bluuebunny/crossref_metadata_2025_split huggingface dataset:
Mast cells as mediators of astrocyte morphology associated with neuroinflammatory disease states
Authors: Sarno Erika L 
Published: January 2023

Abstract
Morphological deficits observed in astrocytes, the most abundant glial cell type in the central nervous system, are associated with various neuroinflammatory diseases. The morphological and molecular astrocyte changes associated with multiple sclerosis are well-characterized and concentrated in the white matter of the brain. While the exact mechanisms behind this autoimmune disease are not fully understood, mast cells play a key role in the progression of white matter demyelination. We hypothesize mast cells orchestrate morphological astrocyte changes that are associated with neuroinflammatory disease states. To test this hypothesis, we used GFAP as a marker to visualize astrocyte morphology in white matter tracts of wild type (WT) and mast cell deficient KitW–sh/W–sh (sash) mice. Using skeleton analysis, we quantified astrocyte characteristics such as number of endpoints, branches, and branch length. Compared with WT mice, sash mice exhibited fewer branches (77 vs. 54 branches/cell) and endpoints per cell (49.5 vs. 24.5 P&lt;0.001). These findings suggest that mast cells may drive altered astrocyte morphology and function in white matter. In order to determine whether this effect is due to altered development, studies using sash mice at time points across the lifespan are in progress. In addition, we are using diphtheria toxin in combination with novel genetic lines to ablate mast cells acutely in adult mice. Along with new molecular techniques, this will allow us to better characterize the interaction between mast cells and astrocytes in the adult and developing brain. Unraveling this interplay will be critical to understanding the role of mast cells in neurodevelopment and neuroinflammatory diseases such as multiple sclerosis.
B cell Ezrin restricts the development of allergen-induced asthma
Authors: Gupta Neetu , Stroberg Alayna , Weiss Kelly , Miao Yanling , Sammeta Ajay , Asosingh Kewal 
Published: January 2023

Abstract
Asthma accounts for substantial morbidity and healthcare burden all over the world. Allergic asthma is characterized by recruitment of immune cells into the lung, mucus production and exaggerated narrowing of the conducting airways. B cells are critical upstream regulators of antibody-mediated immunity and inflammation, with several reports establishing their importance as producers of IgE, presenters of antigen and promoters of the Th2 response in asthma. However, the molecular regulators of the B cell asthma response remain poorly characterized. We have previously reported that Ezrin, a plasma membrane-actin cytoskeleton linker protein regulates B cell function. Here, we show that mice with B cell-specific deficiency of ezrin (Ez-def) display increased lung B cells and eosinophils, IgE production and inflammatory cytokines, and marked deterioration in respiratory function upon sensitization and challenge with house dust mite allergens, as compared to control Mb1cre/+ mice. On a mechanistic level, we observed that Ez-def B cells express higher levels of T cell activating proteins upon antigen stimulation and have enhanced chemotactic ability. Our data suggest that B cell intrinsic ezrin restricts allergic asthma, and may act as an important checkpoint regulator of allergic airway inflammation and hyperresponsiveness by regulating B cell recruitment, activation, antibody secretion and cytokine balance in the lungs.
A novel formulation of budesonide nasal spray (Budesolv 10) potentiates clinical performance in grass pollen allergic patients
Authors: Zieglmayer isabel , Schmutz René , Lemell Patrick , Unger-Manhart Nicole , Nakowitsch Sabine , Goessl Andreas , Savli Markus , Zieglmayer René , Prieschl-Grassauer Eva 
Published: January 2023

Abstract

Objective
Purpose of this DBPC study was to evaluate onset of action and non-inferiority of a novel low dose aqueous solution of Budesonide (“Budesolv 10μg”) to Rhinocort® aqua 64μg (RA) in adult grass pollen allergic patients.

Methods
Budesonide, a poorly water-soluble corticosteroid, currently marketed as suspension, was reformulated to enhance solubility and local concentration on the target mucosa. Subjects received Budesolv, the market comparator RA and placebo once daily for 8 days. Allergic symptoms were induced by 6h grass pollen challenges in the Vienna Challenge Chamber at days 1 and 8 of each treatment period. First dose was applied after 1:45h to evaluate onset of action of either treatment. Nasal, ocular, asthma symptoms and objective measures of nasal secretion and nasal obstruction were evaluated. A 95% confidence interval (CI) was calculated for difference in means between active treatments. Non-inferiority was stated if the upper limit of the CI did not exceed 115% of the reference. Onset of action was defined as first time point when the difference in nasal symptoms change from baseline between active treatment and placebo was p&lt;0.05.

