bluuebunny/crossref_metadata_2025_split huggingface dataset:
Elucidating the role of cytokine signaling in the homeostasis of innate immune cells with JAK inhibitors
Authors: Vian Laura , Lee Mimi , Sciumè Giuseppe , Gazaniga Nathalia , Dell'Orso Stefania , Brooks Stephen , Gadina Massimo 
Published: January 2023

Abstract
The role of the JAK/STAT pathway in the function on innate lymphoid cells (ILCs) has been mostly investigated using genetically modified animals. While elegant, these studies present with the limitation of a complete loss of ILC populations. Therefore, pharmacological manipulation of this signaling cascade with JAK inhibitors (jakinibs) is an attractive alternative strategy. Here we investigated the effect of pan- and JAK-selective inhibitors on the development and functions of murine, IFN-γ producing, ILCs and iNKT cells after oral administration of tofacitinib (JAK1; JAK3 and JAK2), ruxolitinib (JAK1; JAK2), or PF-06651600 (JAK3). We observed a significant reduction in number and function (IFN-γ production) of both splenic and hepatic NKp46+ cells with either tofacitinib or PF- 006651600. The reduction appears to correlate with the number of proliferating Ki67+ NKp46+ cells. In addition, using an iNKT-dependent mouse model of acute liver inflammation, we observed a significant decreased production of IFN-γ by liver iNKT upon tofacitinib administration. Notably, we found that PF-06651600 selectively impairs the thymic development and the proliferation of IFN-γ-producing iNKT1 cells. Overall our data suggest that the transient inhibitory activity with jakinibs has strong impact on proliferation and activity of mouse IFN- γ producing innate cells. These preliminary findings bring us one step closer to elucidating mechanisms underlying innate cells homeostasis.
Expression of GM-CSF is regulated by transcription factor Fli-1
Authors: Zhang Xian , Richard Mara Lennard , Wang Xuan , Henry Brittany , Li Pengfei , Fan Hongkuang , Gilkeson Gary S 
Published: January 2023

Abstract
Granulocyte-macrophage colony-stimulating factor (GM-CSF), also known as colony-stimulating factor 2 (CSF-2) plays an important role in regulating mature myeloid cell populations under both homeostatic and inflammatory conditions. GM-CSF maintains low basal levels under homeostatic conditions, but its levels can quickly become elevated during infection or inflammation. GM-CSF is rapidly produced during inflammatory or autoimmune reactions by a variety of cells, including endothelial cells, macrophages, dendritic cells (DCs), T cells, neutrophils, eosinophils, and more. It has been reported that the expression of GM-CSF is regulated by several transcription factors including NF-kB, AP-1, and RUNX1. Fli-1 belongs to the ETS transcription factor family. We have demonstrated that the Fli-1 transcription factor is a novel regulator in modulating the expression of many inflammatory mediators, including monocyte chemotactic protein 1 (MCP-1), chemokine (C-C motif) ligand 5 (CCL5) and interleukin 6 (IL-6). In this report, we found that murine endothelial cells transfected with Fli-1 specific siRNA produced significant lower levels of GM-CSF after stimulation with Toll-like receptor 4 ligand LPS compared to the cells transfected with control siRNA. Human primary glomerular endothelial cells transfected with Fli-1 specific siRNA had reduced Fli-1 protein and produced significantly less GM-CSF following LPS stimulation compared to the cells transfected with control siRNA. Transient transfection assays show that Fli-1 drives transcription from the GM-CSF promoter in a dose-dependent manner. Together, the results indicate that Fli-1 is a novel, critical transcription factor in regulating the expression of GM-CSF.
Nrf2 selectively regulates IL-22 and IL-17A production in Th17 cells
Authors: Lin Xun , Gaudino Stephen , Kolls Jay , Kumar Pawan 
Published: January 2023

