bluuebunny/crossref_metadata_2025_split huggingface dataset:
Saturated fatty acids promote allergic (Th2) cytokine responses by activation of unfolded protein response (UPR) and ER stress
Authors: Samavedam Unni Krishna SRL , Khodoun Marat , Wu David , Hogan Simon P , Finkelman Fred D 
Published: January 2023

Abstract
Endoplasmic reticulum (ER) stress and an unfolded protein response (UPR) are stimulated by saturated, but not unsaturated fatty acids. We previously showed that saturated medium chain triglycerides (MCT) promote food allergy induction and increase epithelial cell expression of 3 pro-Th2 cytokines, TSLP, IL-25 and IL-33, which stimulate a Th2 cytokine response. These observations led us to hypothesize that the high concentrations of saturated triglycerides in two common food allergens, cow’s milk and chicken eggs, promote food allergy by inducing an epithelial cell UPR response, which in turn, causes these cells to express pro-Th2 cytokines. Indeed, studies with transformed human intestinal epithelial CACO2 cells demonstrated that MCT, egg yolk plasma (the liquid, triglyceride fraction of eggs) and cow’s milk cream each increase expression of the UPR-associated PERK, BiP, CHOP, XBP1 and/or XBP1s genes after 6 hours, followed by increased expression of all 3 pro-Th2 cytokine genes after 24 hours. Each of these stimuli, but not but not protein-rich, lipid-poor egg white, also increase epithelial permeability. Further, the increases in pro-Th2 cytokine expression are blocked by each of 3 UPR inhibitors: metformin, 4PBA and TUCDA, and the egg yolk plasma-induced increase in epithelial permeability is blocked by the only UPR inhibitor tested (metformin). Additionally, monoclonal antibodies (mAbs) to IL-25, IL-33 and TSLP each individually block the induction of egg white food allergy by a combination of egg white and MCTs, and a combination of these mAbs strongly suppress established egg white food allergy. These observations support our hypothesis and provide an explanation for the strong allergenicity of cow’s milk and chicken eggs.
Reduced Suppressor of Cytokine Signaling-1 levels in SLE patients correlates to enhanced STAT1 activation
Authors: Sukka-Ganesh BhagyaLaxmi , Li Yi , Reeves Westley H , Larkin Joseph 
Published: January 2023

Abstract
Systemic Lupus erythematosus (SLE) is a chronic inflammatory autoimmune disorder with unknown etiology. Although the specific events dictating SLE pathology remain unclear, abundant evidence indicates a critical role for dysregulated cytokine signaling in disease progression. Notably, the suppressor of cytokine signaling (SOCS) family of intracellular proteins, in particular the kinase inhibitory region (KIR) bearing SOCS1 and SOCS3, play a critical role in regulating cytokine signaling. Here in this foundational study, we test the hypothesis that regulation of cytokine signaling in SLE patients may be perturbed by a lack of KIR bearing SOCS1 and SOCS3. We analyzed 34 SLE patients, segregated by disease activity (SLEDAI) and prednisone treatment, in comparison with 11 healthy controls. Real time RT-PCR and Western blot analysis showed significant reductions in SOCS1 and SOCS3 in PMBC’s of SLE patients by both mRNA and protein expression when compared to controls. Notably, decreased SOCS1, but not SOCS3 protein levels in the SLE patients were inversely correlated to activation of STAT1, but not Erk 1/2 or Akt. Notably, the inverted SOCS1/pSTAT1 ratio correlated to significantly enhanced MHC class II levels amongst SLE patients. These studies represent a critical first step in implicating a role of SOCS1 and SOCS3 deficiencies in the progression of human SLE, providing impetus for the performance for a larger multi-centered examination. Finally, these studies point to the possibility that peptides, previously shown to mimic SOCS signaling and inhibit rodent autoimmune disease, may have efficacy in the treatment of human SLE.
Identification of Ezrin-Radixin-Moesin proteins as novel regulators of pathogenic B-cell receptor signaling and tumor growth in diffuse large B cell lymphoma
Authors: Gupta Neetu , Pore Debasis , Danda Avinash , Yan Di , Phillips James , Lindner Daniel , Hill Brian , Smith MItchell , Hsi Eric 
Published: January 2023

