bluuebunny/crossref_metadata_2025_split huggingface dataset:
β-catenin engages IKZF factors to control lymphopoiesis
Authors: Cosgun Kadriye Nehir , Jumaa Huda , Robinson Mark E , Xu Liang , Xiao Gang , Arce David Fonseca , Khanduja Dhruv , Chan Lai N , Lee Jaewoong , Schjerven Hilde , Jellusova Julia , Müschen Markus 
Published: August 2023

Abstract
β-catenin-signaling promotes proliferation and survival in epithelial, neuronal, and mesenchymal lineages, but is dispensable for B- and T-cell development. β-catenin activation is a common oncogenic driver throughout all types of cancer with the exception of B- and T-lymphoid malignancies. Unlike epithelial tissues, we found that B- and T-cells consistently lack β-catenin expression. Instead, both B- and T-cells were highly sensitive to β-catenin-activation and critically depend on its negative regulation by GSK3β-dependent phosphorylation and degradation. Inhibition of GSK3β induced dramatic nuclear accumulation of β-catenin, anergy and cell death. In contrast, genetic deletion of β-catenin enabled clonal expansion of premalignant B- and T-cells.
In epithelial cells, β-catenin and TCF-family factors form complexes for transcriptional activation of MYC. Instead of TCF-factors, our interactome studies in B- and T-cells revealed that, β-catenin formed complexes with lymphoid-specific Ikaros zinc finger (IKZF) transcription factors for transcriptional repression of MYC at a recently discovered MYC ‘blood enhancer cluster’ (BENC). Hence, activation of β-catenin engages repressive complexes with Ikaros factors to regulate lymphopoiesis through transcriptional control of MYC.
We propose that β-catenin-accumulation functions as sensing mechanism of pathological B- and T-cell signaling and that this mechanism can be leveraged for targeted eradication of pathological (autoreactive or malignant) clones. To engage this mechanism, targeted accumulation of β-catenin can be achieved by GSK3β-inhibition and represents a selective vulnerability of pathological B- and T-cell clones.
Fluctuation of cell numbers and kinetics reveals dynamical hematopoiesis
Authors: Jia Dongya , Mukherjee Ratnadeep , Altan-Bonnet Grégoire 
Published: August 2023

Abstract
Fluctuations of multiple blood cell types (B cells, neutrophils, reticulocytes, platelets etc.) have been reported in many hematological disorder and leukemia patients. It remains largely elusive about the mechanisms underlying cell fluctuation. To quantify the dynamics of blood cells, we performed a longitudinal studies of blood profiling using identical healthy mice. We combine a pulse protocol of 5-iodo-20-deoxyuridine (IdU) injections with subsequent analysis by mass cytometry (CyTOF and CyTEK) and mathematical modeling of the cell dynamics. We demonstrate that cell abundance exhibits large fluctuations, and a 10-fold change has been observed for the blood neutrophil numbers in healthy mice. Although individual cell type is fluctuating, different cell types exhibit strong correlation/anti-correlations, such as the anti-correlated cell numbers of B cells and neutrophils. The large fluctuation of cell numbers motivated us to characterize cell kinetics, such as the proliferation rate. Through the IdU pulse experiments, we show that cell proliferation rates also exhibit large variation across identical mice. Strikingly, we observe a broad involvement of cell types in exhibiting strong positive correlations of their proliferation rates. Through mathematical modeling, we show that the burst of B cell proliferation often reduces the plasticity of the hematopoietic system and result in regular oscillatory behaviors of B cells, neutrophil etc., which is consistent with the previous reports. A better understanding of the fluctuation of cell numbers and kinetics can afford a better administration of therapies for blood disorder patients.
The obesity-induced expression of T-bet in B cells promotes metabolic dysfunction and alters antibody responses
Authors: Vanz Carlo , Dudley Elizabeth , Enslow Benjamin , Leadbetter Elizabeth 
Published: August 2023

