβRI/II. Therefore, RA modulation of cellular TGFβ signaling pathways may be involved in the upregulation of CD103 expression. In summary, our studies reveal a TGFβ-dependent mechanism for RA-induced regulation of CD103 in human dendritic cells.
Distinct roles of dendritic cell-derived iNOS in the control of effective and regulative dendritic cell differentiation.
Authors: Si Chuanping , Zhang Ruihua , Hu Yuan , Zhang Hui , Xiong Huabao 
Published: January 2023

Abstract
The immune system exists in a delicate equilibrium between response and tolerance. Dendritic cells (DC) are a plastic lineage able to process and integrate signals from the microenvironment. But the regulation how DCs differentiate to effective or regulatory DC cells are incompletely understood. Inducible nitric oxide synthase (iNOS) derived NO plays critical roles in immune suppression of immune cells. But, it is still not clear what the function of DC cells-derived iNOS is in the regulation in inflammatory diseases. In this study, we demonstrated that DC-derived iNOS regulates balance of effective and regulatory DC cell differentiation. iNOS deficient mice displayed an increased effective DC phenotypes, whereas the percentage of regulatory DCs were comparable in wild-type and iNOS deficient mice in vivo and in vitro. The results were further supported by increased effective DCs from iNOS−/− BMDC cells. Activation of DCs by LPS/IFNg resulted in the expression of iNOS in WT mice. The iNOS inhibitor L-NIL enhanced effective DCs differentiation, mimicking the effect observed in iNOS deficient mice. NO donor SNAP suppressed effective DCs. iNOS−/− DCs result in more enhanced T cell activation. iNOS−/− mice infected with Citrobacter Rodentium led to more severe intestinal inflammation compared to WT mice and the results were correlated with more inflammatory cells infiltration in iNOS−/− in colon tissues. And iNOS−/− mice showed increased effective DCs in colon tissues than that in WT mice. Our results suggest that DC-derived iNOS negatively controls effective DC development and targeting DC-derived iNOS would lead to the new therapies for autoimmune/inflammatory diseases.
Activator of G-protein Signaling 3 (AGS3) modulates CXCR2/GRK6 activation and functions: Role of the GPR domain.
Authors: Richardson Micheler , Adekoya Timothy O , Mowatt Tonelia A , Smith Nikia 
Published: January 2023

Abstract
Activator of G-protein Signaling 3 (AGS3) is a receptor-independent activator of G-protein signaling which comprises seven tetratricopeptide (TPR) motifs and four GPR motifs joined by a linker sequence. Previous studies have demonstrated that the TPR domain of AGS3 is important for determining the positioning of AGS3 within the cell, whereas the GPR domain serves as a docking site for Gαi-GDP leading to AGS3-Gαi signaling. We have recently shown that GRK6 complexes with AGS3-Gαi to regulate CXCR2-mediated cellular functions including Ca2+ mobilization, mitogen-activated protein kinase (MAPK) activation, receptor desensitization and down-regulation. In the current study, mutants from the GPR and TPR domains were used to determine which motif(s) of AGS3 interact with GRK6 to modulate CXCR2-mediated inflammatory responses. Co-immunoprecipitation studies in transiently transfected HEK 293 cells, and RBL-2H3 cells stably expressing wild-type and mutants AGS3 demonstrated that interleukin 8 (IL-8/CXCL8) activation increases GRK6 interaction with the GPR domain not the TPR. Interestingly, the TPR motif displayed a robust agonist-independent association with GRK6 which was prevented by CXCL8 activation of the receptor. Overexpression of AGS3 and the GPR motif, not the TPR, inhibited CXCR2 mediated intracellular Ca2+ mobilization and MAPK activation. Taken together, these results indicate that GRK6 interacts with the GPR domain of AGS3 to modulate CXCR2/Gai interaction and signal transduction.
Dengue virus infection causes Nrf2 activation to induce CLEC5A-facilitated TNF-α production in mononuclear phagocytes
Authors: Lin Chiou-Feng 
Published: January 2023