Results
75 patients concluded the study per protocol. The primary endpoint (TNSS; sum of obstruction, itch, sneeze and rhinorrhoea) was met proving non-inferiority of Budesolv compared to RA. A significant difference between Budesolv and placebo was shown for TNSS 2.45 h and for total asthma score 2 h after first dose. On day 8 Budesolv 10μg was significantly better than placebo for all parameters evaluated.

Conclusion
Non-inferiority of Budesolv compared to Rhinocort® was shown on day 8 of treatment. Early onset of action within 3h after first dose was evident for Budesolv only.
Oral administration of Sargassum horneri extract containing Mojabanchromanol attenuates PM-exacerbated allergic airway response in murine model of asthma
Authors: Youngheun Jee , Herath Kalahe Hewage Iresha Nadeeka Madushani , Kim Hyo Jin , Jeon You Jin , Kim Hyun Jung 
Published: January 2023

Abstract
Epidemiological studies indicate correlation with particulate matter (PM) and the pathogenesis of airway inflammatory lung diseases. We sought to identify whether Sargassum horneri ethanol extract containing mojabanchromanol (SHE) confers maximal health benefit against PM exacerbated allergic asthma. Using BALB/c mice undergoing sensitization and challenge with ovalbumin (OVA, 10 μg) we developed a PM exacerbated mouse model of asthma. After 2 weeks of sensitization, mice were challenged with PM (5 mg/m3) for 7 days consecutively together with oral administration of SHE (200, 400 mg/Kg), Prednisone (5mg/Kg) or PBS. SHE restrained Th2 polarization by attenuating transcription factors GATA3 and Signal transducer and activator of transcription (STAT) 5. This resulted in mitigated eosinophil infiltration in airway and balf and secretion of Th2 cytokines interleukin (IL)-4, IL-5, IL-13 in lung homogenates of PM exacerbated asthmatic mice. Immunoglobulin (Ig) E secretion in serum and activation of mast cells in trachea were markedly attenuated. Concomitantly, SHE further restrained the Th17 cell response in PM exposed allergic mice through attenuating expression of transcription factors RORγT, STAT3 and expression of relevant effector cytokines IL-17a. This further mitigated CD11b+ Ly6G+ neutrophil population in lung. Taken together, SHE significantly suppressed PM exacerbated histopathological changes, hyper secretion of mucus in asthmatic mice. These results suggest that SHE might portend a natural candidate against against PM exacerbated allergic asthma via concomitant inhibiting of Th2/Th17 responses. This research was supported by the Ministry of Oceans and Fisheries, Korea (No. 20170285).
TNFSF14 (LIGHT) Induces Airway Smooth Muscle Contraction
Authors: Miki Haruka , Kiosses William B , Herro Rana , Croft Michael 
Published: January 2023

Abstract
Asthma is a chronic inflammatory disorder characterized by reversible airway obstruction and airway hyperresponsiveness (AHR). The precise mechanism responsible for AHR is not known but it may involve excess mucus production and alterations in airway smooth muscle cell (SMC) activity. SMC from asthmatic patients are thought to generate more force and contract to a greater extent to allergens or certain inflammatory stimuli, but which inflammatory stimuli in asthmatics drive contraction is still not clear. Previously, we showed that the tumor necrosis factor superfamily member LIGHT (TNFSF14) promotes airway remodeling and AHR in mouse models of chronic asthma, despite having little effect on airway eosinophilia. Exogenous administration of rLIGHT to the mouse airways also induced smooth muscle hyperplasia. We found that LTβR and HVEM, the receptors for LIGHT, are expressed on both human and mouse SMC from the lungs, with LTbR primarily expressed on human cells, suggesting a direct effect of this T cell-derived cytokine. From studies in vitro with primary human SMC, we found that rLIGHT administration induced contraction of SMC in collagen-gels in 3D structures, and migration of SMC in monolayers. rLIGHT induced both actin polymerization and phosphorylation of myosin light chain which leads to actomyosin formation to induce contraction. rLIGHT promoted both canonical and non-canonical NF-kB in airway SMC, and these signals activated the small GTPase Rac1 and P21-Activated Kinase 1 (PAK1) which are involved in actin rearrangement and myosin light chain kinase activity. These results reveal direct evidence that LIGHT can drive SMC contraction and may directly regulate airway hyperresponsiveness relevant to asthma pathogenesis.
Allergic sensitization upon transdermal exposure to gluten and oral anaphylaxis in an adjuvant-free mouse model of wheat gluten allergy
Authors: Gangur Venugopal , Jorgensen Rick , Gao Haoran , Othman Aqilah , Raghunath Rajsri , Wade Labrawn , Chandra Shivam , Ng Perry KW 
Published: January 2023