Abstract
Obesity is a leading risk factor for premature mortality and poor medical outcomes due to its increasing global prevalence and its profound impact on the human body. Obesity also has a significant immune component as the establishment of a chronic inflammation in obese individuals is a significant driver of metabolic dysfunction. Additionally, obesity alters anti-tumor immunity, and it impairs protective antibody responses during infection or vaccination. The outcome can be extremely catastrophic, as highlighted in the COVID-19 pandemic with obese patients being particular susceptible to the disease.
This relationship warrants more investigation into the obesity-associated changes occurring in B cells, central players in both the obesity-associated chronic inflammation and in the production of antibodies.
Our lab has identified a subset of B cells which is expanded in both humans and mice during obesity and is characterized by the expression of the transcription factor T-bet.
In vivo studies using obese mice fed a high fat diet revealed that these Tbet+ B cells promote inflammation and metabolic dysfunction through the production of proinflammatory antibodies. Additionally, blocking the expression of T-bet in the B cells of obese mice resulted in significant changes in antibody responses, with a greater expansion of germinal center B cells and an increased ability to generate antigen-specific B cells following immunization.
Based on our findings, T-bet+ B cells represent an interesting link between obesity, inflammation, and antibody responses. Identifying the mechanisms regulating their function will provide new potential ways to reduce inflammation and enhance protection against infectious diseases in obese patients.
Impact of a high fibre diet on immune cells and the multiple sclerosis animal model
Authors: Sen Monokesh Kumer , Ge Anjie , Liao Eileen , Gard Harrison , Ni Duan , Macia Laurence , Piccio Laura 
Published: August 2023

Abstract
Multiple sclerosis (MS) is an inflammatory demyelinating disease of the central nervous system (CNS). Studies demonstrated the association between inadequate dietary fibre intake and dysregulation of the immune response, the impact of which in MS remains controversial. Using experimental autoimmune encephalomyelitis (EAE) animal model of MS, this study investigated how dietary fibre regulates adaptive immune cells, gut-microbial composition, and metabolite secretion. Following EAE induction, the high fibre (HF) group showed an earlier onset, higher disease incidence and severity compared to the zero fibre (ZF) group. Immune profiling of peripheral blood cells and splenocytes after 5-weeks on the HF diet revealed a pro-inflammatory immune phenotype, with increased numbers of pro-inflammatory Ly6Chi monocytes and decreased numbers of anti-inflammatory IL-10+CD4+ T-cells and T-regs the spleen compared to the ZF-fed mice. Short chain fatty acids (SCFAs) measurements at 5-weeks on the diet, showed a global increase of acetate, propionate and butyrate concentrations in the HF group compared to ZF cohorts. After EAE induction, Ly6Chi monocytes were decreased peripherally, while there was an increased number of dendritic cells and infiltration of monocytes in CNS in the HF compared to the ZF group. In conclusion, a HF diet was associated with a more pro-inflammatory systemic profile and a worse EAE clinical course. This is likely due to the complex biology of SCFAs, which could have pro- or anti-inflammatory effects depending on the context of immune cell activation. Further research is needed to clarify these mechanisms.
Starter funding support
Antioxidative and anti-inflammatory effect of ethanol extracts from Magnolia kobus DC on LPS-induced in vitro and in vivo model
Authors: Kim Yeyoung , Kim Sanghyun 
Published: August 2023

Abstract
Magnolia kobus DC (M. kobus) has biological effects such as antioxidant, anti-inflammatory and antibacterial properties in its flower, bud, and stem bark extracts. Despite of diverse effectiveness of M. kobus, the pharmacological effects supporting inhibition of oxidation and inflammation on acute lung inflammation states have not been studied yet. The purpose of this study was to evaluate the pharmacological activity of M. kobus leaf ethanol extract (MkDE) by antioxidant and anti-inflammatory effects on acute lung inflammatory diseases. The antioxidant and anti-inflammatory effects of MkDE was evaluated using ROS detection assay, NO assay, qPCR, ELISA, and Western blot on LPS-induced macrophages. The therapeutic effect of MkDE was investigated in vivo oxidative and inflammatory responses by histological observations, qPCR, ELISA, and Western blot using the LPS-induced acute lung inflammation mouse model. MkDE decreased ROS production and protein of Nrf2. MkDE showed a protective effect against H2O2 as well as a decrease in NO production. MkDE reduced the levels of pro-inflammatory cytokines and chemokine, the activation of COX-2 and iNOS, and NF-κB translocation in LPS-induced macrophage. The intraperitoneal injection of MkDE showed to decrease the lung/body weights, infiltrated inflammatory cells into the lung alveoli, pro-inflammatory mediators, and serum released proteins. Furthermore, MkDE inhibited the activation of Nrf2, COX-2 and NF-κB in LPS-induced acute lung tissue. MkDE exhibits the pharmacological effect by reducing oxidative and inflammatory mediators on LPS-induced macrophages and acute lung inflammation mouse model. Taken together, MkDE might be used to treat acute lung disease.
The inhibitory effects of Bakuchicin on ovalbumin-induced allergic airway inflammation via regulating M2 macrophage polarization
Authors: Lee Soyoung , Kim Yeon-Yong , Kim Sang-Hyun 
Published: August 2023