Abstract
Th17 cell-derived IL-17A and IL-22 are critical for mounting both inflammatory and tissue protective responses. It remains unclear whether cytokine responses can be modified differently to achieve targeted functional outcome. A therapeutic strategy which inhibits CD4+ T cell-derived inflammatory IL-17A responses but concomitantly promotes IL-22-dependent tissue protective or regenerative response is of great clinical significance.
Here, we showed that nuclear factor (erythroid-derived 2)-like 2 (Nrf2) selectively regulated IL-17A and IL-22 responses in CD4+ T cells. We found that Nrf2−/− mice had reduced IL-22 responses in Ovaalbumin (Ova) + LPS and separately concanavalin A (Con A) administered mice. Furthermore, CDDO-Im, a selective Nrf2 activator, induced IL-22 but suppressed IL-17A response in CD4+ T cells polarized under Th17 cell condition. Our qPCR data revealed that CDDO-Im-activated CD4+ T cells had lower Rorc, but increased Cybb, Sod1 and Sod3 transcript. The expression pattern of Il23r and Sod2 was unaltered. CDDO-Im-dependent IL-17A but not IL-22 response was regulated by Sod3. Interestingly, we found that CDDO-Im induced aryl hydrocarbon receptor (Ahr) and its downstream Cyp1a1 and Cyp1b1 gene expression. The luciferase reporter assay data showed that CDDO-Im regulated Ahr promoter activity in a dose-dependent manner. Additionally, CDDO-Im induced Nqo1 expression, a Nrf2-activated gene, in WT mice but not in Ahr−/− mice. Finally, we confirmed that the CDDO-Immediated induction of IL-22 production in CD4+ T cells was abrogated in Ahr−/− mice.
Collectively, our data show that Nrf2 promotes IL-22 production while it inhibits IL-17A expression in Th17 cells.
Bone marrow transplantation rescues monocyte recruitment defect and improves cystic fibrosis in mice
Authors: Fan Zhichao , Miller Jacqueline , Herro Rana , Ehinger Erik , Conrad Douglas J. , Mikulski Zbigniew , Zhu Yanfang Peipei , Marcovecchio Paola M. , Hedrick Catherine C. , Ley Klaus 
Published: January 2023

Abstract
Cystic fibrosis (CF) is an inherited life-threatening disease accompanied by repeated lung infections and multi-organ inflammation that affects tens of thousands of people worldwide. The causative gene, cystic fibrosis transmembrane conductance regulator (CFTR), is mutated in CF patients. Monocytes from CF patients show a deficiency in integrin activation and adhesion. Since monocytes play critical roles in controlling infections, defective monocyte function may contribute to CF progression. In this study, we demonstrate that monocytes from CFTRΔF508 mice (CF mice) show defective adhesion under flow. Transplanting CF mice with wild-type bone marrow after sublethal irradiation replaced most (60–80%) CFmonocytes with wild-type monocytes, significantly improved survival, and reduced inflammation. Wild-type/CFmixed bone marrow chimeras directly demonstrated defective CF monocyte recruitment to the bronchoalveolar lavage and the intestinal lamina propria in vivo. Our findings show that providing wild-type monocytes by bone marrow transfer rescues gastrointestinal (GI) mortality in CF mice, suggesting that wild-type bone marrow stem cells might mitigate CF inflammation.
Understanding the role of IL-33 in endometriosis associated inflammation and pathology
Authors: Miller Jessica E , Koti Madhuri , Tayade Chandrakant 
Published: January 2023

Abstract

Introduction
Endometriosis (EM) is a chronic inflammatory disease categorized by the growth of endometrial tissue on the ovaries, peritoneal wall and other internal organs. Despite it’s prevalence (176 million women worldwide), the etiology is unknown. Currently, there is a significant knowledge gap regarding how the immune microenvironment contributes to the progression of EM (specifically inflammation, pain and fibrosis). We have shown that interleukin(IL)-33 is produced by EM lesions and drives pathology in a mouse model of EM. We are now investigating, mechanistically, how IL-33 contributes to EM and whether IL-33 neutralization could alleviate the pathology.

Methods
Female C57BL/6 mice were induced with EM and were treated with PBS (n=10) or IL-33 (n=10) every other day. After 2 weeks, the mice were euthanized and plasma, peritoneal fluid (PF) and EM lesions were collected. Cytokines in the plasma and PF were analyzed using a multiplex array. Immune cell populations in the PF were evaluated using CyTOF. Finally, sectioned lesions were stained for markers of innervation, proliferation and fibrosis. To establish cause and effect, mice were induced with EM and treated with IL-33+anti-IL-33 antibody (n=10) or IL-33+isotype control (n=10).

Results
Mice treated with IL-33 had elevated cytokines (e.g. IL-5) in the plasma and PF and EM lesions exhibited drastic changes in morphology. Additionally, both innate and adaptive immune cells were altered in the PF of IL- 33 treated mice. Neutralizing IL-33 reduced inflammation and immune cell recruitment.