Abstract
Diffuse large B cell lymphoma (DLBCL) is a hematological cancer associated with an aggressive clinical course. The predominant subtypes of DLBCL display features of chronic or tonic B cell antigen receptor (BCR) signaling. However, it is not known if the spatial organization of the BCR contributes to regulation of pro-survival signaling pathways and cell growth. Here, we show that primary DLBCL tumors and patient-derived DLBCL cell lines contain high levels of phosphorylated Ezrin-Radixin-Moesin (ERM) proteins. The surface BCRs in both activated B cell and germinal B cell subtype DLBCL cells co-segregate with phosphoERM suggesting that the cytoskeletal network may support localized BCR signaling and contribute to pathogenesis. Indeed, ablation of membrane-cytoskeletal linkages by dominant negative mutants, pharmacological inhibition and knockdown of ERM proteins disrupted cell surface BCR organization, inhibited proximal and distal BCR signaling, and reduced the growth of DLBCL cell lines. In vivo administration of the ezrin inhibitor retarded the growth of DLBCL tumor xenografts, concomitant with reduction in intratumor phosphoERM levels, dampened pro-survival signaling and induction of apoptosis. Our results reveal a novel ERM-based spatial mechanism that is coopted by DLBCL cells to sustain tumor cell growth and survival.
Monocytes and alveolar macrophages skewing in a non-human primate model of HIV-associated pulmonary arterial hypertension (PAH)
Authors: Schweitzer Finja , Kling Heather M , Tarantelli Rebecca , Stehle Alexandria , Simon Mark A. , Norris Karen A 
Published: January 2023

Abstract

Background
PAH is a progressive disease of the pulmonary vasculature and right heart, with an increased prevalence in HIV-infected individuals. The causes of HIV-PAH are not known, though evidence suggests immune-mediated pathogenesis. We hypothesize that chronic inflammation contributes to increased pro-inflammatory monocytes and fibrotic alveolar macrophages, which may promote the vascular remodeling characteristic of PAH. We have developed a primate model of simian immunodeficiency virus (SIV)-PAH. This model was used to address the relationship between phenotypic changes in monocyte/macrophage and the development of SIV-PAH.

Methods
Macaques (n=22) were infected with SIV and serial blood and bronchoalveolar lavage fluid cells were analyzed by flow cytometry. Serial right heart catheterizations were performed to assess mean pulmonary arterial pressure (mPAP).

Results
Nine macaques showed no change in mPAP over the course of infection, whereas 13 developed PH (mPAP &gt;25mm Hg). Higher frequencies of pro-inflammatory, non-classical monocytes were observed in PH+ animals (p=0.0001), correlating with mPAP (p=0.03). PH- animals had a higher frequency of phagocytic, classical monocytes (p=0.046), negatively correlating with mPAP (p=0.02). PH+ animals had a higher frequency of fibrotic M2a macrophages (p=0.02), correlating with mPAP (p=0.035). PH- animals had a higher frequency of regulatory, M2c macrophages (p=0.0003), negatively correlating with mPAP (p=0.005).

Conclusion
These results support the hypothesis that HIV-associated PAH is associated with skewing of monocytes and macrophages toward a pro-inflammatory and fibrotic phenotype that contributes to vascular remodeling associated with HIV-PAH.
Innate correlates of influenza clinical outcomes in a multicenter, longitudinal study of critically ill children
Authors: Fiore-Gartland Andrew , Panoskaltsis-Mortari Angela , Agan Anna A , Thomas Paul Glyndwr , Hertz Tomer , Randolph Adrienne 
Published: January 2023

Abstract
Paradoxically, influenza infection can trigger pro- and anti-inflammatory responses, both of which can lead to significant morbidity and mortality. Inflammation can lead to septic shock and acute lung injury (ALI), while suppression can slow viral clearance and increase susceptibility to bacterial coinfection (BCo). We collected and analyzed lung and peripheral blood samples from a multi-center cohort of critically ill children with influenza infection (N = 171) to better understand innate signatures of disease. Samples were collected at admission to the PICU and assayed for levels of 42 cytokines and chemokines. We found intra-compartment analyte correlations were high, while those between compartments were comparatively weak. To increase statistical power and identify groups of co-signaling cytokines, we pre-specified an unsupervised hierarchical clustering analysis to form influenza-specific modules. Some modules were consistent with the literature; e.g. IL4, IL5, IL9 and IL13 (Th2-like) clustered within both compartments. We hypothesized that modules would associate with shock, ALI and death or near death (ECMO). A pro-inflammatory PB module including IL6, IL8, IL10, IP10, GCSF and MCP1 was associated with shock (FWER p&lt;1e-4; OR 3.4) and ALI (FWER p=0.003; OR 2.2), validating previous studies. Inverse associations were also identified with lung and serum modules, only after adjusting for patients’ mean analyte levels, suggesting that relative levels are important. An integrative analysis of lung and PB analytes showed that BCo has a distinct signature from shock that can be used as a biomarker to distinguish the two. Significant modules also generated hypotheses about analytes that could be targeted by novel therapies.
The lectin complement pathway and Ficolin-2 in patients with necrotizing soft tissue infection
Authors: Hansen Marco Bo , Rasmussen Lars Simon , Pilely Katrine , Hellemann Dorthe , Hein Estrid , Madsen Martin Bruun , Hyldegaard Ole , Garred Peter 
Published: January 2023