Abstract
Asthma is an airway inflammatory disease caused by the activation of many immune cells, including macrophages. Bakuchicin (BKC), a furanocoumarin, has anti-inflammatory properties. This study aimed to evaluate the effects of BKC on allergic airway inflammation and demonstrate the mechanisms of macrophage activation and differentiation. We assessed the effects of BKC by evaluating inflammatory markers in an ovalbumin (OVA)-induced airway inflammation mouse model and macrophage cells. BKC treatment alleviated histological changes, mast cell infiltration, and collagen deposition, and reduced the levels of myeloperoxidase, eosinophil peroxidase, β-hexosaminidase, and transforming growth factor-β in the bronchoalveolar fluid (BALF) and the level of immunoglobulins in serum. BKC ameliorated inflammatory symptoms, including the level of inducible nitric oxide synthase (iNOS) in the lung and the expression and secretion of pro-inflammatory cytokines in serum. BKC treatment reduced not only the level of Th2 cytokines but M2 macrophage marker expression and population in the BALF. In vitro, BKC inhibited LPS-stimulated production of nitric oxide and expression of pro-inflammatory cytokines through inhibition of iNOS, COX-2, Akt, MAPKs, IκBα, and NF-κB in J774 A.1 mouse macrophages. Moreover, BKC suppressed IL-4-induced M2 macrophage polarization by inhibiting arginase-1, YM-1, and Fizz-1 and regulating sirtuin 2 levels in bone marrow derived macrophages. Collectively, BKC may help in the prevention and treatment of airway inflammation by regulating macrophage activation and polarization.
Unfolded Protein Response Factor ATF6 Augments T Helper Cell Responses and Promotes Mixed Granulocytic Airway Inflammation
Authors: Wu Dandan , Zhang Xing , Zimmerly Kourtney M , Wang Ruoning , Wang Chunqing , Liu Meilian , Yang Xuexian 
Published: August 2023

Abstract
The unfolded protein response (UPR) plays a critical role in many diseases, including airway inflammation. Several recent studies demonstrated a pathogenic role of Activating transcription factor 6a (ATF6a or ATF6), one of the essential arms of UPR, in airway structural cells. However, its role in T helper (TH) cells has not been well examined. In this study, we found that ATF6 was selectively induced by STAT6 and STAT3 in TH2 and TH17 cells, respectively. ATF6 upregulated UPR genes and promoted the differentiation and cytokine production of TH2 and TH17 cells. T cell-specific Atf6-deficiency impaired TH2 and TH17 responses in vitro and in vivo and attenuated mixed granulocytic experimental asthma. ATF6 inhibitor Ceapin A7 suppressed ATF6 downstream gene expression and TH cell cytokine expression in both murine and human memory CD4+ T cells. Administration of Ceapin A7 lessened both TH2 and TH17 responses in vivo, leading to alleviation of both airway neutrophilia and eosinophilia. Thus, our results demonstrate a novel role of ATF6 in TH2 and TH17 cell-driven mixed granulocytic airway disease, suggesting a novel option to combat steroid-resistant mixed and even T2-low endotypes of asthma through targeting ATF6.
This work was supported in part by NIH grants HL148337 and AI142200 (X.O.Y.), and DK110439 and DK132643 (M.L.). We acknowledge the University of New Mexico Comprehensive Cancer Center Flow Cytometry Core supported by NIH CA118100 and the Autophagy, Inflammation, and Metabolism in Disease Center Inflammation and Metabolism Core supported by NIH GM121176
Macrophages promote survival of granulosa cells
Authors: Brodeur Tia Y , Bonney Elizabeth A , McGee Elizabeth , Krementsov Dimitry 
Published: August 2023