Conclusions
Overall, these results show that IL-33 drives hallmark pathologies of endometriosis and neutralization of IL-33 could provide a novel therapeutic target for EM.
PAM3 supports the generation of M2-like macrophages from lupus patient monocytes and improves disease outcome in murine lupus
Authors: Horuluoglu Begum Han , Bayik Defne , Kayraklioglu Neslihan , Goguet Emilie , Blanco Luz P , Kaplan Mariana J , Klinman Dennis M 
Published: January 2023

Abstract
Systematic Lupus Erythematosus (SLE) is an autoimmune syndrome of unclear etiology. While T and B cell abnormalities contribute to disease pathogenesis, recent work suggests that inflammatory M1-like macrophages also play a role. Previous work showed that the TLR2/1 agonist PAM3CSK4 (PAM3) could stimulate normal human monocytes to preferentially differentiate into immunosuppressive M2-like rather than inflammatory M1-like macrophages. This raised the possibility of PAM3 being used to normalize the M1:M2 ratio in SLE. Consistent with that possibility, monocytes from lupus patients differentiated into M2-like macrophages when treated with PAM3 in vitro. Furthermore, lupus-prone NZB x NZW F1 mice responded similarly to weekly PAM3 treatment. Normalization of the M2 macrophage frequency was associated with delayed disease progression, decreased autoantibody and inflammatory cytokine synthesis, reduced proteinuria and prolonged survival in NZB x NZW F1 mice. The ability of PAM3 to bias monocyte differentiation in favor of immunosuppressive macrophages may represent a novel approach to the therapy of SLE.
Mitochondrial changes synergize with long chain fatty acid derivatives to support Th17 inflammation in diabetes
Authors: Agrawal Madhur , Nicholas Dequina A , Proctor Elizabeth A , Belkina Anna C , Jones Albert , Panneerseelan-Bharath Leena , Raval Forum , Ip Blanche , Zhu Min , Cacicedo Jose , Habib Chloe , Sainz-Rueda Nestor , Persky Leah , Sullivan Patrick G , Corkey Barbara E , Apovian Caroline M , Kern Philip A , Lauffenburger Douglas A , Nikolajczyk Barbara S 
Published: January 2023

Abstract
Obesity-associated Type 2 diabetes (T2D) is driven by chronic inflammation. A combinatorial Th17 cytokine profile characterizes and mathematically predicts T2D in people, but the mechanisms that generate the Th17 profile are not clear. We tested the possibility that anaerobic glycolysis, which fuels inflammatory cytokine production from multiple immune cell types, drives the T2D-associated Th17 profile. We showed that activated PBMCs and purified CD4+T cells from T2D subjects prefer anaerobic glucose metabolism to produce ATP regardless of fuel availability. Unexpectedly, glucose starvation did not abrogate the T2D-predictive Th17 profile. Gene expression array suggested that mitochondrial fatty acid uptake catalyzing protein CPT1a differentiated PBMCs from T2D and ND subjects. CPT1a inhibition by etomoxir strongly down-regulated the Th17 profile, surprisingly independent of CPT1a-mediated fatty acid oxidation (OXPHOS). These data suggest that OXPHOS-independent mitochondrial changes that are also glucose-independent support the Th17 profile in T2D. Analyses from T2D vs ND PBMCs showed a lower CACT:CPT1a protein ratio in T2D, indicating defects in lipid uptake and thus defects in lipid flux. We knocked down CACT protein and overloaded PBMCs from lean subjects with fatty acylcarnitines to mimic lipid uptake defects in T2D. 16C-fatty acylcarnitine, but not 6C- or 10C-derivatives, increased frequency of CD4+IL-17+T cells, and phenocopied the Th17 profile only in CACT knockdown cells. 16C-fatty acylcarnitine alone had no effect. We conclude that excessive long chain fatty acylcarnitine combines with dysfunctional mitochondria to support a T2D-associated Th17 profile largely independent of glycolysis.
Newfound role for noncanonical NF-κB signaling in Inflammatory Bowel Disease: Gene expression levels serve as a proxy for predicting anti-TNF therapy responsiveness
Authors: Morrison Holly , Eden Kristin , Nguyen Vu Q , Sorrentino Dario R , Brock Rebecca M , Allen Irving C 
Published: January 2023