Abstract
Wheat allergies are growing globally, similar to many other major food allergies. Exposure to wheat in sensitized subjects can be life-threatening because of the high risk of anaphylaxis. Wheat contains both gluten and non-gluten protein allergens. Previous animal model studies have shown that gluten, when co-administered with powerful adjuvants like alum, can elicit IgE responses and anaphylaxis upon systemic injections. Currently, it is unknown whether skin exposure to gluten, without adjuvants, can cause sensitization for oral anaphylaxis. Here, we tested the hypothesis that transdermal exposure to alcohol-soluble wheat gluten (ASWG) will sensitize mice for oral gluten-induced anaphylaxis. Balb/c mice were produced and maintained on a wheat-free diet during this study. Groups of mice were exposed to ASWG prepared from durum wheat, without adjuvant, using a novel transdermal exposure (TDE) method. Mice were sensitized by nine weekly exposures. A significant and robust ASWG-specific IgE antibody response was observed by the 4th TDE. Anaphylaxis upon oral challenge with ASWG after the 9th TDE was quantified by measuring elevation of plasma MMCP-1, which is a specific immune marker of IgE-mediated anaphylaxis in mice. Mice showed significant elevation of MMCP-1, confirming IgE-mediated anaphylaxis. These data demonstrate for the first time that skin exposure to ASWG, without an adjuvant, can clinically sensitize mice for oral gluten-induced anaphylaxis.
Attenuation of mast cell degranulation and pro-inflammatory cytokine release by rosemary extract and carnosic acid
Authors: Crozier Robert W.E. , Yousef Michael , Hicks Natalie J. , Tsiani Evangelia , MacNeil Adam J. 
Published: January 2023

Abstract
Mast cells are sentinel immune cells that drive normal and pathological inflammatory responses, most notably allergic inflammation. Allergen-induced mast cell activation results in rapid degranulation of preformed pro-inflammatory mediators in the early phase, and sustained release of newly synthesized pro-inflammatory mediators in the late phase. Plant compounds known as polyphenols, have been examined in models of pathology due to their inhibition of pro-inflammatory mediator release. Rosemary extract (RE) and three polyphenolic constituents: carnosic acid (CA), carnosol (CO) and rosmarinic acid (RA) have been found to inhibit signaling cascades required for pro-inflammatory mediator release. The objective of this study was to establish the inhibitory effects of RE in a mast cell model and dissect the polyphenolic mixture, focusing on CA, CO, and RA, evaluating their potential as novel therapeutics. Sensitized mast cells were stimulated with allergen and treated with RE (5–50 μg/ml), CA, CO or RA (1–100 μM). The β-hexosaminidase release assay was used to measure degranulation, and cytokine release was measured by ELISA. Degranulation was inhibited dose dependently to 10% when treated with RE, 14% CA and 17% CO (p&lt;0.001), while RA had no effect. ELISA analysis showed RE and CA inhibit release of IL-6 (p&lt;0.05, p&lt;0.0001), TNF (p&lt;0.05, p&lt;0.0001), and IL-13 (p&lt;0.05, p&lt;0.0001) while CO and RA had no effect. These novel findings identify RE and CA as potent regulators of mast cell functional responses. Further dissecting the mechanism behind RE and CA mediated inhibition of pro-inflammatory mediator release, will support the establishment of these natural plant products as effective anti-inflammatory therapeutics.
A novel neuroinvasive infection modality for Francisella tularensis elicits neuroinflammation resulting in cellular damage
Authors: Muniz Mireya G Ramos , Spencer Charles T 
Published: January 2023