Abstract
The ovary contains numerous macrophages, and macrophage depletion in mice leads to dysfunctional ovulation. Macrophage function in the ovary is presumed to be related efferocytosis, however, the absence of macrophages also disrupts follicular development and corpus luteum development. Granulosa cells (GC) are critical to ovarian follicle development and survival, and we hypothesized that macrophage-GC crosstalk promoted GC function. To determine whether macrophage-GC interaction has an anti-apoptotic effect on GCs, BMDM were polarized to proinflammatory phenotype with LPS (M1), alternative activation phenotype with IL-4 (M2), or not stimulated (M0). After removing stimuli, primary mouse GCs were co-cultured with macrophages and serum-starvation was used to induce apoptosis of GCs. The cells were analyzed by flow cytometry, assessing viability by exclusion of propidium iodide and Annexin V. Co-culture with macrophages protected GCs from serum-starvation induced cell death. In co-cultures with quiescent BMDM, 60% of GCs were late apoptotic/early necrotic compared to 81% without co-culture, (p=0.0031). Unexpectedly, LPS-treated macrophages promoted survival of GC slightly more effectively than IL-4-treated or quiescent macrophages (45% versus 60% and 53% apoptotic, respectively p=0.0230). Both quiescent and inflammatory macrophages promote survival of GCs. This result is unexpected, as LPS-treated macrophages secrete TNF-α, a cytokine that is known to induce death in GCs. This study elucidates the role of macrophages in ovarian function by supporting GC survival and may also have implications for the promotion of GC tumors by tumor-associated macrophages.
Supported by grant from the NIH 3P30GM118228-05S3
A computational analysis demonstrating vitamin E nicotinate promoting anti-inflammatory signals
Authors: Suzuki Dante I , Marcocci Lucia , Suzuki Yuichiro J 
Published: August 2023

Abstract
Vitamin E nicotinate is an ester of tocopherol (vitamin E) and niacin (vitamin B3). Niacin is linked to the hydroxyl group of active vitamin E, blocking free radical scavenging properties. While this ester can be chemically synthesized, whether vitamin E nicotinate is formed from vitamin E and niacin in the biological system is unclear. Metabolomics analysis performed in our laboratory demonstrated that the level of vitamin E nicotinate is 30-fold lower in rats suffering from an inflammatory state. The rat diet contained vitamin E acetate and niacin separately (but not in the form of vitamin E nicotinate), and only vitamin E nicotinate (but not other forms of vitamin E) was decreased, suggesting that vitamin E nicotinate is formed in the biological system. To test if vitamin E nicotinate functions independently from simply serving as a source of active vitamin E, we also performed metabolomics to compare the effects of vitamin E nicotinate on cultured cells to those of vitamin E acetate + niacin added separately. Results revealed that cells treated with vitamin E nicotinate for 10 min had significantly higher levels of molecules with anti-inflammatory properties including anandamide, virodhamine, palmitamide, oleamide, and oleoylethanolamide. Vitamin E nicotinate (but not vitamin E acetate + niacin) phosphorylated and activated extracellular signal-regulated kinase (ERK), which also serves as an anti-inflammatory signal. These results suggest a new biological function of vitamin E nicotinate as an anti-inflammatory molecule through non-direct free radical scavenging effects.
Supported by grants from NIH (R21 AG73919, R03 AG71596)
Neutrophil extracellular trap (NET) degradation attenuates acute lung injury and protects mice from ricin-induced acute respiratory distress syndrome (ARDS)
Authors: Sapoznikov Anita , Gal Yoav , Israeli Ofir , Aftalion Moshe , Evgy Yentl , Erez Noam , Falach Reut 
Published: August 2023

Abstract
ARDS is a life-threatening respiratory condition associated with pulmonary vascular hyperpermeability and loss of aerated lung tissue. Ricin is a plant-toxin derived from the seeds of Ricinus communis, irreversibly inactivates ribosomes and arrests protein synthesis. Pulmonary exposure to ricin represents a bona fide model for ARDS, is characterized by pulmonary inflammation with massive neutrophil recruitment and severe disruption of the alveolar-capillary barrier leading to pulmonary edema, compromised gas exchange and respiratory failure. We have shown that upon ricin exposure, neutrophil infiltration into lungs, a hallmark of ARDS, mediate proteolysis of junction proteins. Recently, there is an increasing concern about the deleterious effect of NETs in sterile inflammation, such as in ricin case. During NETosis, PAD4 drives histone citrullination and chromatin decondensation. Decondensed chromatin decorated with citrullinated histones (citH3) and cytoplasmic granular enzymes, such as MPO is expelled from the neutrophil. Herein, we show increasing levels of PAD4, citH3 and MPO in the BALF of ricin exposed mice. BALF neutrophils efficiently produced NETs which were associated with MPO and citH3. Immunohistology of lung sections upon ricin exposure demonstrated propagating NETosis. Treatment of ricin exposed mice with recombinant DNase, targeted against NET-associated extracellular DNA, administrated with anti-ricin antibodies, dramatically decreased the level of extracellular DNA and proinflammatory cytokines in the lungs and conferred higher protection levels to mice in comparison to sole administration of antitoxin. This data highlights the potential clinical benefit of NET inhibiting drugs in ARDS.
Fc modification to transform a pathogenic antibody into a potential therapeutic for thromboinflammatory disease
Authors: Sarkar Amrita , Gollomp Kandace , Khandelwal Sanjay , Arepally Gowthami , Cines Douglas B , Kowalska M Anna , Rauova Lubica , Poncz Mortimer 
Published: August 2023