Abstract

Background
Mannose-binding lectin (MBL) and ficolins are pattern recognition molecules (PRMs) that play an important role during infection through activation of the lectin complement pathway. We assessed whether blood concentrations of the PRMs were associated with mortality in patients with necrotizing soft tissue infection (NSTI).

Methods
We conducted a prospective, observational study over 25 months involving 135 NSTI patients with a maximum follow-up time of 2.7 years. Plasma PRM level were measured upon admission. Non-infected surgical patients served as controls.

Results
PRMs levels of the lectin complement pathway were significantly lower compared to non-infected patients. Ficolin-2 level below median was associated with mortality at the end of follow-up (p = 0.007, log-rank), whereas no significant association was found for MBL, Ficolin-1 and Ficolin-3. Ficolin-2 level below median had a positive predictive value of 0.27 and a negative predictive value of 0.94 for 28-day mortality. When optimal cut-off was used, the multivariate cox-regression analysis revealed that low Ficolin-2 level was independently associated with 28-day mortality when adjusted for age, gender and chronicity (HR 6.27 [95% CI, 2.28–17.21], p &lt; 0.0001) and also when SAPS II was included (HR 3.16 [95% CI, 1.03–9.73], p = 0.045).

Conclusions
All PRMs of the lectin complement pathway were significantly lower in patients with NSTI than in non-infected controls upon admission. Only plasma Ficolin-2 was significantly associated with both short-term and long-term mortality. Additionally, a high Ficolin-2 level above the median indicated a 94% chance of surviving the first 28 days after admission.
ClinicalTrials.gov Identifier: NCT2180906.
Beta-arrestin 2 plays a critical role in sepsis-induced cardiac dysfunction
Authors: Yin Deling , Yan Hui , Li Hui , Daniels Christopher , Singh Krishna , Chua Balvin , Stuart Charles , Caudle Yi , LeSage Gene 
Published: January 2023

Abstract
Sepsis, a major clinical problem with high morbidity and mortality, is caused by overwhelming systemic host-inflammatory response. β-arrestin 2, a key regulator and scaffolds of various signaling, modulates cell survival and cell death in various systems. However, the effect of β-arrestin 2 on sepsis-induced cardiac dysfunction is not yet known. Here, we show that β-arrestin 2 overexpression significantly enhances animal survival following cecal ligation and puncture (CLP)-induced sepsis. Importantly, overexpression of β-arrestin 2 in mice prevents CLP-induced cardiac dysfunction. In addition, β-arrestin 2 overexpression dramatically attenuates CLP-induced myocardial gp130 and p38 mitogen-activated protein kinase (MAPK) phosphorylation levels following CLP. Therefore, β-arrestin 2 prevents CLP-induced cardiac dysfunction through gp130 and p38. These results suggest that modulation of β-arrestin 2 might provide a novel therapeutic approach to prevent cardiac dysfunction in patients with sepsis.
Strain differences in lung inflammation and injury following progressive exposure to tobacco smoke in rats
Authors: Pham Alexa , Uyeminami Dale , Pinkerton Kent 
Published: January 2023

Abstract

Rationale
Chronic obstructive pulmonary disease (COPD) is currently the third leading cause of death worldwide and has been strongly associated with lung inflammation. To determine whether susceptibility to lung inflammation can lead to an enhancement of COPD-like features, we chose to examine normotensive Wistar-Kyoto (WKY) and spontaneously hypertensive (SH) rats following progressive exposure to tobacco smoke (TS) to determine the relative degree of lung injury and inflammation in each strain of rat.