Abstract
Francisella tularensis (Ft.) is a gram-negative coccobacillus bacterium that causes the zoonotic disease tularemia in humans. Ft. causes the most severe form of the disease through inhalation, but is most commonly transmitted through direct contact with infected animal carcasses such as rodents and rabbits. Due to its extremely low infectious dose, high mortality rate, and potential use as a biological warfare agent, Ft. is classified by the CDC as a Tier 1 select agent. Ft. infection triggers an overactive inflammatory response, termed a “cytokine storm”, which produces excessive tissue damage of vital organs, leading to rapid death of the host before its adaptive immunity responses can be brought to bear against the infection. In the periphery, macrophages, paradoxically the target cell for Ft., provide innate immune defense against foreign material, including bacteria. Microglia, the resident macrophage-like cells of the central nervous system, rapidly respond to pathological changes, serving a similar function as macrophages. Their rapid activation is an important factor in guarding the neural parenchyma against infectious diseases, inflammation, and neurodegeneration while maintaining and facilitating the return to tissue homeostasis. In the United States, several clinical cases of tularemic meningitis were diagnosed since 1931; however, there is no further research exploring the condition. We hypothesize that, after peripheral inoculation of Ft., the bacteria infiltrate the central nervous system using a Trojan horse-type mechanism and infect microglia, leading to overproduction of pro-inflammatory cytokines in the brain which then cause damage to surrounding neurons, ultimately leading to death.
Identification of antimicrobial molecules released by Th17 targeting both Gram positive and Gram negative bacteria
Authors: Agak George W , Mouton Alice , Teles Rosane M. B , Weston Thomas , Morselli Marco , Pellegrini Matteo , Modlin Robert L 
Published: January 2023

Abstract
TH17 cell subpopulations have been defined that contribute to inflammation and homeostasis, yet the characteristics of TH17 cells that contribute to host defense against infection are not clear. To elucidate the antimicrobial machinery of the TH17 subset, we studied the response to Cutibacterium acnes, a skin commensal that is resistant to IL-26, the only known TH17 secreted protein with direct antimicrobial activity. We generated C. acnes-specific antimicrobial TH17 clones (AMTH17) with varying antimicrobial activity against C. acnes. A combination of RNA-seq and informatics analysis unraveled the transcriptional and antimicrobial gene profiles present in modules associated with the AMTH17 vs. non-antimicrobial TH17 cells. The expression of antimicrobial genes such as GNLY, GZMB, HIST2H2B also correlated with secreted antimicrobial proteins as measured by ELISA, and antimicrobial activity as determined in CFU assays. Scanning electron microscopy reveal that AMTH17s can release antimicrobial molecules that kill C. acnes and other Gram-positive and Gram-negative bacteria. Our study identifies a functionally distinct subpopulation of TH17 cells with an ability to secrete antimicrobial proteins in order to capture and kill bacteria.
Repeated febrile malaria exposure remodels monocytes/macrophages toward a regulatory/tolerogenic phenotype
Authors: Guha Rajan , Mathioudaki Anna , Arora Gunjan , Li Shangping , Siddiqui Shafiuddin , Doumtabe Didier , Doumbo Safiatou , Ongoiba Aissata , Traore Boubacar , Zaugg Judith , Crompton Peter D 
Published: January 2023

Abstract
In malaria-naïve individuals, P. falciparum (Pf) infection results in numerous Pf-infected red blood cells (iRBCs) that trigger systemic inflammation and fever. Conversely, repeatedly infected individuals in endemic areas are often asymptomatic and have low levels of iRBCs, even children who have yet to acquire reliably protective antibodies. The molecular mechanisms underlying these clinical observations are unclear. PBMCs collected from Malian children before the malaria season responded to iRBCs by producing pyrogenic, pro-inflammatory mediators such as IL-1β, IL-6 and TNF. However, following febrile malaria there was a marked shift in the response to iRBCs with the same children’s PBMCs producing lower levels of those cytokines. These data suggest that malaria-induced epigenetic reprogramming of innate immune cells may play a role in immunity to malaria. Accordingly, age-stratified analysis of monocytes collected before the malaria season showed an inverse relationship between age and pro-inflammatory cytokine production capacity. Monocytes of Malian adults expressed higher levels of CD163, CD206, Arginase-1, TGM2, molecules which are known to be associated with regulatory phenotype. These observations were recapitulated with an in vitro system of monocyte-macrophage differentiation whereby re-exposure to iRBCs was associated with diminished expression of pro-inflammatory mediators and a corresponding decrease in epigenetic markers of active gene transcription (i.e. H3K4me3) at the TSS of the same pro-inflammatory mediators. Together these data support the hypothesis that epigenetic reprogramming of monocytes/macrophages toward a regulatory phenotype contributes to clinical immunity to malaria.
Vps33B is a crucial regulator of Type I Interferon response downstream of the cGAS-STING pathway
Authors: Meibers Hannah , McDaniel Margaret , Pasare Chandrashekhar 
Published: January 2023