Abstract
The canonical arm of NF-κB signaling is well studied in Inflammatory Bowel Disease (IBD) while its noncanonical counterpart has yet to be fully defined. The activation of the noncanonical pathway initiates the nuclear transcription of chemokines associated with chronic inflammation and other diverse immunological processes. Infliximab is an effective anti-TNF treatment that reduces inflammation in IBD, yet a significant percentage of patients are unresponsive or lose responsiveness. Here, we show that noncanonical NF-κB signaling has more relevant implications on IBD and its expression levels correlate to infliximab responsiveness. Our study evaluated noncanonical NF-κB signaling in 27 IBD patient and 9 non-IBD control patient tissue biopsies. Data from these studies were analyzed using bioinformatics to predict its influence on cellular pathways. Genes related to the noncanonical NF-κB pathway were significantly upregulated in IBD lesions compared to healthy tissue. IBD patients that positively respond to infliximab had significantly decreased expression levels compared to nonresponsive patients. These results suggest infliximab, when effective, decreases noncanonical signaling to lessen inflammation. Through targeting in part, the noncanonical NF-κB pathway has prominent emerging roles in IBD pathobiology and is an indicator for improving drug efficacy.
Enhanced adenosinergic signaling and immune cell exhaustion after trauma
Authors: Tiwari-Heckler Silpa , Longhi Maria Serena , Harbison James , Otterbein Leo E. , Hauser Carl J. , Robson Simon C. 
Published: January 2023

Abstract
Trauma is currently the leading cause of death in young adults, in some cases due to infection as a consequence of acquired immune suppression. The pathogenesis for this is poorly understood. Extracellular ATP released from cells during injury serves as a danger molecule, but is rapidly converted to AMP by the ectonucleotidase CD39; AMP is then hydrolyzed to immunosuppressive adenosine by CD73 ecto-5’-nucleotidase.
Here, we studied the impact of purinergic signaling in trauma patients over time (day 0/1 after trauma (D1) vs day 2 after trauma (D2) vs controls undergoing elective surgery). We noted higher expression of Adenosine A2A- and A2B- receptor mRNA levels in blood PBMCs on D2 and later, when compared to D1 trauma patients and control samples. Analyses of BAL-derived mononuclear cells revealed decreases in CD39 activity in D1 trauma patients and marked decreases in CD73 activity in D2 trauma patients, when compared to controls. Notably, there was increased CD39 and CD73 expression in PBMC-derived CD8 T-cells of trauma patients, suggesting these cells as the prominent subset involved in the purinergic signaling during trauma. Importantly, CD39+CD8+cells from trauma patients displayed features of “immune exhaustion” phenotype (i.e. high PD-1 and Tim-3 levels) and exhibited less cytotoxicity.
We conclude that the early phase after trauma is initially characterized by heightened systemic inflammation with boosted ATP-mediated signaling, linked with loss of CD39 activity. This is followed by an immunosuppressive phase characterized by enhanced adenosinergic signaling and by increase in exhausted CD39+CD8+cells, which might impair the innate immune responses and lead to increased susceptibility to infections in trauma patients.
Dysregulated monocyte compartment in human obesity
Authors: Friedrich Kathleen , Sommer Miriam , Thrum Stephan , Blüher Matthias , Wagner Ulf , Rossol Manuela 
Published: January 2023

Abstract

Background
Monocytes can be divided in classical monocytes (CM), intermediate monocytes (IM) and non-classical monocytes (NCM). CD56+ monocytes are part of the classical monocytes. Aim of the study was to assess the occurrence of the different monocyte subpopulations in human obesity.

Methods
110 age-matched subjects were included in the study and classified according to the definition of the World Health Organization into lean (n=27), overweight (n=23) and obese (n=60). Monocyte subpopulations were analyzed by flow cytometry (antibody staining of CD14, CD16, CD56).

Results
Obese subject showed a higher BMI, fat mass, and waist circumference, deterioration of metabolic parameters, and the absolute amount of leukocytes and monocytes were increased. The calculated absolute numbers of CM, IM and CD56+ monocytes were significantly increased in obese subjects compared to lean and overweight. In contrast, the absolute numbers of NCM were equal between lean, overweight and obese subjects. Strong associations between the absolute numbers of CM, IM and CD56+ monocytes with the BMI, fat mass, and waist circumference were detectable in the whole cohort. Triglyceride, HDL-c values and HbA1c were also strongly correlated with numbers of CM, IM and CD56+ monocytes. Obese subjects with impaired glucose tolerance had increased numbers of CD56+ monocytes in comparison to obese subsects with normal glucose tolerance. Stratification of obese subjects in subjects with and without type 2 diabetes mellitus showed no difference in absolute numbers of CM but significant increased numbers of IM and NCM.