Methods
WKY and SH rats were exposed to either filtered air or tobacco smoke at a particulate concentration reaching 80mg/m3 for 4, 8, or 12 weeks. Necropsy was performed 24 hours after the last exposure, followed by bronchoalveolar lavage (BAL) fluid to determine total and differential cell count. Histological scoring and immunohistochemical staining for M1 (classically activated) and M2 (alternatively activated) macrophages were performed on paraffin embedded and sectioned lung tissues.

Results
Following progressive smoke exposure, TS-exposed SH rats demonstrated significant increases in BAL total cell number, including elevated numbers of macrophages and neutrophils and higher inflammation scores in lung tissues compared to their FA control and TS-exposed WKY rats. Moreover, TS-exposed SH rats also had increased expression of the M1 but not the M2 markers in alveolar macrophages compared to their FA control and TS-exposed WKY rats.

Conclusion
These findings suggest that progressive tobacco smoke exposure contributes to persistent lung inflammation that is enhanced by rat strain susceptibility in the genesis of COPD.
Cigarette smoke extracts enhance neutrophil elastase-induced IL-8 production via up-regulation of proteinase-activated receptor-2 in human bronchial epithelial cells
Authors: Lee Kyoung-Hee , Jang An-Hee , Jeong Jiyeong , Lee Chang-Hoon , Yoo Chul-Gyu 
Published: January 2023

Abstract
Inflammation, oxidative stress, and protease-antiprotease imbalance have been suggested as a pathogenic triad in chronic obstructive pulmonary disease (COPD). However, little is known about how they interact. The objectives of this study were to elucidate the effect of cigarette smoke extract (CSE) on the neutrophil elastase (NE)-induced inflammatory response and its molecular mechanism in bronchial epithelial cells. NE activated extracellular signal-regulated kinase (ERK) and induced IL-8 production. Blocking ERK activation by MEK inhibitor (U0126) suppressed NE-induced IL-8 secretion and pre-incubation with proteinase-activated receptor 2 blocking peptide (PAR2BP) inhibited both NE-induced ERK activation and subsequent IL-8 release, suggesting that NE-induced IL-8 production is dependent on PAR2-mediated ERK activation. Interestingly, pre-exposure with CSE markedly enhanced NE-induced IL-8 production. Knock-down of PAR2 expression by transfection with siRNAs blocked the synergistic effect of CSE on NE-induced IL-8 production. Therefore, we next investigated the effect of CSE on PAR2 expression. CSE, but not NE, increased the expression of PAR2 mRNA and surface membrane protein. Inhibition of p38 MAP kinase reduced PAR2 expression by CSE, while inhibition of ERK and Akt pathway was without effect. Moreover, p38 inhibition completely abrogated CSE-induced enhancement of IL-8 production in NE-treated cells. Taken together, these results suggest that CSE up-regulates PAR2 in normal human bronchial epithelial cells, thereby enhancing the inflammatory response to NE.
Adipose Fatty Acid Binding Protein Promotes Saturated Fatty Acid-induced Cell Death through Ceramide Production in Macrophages
Authors: Zhang Yuwen , Rao Enyu , Zeng Jun , Hao Jiaqing , Sun Yanwen , Sauter Edward , Cleary Margot , Li Bing 
Published: January 2023

Abstract
Macrophages play a critical role in obesity-associated chronic inflammation and disorders. However, the molecular mechanisms of how macrophages respond to elevated fatty acids (FAs) and contribute to sterile inflammation in obesity remain to be fully elucidated. Here, we report a new mechanism by which dietary FAs, in particular saturated FAs, were able to directly trigger macrophage cell death. We demonstrated that excess saturated FAs, but not unsaturated FAs, induced the production of cytotoxic ceramides in macrophages. Most importantly, expression of adipose fatty acid binding protein (A-FABP) in macrophages facilitated metabolism of excess saturated FAs for ceramide synthesis. Inhibition or deficiency of A-FABP in macrophages decreased saturated FA-induced ceramide production, thereby resulting in reduced cell death. Furthermore, A-FABP-deficient obese mice exhibited increased percentage of CD36+ macrophages in peripheral as compared to WT control mice. Altogether, our data suggest that excess saturated FAs in diets serve as new triggers in inducing ceramide production and macrophage cell death through elevated expression of A-FABP, thus contributing to sterile inflammation in obesity.
The type 2 diabetes-associated Th17 cytokines IL-21 and IL-22 promote breast cancer cell survival.
Authors: Nicholas Dequina , Strissel Katherine J , Andrieu Guillaume , Tran Anna H , Nikolajczyk Barbara S , Denis Gerald V 
Published: January 2023