Abstract
Vacuolar protein sorting-associated protein 33B (Vps33B) plays a critical role in the trafficking of endosomal contents to lysosomes in macrophages, particularly following Toll-like receptor (TLR) activation. Upon activation by microbial ligands, TLRs are internalized into endosomes, then trafficked to lysosomes for degradation. We have previously shown that endosomal to lysosomal trafficking, and subsequent degradation of TLR4, is mediated by Vps33B. Without this crucial degradation step, TLRs remain trapped within altered endosomes, leading to an enhanced inflammatory response. Since Vps33B is critical for termination of signaling following TLR ligation, we wanted to determine if it had a conserved role in regulating other pattern recognition receptor (PRR) signaling pathways. Specifically, we investigated the role of Vps33B in regulating cytosolic DNA sensing by the cGAS-STING pathway. Absence of Vps33B in macrophages and mouse embryonic fibroblasts resulted in an exaggerated type 1 interferon and interferon-stimulated gene response after stimulation with dsDNA and other STING ligands. Our findings suggest that Vps33B has a conserved role as a regulator of innate inflammatory responses downstream of both plasma membrane as well as cytosolic PRRs. Mechanistically, we hypothesize that Vps33B plays a role in STING degradation, similarly to how it permits TLR4 degradation, through mediating endo-lysosomal trafficking. This would suggest a broad and critical role for Vps33B in PRR-induced vesicular transportation and receptor degradation. Future work will investigate the mechanisms by which Vps33B regulates STING-mediated signaling as well as its importance for anti-viral immunity.
Endogenous oxidized phospholipids reprogram cellular metabolism and boost hyperinflammation
Authors: Zanoni Ivan , Di Gioia Marco 
Published: January 2023

Abstract
Pathogen-associated molecular patterns (PAMPs) have the capacity to couple inflammatory gene expression to changes in macrophage metabolism, both of which influence subsequent inflammatory activities. Similar to their microbial counterparts, several self-encoded damage-associated molecular patterns (DAMPs) induce inflammatory gene expression. However, whether this symmetry in host responses between PAMPs and DAMPs extends to metabolic shifts is unclear. Here we report that the self-encoded oxidized phospholipid oxPAPC alters the metabolism of macrophages exposed to lipopolysaccharide (LPS). While cells activated by LPS rely exclusively on glycolysis, macrophages exposed to oxPAPC also use mitochondrial respiration, feed the Krebs cycle with glutamine and favor the accumulation of oxaloacetate in the cytoplasm: this metabolite potentiates IL-1beta production, resulting in hyperinflammation. Similar metabolic adaptions occur in vivo in hypercholesterolemic mice and human subjects. Drugs that interfere with oxPAPC-driven metabolic changes reduce atherosclerotic plaque formation in mice, thereby underscoring the importance of DAMP-mediated activities in pathophysiological conditions.
Human monocyte chromatin accessibility variations identify inflammaging heterogeneity
Authors: Singh Amit K , Mazan-Mamczarz Krystyna , Roy Roshni , Kaileh Mary , Sarantopoulou Dimitra , Yin Jinhu , Bektas Arsun , De Supriyo , Zukley Linda , Weng Nan-Ping , Sen Ranjan 
Published: January 2023

Abstract
Human aging is associated with low grade chronic inflammation termed, inflammaging, which is a significant risk factor for morbidity and mortality in elderly population. The innate immune system is implicated as master regulator of this process via expression of cytokines and other key mediators. We used ATAC-seq to identify chromatin signatures in monocytes obtained from healthy donors of the GESTALT cohort. State of differentially open chromatin (DOC) between young (&lt;60y) and older (&gt;60y) donors were identified. Older donors segregated in two clusters, young-like and distinct old-like cluster. Old-like DOC’s enriched for intergenic enhancer-like elements dominated by the DNA binding motif of the transcription factor NF-κB. The relationships of age-associated DOC to gene expression and DNA methylation reveled enrichment of cytokine mediated inflammatory pathways. Ongoing studies of cytokine expression using high-dimensional flowcytometry will be used to determine the functional consequences of chromatin structural changes associated with age.