Abstract
KKO is a HIT (heparin-induced thrombocytopenia)-like mouse monoclonal antibody (moAb) that binds to platelet factor 4 (PF4) when complexed to polyanions like heparin and neutrophil extracellular traps (NETs). Human (h) PF4 protected NETs from DNases and was further enhanced by KKO as it activates platelets and neutrophils via both FcgRIIA and complement, causing prothrombotic state in transgenic mice expressing FcgRIIA and hPF4. We posited through that if Fc activity of KKO were eliminated then it may stabilize NETs and potentially be therapeutic by stabilizing NETs without FcgRIIA and complement activation. We deglycosylated Fc region of KKO to make DGKKO, and tested if we can avoid detrimental effects without interfering with KKO protection of PF4:NET complexes. We also speculated that DGKKO may bind to hPF4:polyanions and prevent them from inducing HIT. Binding efficacy of DGKKO to PF4-heparin complexes was studied by ELISA and dynamic light scattering. Platelet and complement activation were also studied for DGKKO, and we found that DGKKO still bind to PF4-polyanion complexes, with no platelet activation and significantly lower complement activation. DGKKO also enhanced NET nuclease resistance to improve microbial capture by PF4-NETs, preventing thrombocytopenia and improving survival in murine sepsis models. Also, our humanized in vitro microfluidics studies as well as HIT mice studies showed that infusion of DGKKO prevented both thrombocytopenia and thrombosis in a murine model of HIT. These results showed that Fc-modified KKO has protective effects in at least two models of thromboinflammation. Further studies are underway to examine the role of NET stabilization by modified KKO in other thromboinflammatory disorders.
R35 to Mortimer Poncz and CHOP Foerderer Grant to Amrita Sarkar
Biological scaffold implants in a murine volumetric muscle loss trauma model cause time dependent CD62L and CD101 upregulation on “regulatory like” eosinophils
Authors: Lokwani Ravi , Josyula Aditya , Fertil Daphna , Sadtler Kaitlyn 
Published: August 2023

Abstract

Introduction
Previously, we reported a strong increase in the recruitment of eosinophils at injured muscle when treated with a biologic scaffold implant. As such, we sought to characterize the surface marker expression of these eosinophils to understand their role at the site of injury.

Method
Volumetric muscle loss (VML) model was performed on C57BL/6 mice and was subsequently treated with a biologic scaffold (decellularized extracellular matrix). After 7 and 21 days, post-injury, implanted material along with injured tissue was dissected and converted to single cell suspension for flow cytometry.

Results
Compared to uninjured mice, at both 7 and 21 days time point, mice that received biological scaffold featured significantly increased presence of eosinophils at the site of injury. These eosinophils had a ring-shaped nucleus which has been previously associated with regulatory eosinophils. Eosinophils at the site of injury showed time dependent upregulation of CD101 (Mean fold change from uninjured muscle after 7 days post implant was 2.73 and the same was 9.90 after 21 days, (p&lt;0.0001)), and CD62L (Mean fold change from uninjured muscle after 7 days post implant was 3.65 and the same was 11.64 after 21 days(p&lt;0.0001)) expression. Interestingly, the same pattern was not observed with blood eosinophils except that the blood eosinophils at 3-week timepoint were featuring a significant increase in CD62L expression compared with 1 week time point, suggesting potential return of homeostasis in circulatory compartment.

Conclusion
Here, we describe time-dependent transformation in eosinophil phenotype in response to biologic scaffold implantation, including upregulation of adhesion molecule CD62L and a regulatory marker CD101.