Abstract
Infection of dengue virus (DENV), an arthropod-borne flavivirus, threatens global public health due to its high prevalence and the lack of effective treatment. Multiple risk factors are believed to be involved, including virus virulence, antibody-dependent enhancement, T cell response, complement activation, autoimmune response, host factors, cytokine storm, and vascular leakage. Regarding host factors may contribute to DENV infection, replication, and pathogenesis, here we investigate the role for nuclear factor (erythroid-derived 2)-like 2 (Nrf2), which is activated by DENV in mononuclear phagocytes. DENV infection selectively activates Nrf2 through a mechanism involving endoplasmic reticulum stress and protein kinase R-like ER kinase activation. After DENV infection, activation of Nrf2 facilitates an increase in C-type lectin domain family 5, member A (CLEC5A) expression through the binding of activated Nrf2 to the CLEC5A promoter. The downstream signaling of the Nrf2-CLEC5A interaction enhances TLR3-independent TNF-α production following DENV infection. Forced expressing the viral protein NS2B3 induces Nrf2 activation and CLEC5A expression to increase DENV-induced TNF-α production. Further animal studies confirm Nrf2-induced CLEC5A and TNF-α in brains from DENV-infected mice. These results demonstrate that, in addition to TLR3, DENV infection also causes Nrf2-facilitated TNF-α production by increasing levels of CLEC5A.
A fluorescent reporter mouse for inflammasome assembly demonstrates an important role for both cell bound and free ASC specks during in vivo infection
Authors: Tzeng Te-Chen 
Published: January 2023

Abstract
Inflammasome activation is associated with numerous diseases. However, in vivo detection of the activated inflammasome complex has been limited by a dearth of tools. We developed transgenic mice that ectopically express the fluorescent adaptor protein, ASC (apoptosis-associated speck-like protein containing a caspase recruitment domain), and characterized the formation of assembled inflammasome complexes (“specks”) in primary cells and tissues. In addition to hematopoietic cells, we found that a stromal population in the lung tissues forms specks during the early phase of influenza infection whereas myeloid cells showed speck formation after two days. In a peritonitis and Group B streptococcus infection models, a higher percentage of neutrophils formed specks at early phases of infection, while dendritic cells formed specks at later time points. Furthermore, speck-forming cells underwent pyroptosis, and extensive release of specks to the extracellular milieu in vivo. These data underscore the importance of free specks during inflammatory processes in vivo.
‘Farm dust extract increases the epithelial barrier function of human bronchial epithelial cells partly via MyD88 signalling’
Authors: van der Vlugt Luciën E.P.M. , Eger K. , Amatngalim G.D. , Müller C. , Bracher F. , von Mutius E. , Smits H. H. , Hiemstra P. S. 
Published: January 2023

Abstract
Epidemiological studies showed that farmer’s children have a lower incidence of childhood asthma, which was partly attributed to a higher microbial exposure. Recently, distorted airway epithelium is considered an active player in pathogenesis of asthma. Interestingly, Toll-like receptor (TLR) ligation in the gut was found to enhance the gut epithelial barrier function. We hypothesize that exposure of the airways to microbial-rich farm dust may have barrier-enhancing effects on the airway epithelium and thereby may contribute to the protection against asthma in farmer’s children.
In this study, the effect of farm dust extracts (FDE) collected from traditional German farms was investigated on barrier function and -repair in primary bronchial epithelial cells (PBECs). The expression of tight (TJs) and adherens junctions (AJs)-important to maintain the barrier function- and the involvement of TLR-induced MyD88 signalling were investigated.
FDE exposure induced a dose-dependent two-fold increase in resistance measured by ECIS and up to 70% reduction in permeability in undifferentiated PBECs. Furthermore, restoration of barrier function of fully differentiated PBECs after cigarette smoke exposure was accelerated in the presence of FDE. The increase in barrier function was accompanied by an 1.5 to 2-fold enhanced mRNA expression of TJs occludin-1, claudin-1 and −4 and AJ E-cadherin. In search for the underlying mechanisms, we found that the increased barrier resistance could be significantly attenuated by blocking MyD88 signalling.
These data altogether suggest that FDE exposure strengthen the epithelial barrier function partly via MyD88 signalling and, thereby, possibly reduce the risk of development of asthma and allergies.