Abstract
Obesity-induced inflammation has taken center stage as a driving force in metabolic disease and type 2 diabetes (T2D). As the epidemic of obesity deepens, it has become imperative to dissect mechanisms by which obesity-induced inflammation contributes to increased cancer morbidity. Recent studies have shown that increased breast cancer mortality rates are associated with obesity-related T2D. Our goal is to understand the immunological mechanisms in T2D that contribute to increased breast cancer risk. We previously showed that PBMCs treated with T cell-targeted stimuli produce a pro-inflammatory Th17 cytokine profile that differentiates T2D from obese non-T2D subjects. We therefore tested the hypothesis that Th17 cytokines support breast cancer cells. Proliferation assays showed that IL-21 and IL-22, but not IL-17A/F, or the Th1 cytokine IL-6, maintained the proliferation of MCF7 cells, an estrogen dependent breast cancer cell line, in the absence of estrogen. Building on this result, we tested the effect of IL-21/22 on MCF7 survival. Immunoblots and mRNA arrays demonstrated that IL-21 but not IL-22 upregulated steady-state expression of BCL-2 family survival mRNA/protein. Both IL-21 and IL-22 survival was blocked by JQ1, an inhibitor of the Bromodomain and ExtraTerminal (BET) family of chromatin regulating proteins. The inferred cross-talk between BET- and Th17 cytokine-triggered pathways implicate the Th17 cytokine signature from PBMCs of patients with T2D in the higher recurrence of post-menopausal breast cancer after tamoxifen treatment. The public health impact of these data is that monitoring Th17 cytokine production by PBMCs may inform risk assessment for relapse or recurrence in breast cancer patients with T2D.
Human adenosine deaminases control the immune cell responses to activation signals by reducing extracellular adenosine concentration
Authors: LIU Chengqian , Mukienko Yulia , Wu Chengxiang , Zavialov Andrey 
Published: January 2023

Abstract
Adenosine rapidly accumulates in the sites of inflammation and tumor growth. It binds to adenosine receptors expressed on the cell surface of immune cells and induces either suppression or activation of inflammatory responses to pathogens. In humans the level of extracellular adenosine is regulated by two adenosine deaminases ADA1 and ADA2. Decrease in ADAs concentration due to genetic defects in the ADA genes leads to serious perturbation in the immune system function while increase in ADA activity associates with numerous immune diseases and cancers. The immune responses to extracellular adenosine have largely been studied using pharmacological approach where non-hydrolysable adenosine receptors agonists substitute adenosine to form the activated state of adenosine receptors. On contrary, adenosine receptors bound to adenosine receptor antagonists mimic inactivated state of adenosine receptors.
Here, the effect of adenosine receptor agonists and antagonists on the monocytes function as well as and T helper cell proliferation and differentiation was compared with the effect of adenosine and adenosine deaminases. It was demonstrated that adenosine deaminases control the immune cells responses to activation signals by reducing the concentration of extracellular adenosine and that the cells sensitivity to adenosine greatly depends on the type of the cell activation. Therefore, our data suggests that ADAs could be considered as new drug candidates for the treatment of immune disorders and cancers.
ImmuneSpace: Enabling integrative modeling of human immunological data
Authors: Sauteraud Renan , Dashevskiy Lev , Finak Greg , Gottardo Raphael 
Published: January 2023

Abstract
Recent technical advances have transformed the field of immunology. We are now capable of measuring features of immune responses, including B- and T-cell specificity and repertoire, serum and intracellular cytokines, and more, on a scale never imagined before. As a consequence, the generation of big data sets has become routine and there is an urgent need for an analysis platform to facilitate data exploration and integration across assays and studies. Here we present ImmuneSpace, the data repository and analysis platform of the Human Immunology Project Consortium (HIPC). The HIPC program, funded by the NIH, is a multi-center collaborative effort to characterize the status of the immune system in different populations under diverse stimulations and disease states. This ongoing effort has generated large amounts of varied high-throughput, high-dimensional biological data (flow cytometry, CyTOF, RNA-Seq, Luminex, among others). All data generated to date by HIPC, along with other selected datasets generated by other NIAID funded projects, have been made publicly available through ImmuneSpace and are ready to be explored using visualization and analysis tools built in ImmuneSpace. To this end, we hope that ImmuneSpace will act as a central immunological hub, allowing experimentalists, statisticians, and bioinformaticians to freely retrieve, explore and compare data across assays and across studies generated within and outside of HIPC.