Conclusion
The amount of CM, IM and CD56+ monocytes are expanded in the blood of obesity subjects and contribute to monocytosis in obesity.
Mathematica as a Tool for Interactive Display of Flow Cytometry and Clinical Data
Authors: Loewendorf Andrea I , Collier Ai-ris Y , Kahn Daniel A , Nevell Julian , Nguyen Tina A 
Published: January 2023

Abstract
In a prior study, we used flow cytometry to characterize lymphocytes from mother-infant pairs from healthy and preeclamptic pregnancies. Despite a relatively low number of study participants, we acquired a large, multidimensional dataset and felt limited in our capacity to fully explore it. Here we describe the use of Mathematica to create an interactive display tool that allows dynamic data exploration. The end result is a HIPAA compliant data library and code that can be exported, published, and explored by readers with the freely available MathReader application.
Our database included flow cytometry data from 8 staining panels with up to 15 markers each, clinical, and obstetric data in MS Excel. By combining Mathematica’s Chart, Manipulate, and Tooltip functions, we incorporated the clinical variables including neonatal sex, birth weight, and prior obstetric history into each graph, while the Tooltip function displays the participant study ID.
We have coded an interactive tool that allows the rapid display of data from multiple complex datasets in a single, interactive graph allowing the scientist to compare immunologic parameters between specific clinical conditions. This makes it possible to highlight, for example: activated NK-, NKT-, γδT -, naïve CD4 T, CD8 T-, memory CD4 T, and memory CD8 T cells from mothers with PE who gave birth to female neonates who were small for gestational age, and easily change all those graphs to highlight those patients who gave birth normal size fetuses. Interactive tools are ideal to display complex, multidimensional data such as human immune phenotyping. Ideally, they should also be publishable as interactive tools for the reader to explore on their own. Mathematica allows for this.
Construction of humanized mice, kinetics of human immune system development and induction of matured and specific T-dependent and T-independent antibody responses
Authors: Chupp Daniel P , Acosta Ometeotl , Zan Hong , Casali Paolo 
Published: January 2023

Abstract
Inbred mice, the most widely used surrogates for human biology, recapitulate many features of the human immune system and immune response. They, however, diverge from humans in important immune elements and functions, such as differential TLR expression, certain antibody and T cell responses, species-specific viral and/or bacterial infections and drug interactions, thereby underscoring the need for a human model that mimics the in vivo human immune response. Humanized mice have recently provided some data on human infections, autoimmunity and cancer, with limited results.
We have undertaken a systematic approach to the generation of humanized mice by grafting NOD.Cg-KitW-41J Prkdcscid Il2rgtm1Wjl/WaskJ (NSGW41) mice within 48 hours of birth, devoid of prior irradiation, with human hematopoietic (CD34+) stem cells. Human umbilical cord hematopoietic stem cells were collected within 30 minutes post-partum and injected intracardially, consistently yielding up to 95% human cell peripheral reconstitution. Human leukocyte development, differentiation and long-term persistence in our CD34+ cell-grafted NSGW41 mice revealed B and T cell maturation as part of a full immune system development, which led to emergence of IgM, IgG, IgA and IgE antibody titers comparable to wild type mice. CD34+ cell-grafted NSGW41 mice supported specific T-dependent and T-independent antibody responses that include human B cell class switch DNA recombination, plasma cell and memory B cell differentiation. They also supported a hydrocarbon-induced autoantibody response leading to symptoms mimicking systemic lupus. Thus, we have devised a robust in vivo platform allowing for generation and maturation of human antibody and autoantibody responses.
The effect of bee venom phospholipase A2 (bvPLA2) on high-fat-diet-induced obesity in mice
Authors: JEONG hYUNJU , Lee Hyunji , Bae Hyunsu 
Published: January 2023

Abstract
Obesity is a medical condition which shows excess body fat accumulation and is a complex metabolic disorder accompanied with cardiovascular disease, high blood pressure, type 2 diabetes and high cholesterol. Further, it is characterized by the accumulation of inflammatory immune cells into white adipose tissue (WAT) in obesity as a feature of the dysfunction of AT. Bee venom is a complex mixture of proteins and compounds and has been reported to have anti-tumor, anti-inflammatory and anti-obesity function. However, the specific compound of bee venom which is responsible for its anti-obesity effect in obesity is still unknown. In this study, the therapeutic effect of PLA2 on high-fat-diet (HFD)-induced obesity was confirmed. As a result, we confirmed that bvPLA2 markedly decreased body weight and WAT weight and significantly lowered the liver and kidney weight in HFD-fed mice. The fat accumulation in liver was also decreased by bvPLA2 in HFD-fed mice. bvPLA2 also decreased adipocyte size. We further confirmed that bvPLA2 decreased the inflammatory cell accumulation in HFD-fed mice. Thus, bvPLA2 can be used as a therapeutic agent for obesity by regulating immune homeostasis.