bluuebunny/crossref_metadata_2025_split huggingface dataset:
MIA-reprogramed ILC2s promote enhanced lung allergic inflammation in offspring postnatally and into adulthood
Authors: Lopez Diego A , Griffin Aleah , Beaudin Anna E 
Published: August 2023

Abstract
Innate lymphoid cells (ILCs) are a relatively recently identified class of specialized innate-like lymphocytes that are the topic of intense investigation for their role in immune function during homeostasis and disease states. Accumulating evidence suggests that dysregulation of ILC2s and ILC2-derived Type II cytokines plays a critical role in the development of allergic airway hyper-responsiveness and asthma. To test how prenatal inflammation impacts ILC2 establishment, I profiled changes to a committed progenitor to all ILC lineages in the fetal liver (FL). MIA induction during mid-gestation expanded FL Common helper Innate Lymphoid Progenitors, resulting in robustly expanded and hyper-proliferative neonatal ILC2s exhibiting a greater inflammatory phenotype, producing more IL-5 and IL-13 cytokine on a per-cell basis. Hyper-activated ILC2s drove remodeling of the lung immune landscape, with multiple immune cell compartments, including eosinophils and alveolar macrophages, exhibiting expansion during the first two weeks of life in MIA-treated offspring. Surprisingly, levels of IL-33, a potent ILC2 activator, significantly decreased after MIA, and ILC2s were hyper-responsive to IL-33 in ex vivo culture. Single-cell RNA sequencing of neonatal lung ILC2s revealed extensive heterogeneity between MIA and saline litters, including clusters unique to MIA-exposed litters, and transcriptional similar to ILC2 signatures in human asthma patients. Altogether, my data suggests prenatal inflammation imparts lasting changes to lung immunity by perturbing the establishment of committed ILC progenitors in the FL, affecting the generation of neonatal lung ILC2s poised to hyperactively respond to secondary immune activation.
NIH/NICHD training grant T32HD007491 The Pew Biomedical Scholars Award
B1 B cells contribute to inflammation and metabolic dysfunction in aged adipose tissue during endotoxemia
Authors: Carey Anna F , Kandikonda Pranathi , Dahlquist Korbyn , Cholensky Stephanie , Camell Christina 
Published: August 2023

Abstract
The elderly are at the greatest risk for severe endotoxemia and bacterial infections. The increase in low grade chronic inflammation and the decline of the immune response during aging contributes to this disease severity. Visceral adipose tissue (vWAT) exhibits immune recruitment and activation during pathogen challenge and metabolic diseases. Immune cells regulate lipolysis in vWAT which is required for the regulation of inflammation, but the intersection of bacterial inflammation and metabolism during aging is not clear. We investigated the contribution of B cells to metabolic dysfunction and inflammation during endotoxemia in vWAT. Old vWAT exhibited elevated inflammation and altered activation of resident B cells during LPS-induced endotoxemia. LPS also induced vWAT lipolysis in young mice but not in old mice. Diet induced obesity resulted in elevated LPS-induced inflammatory cytokines and B cells that failed to become activated by LPS. Deficiency of total B cells improved the homeostatic balance of immune cells within vWAT microenvironment, resulting in increased lipolysis and reduced Tnfα during endotoxemia in old mice. In contrast, B2 B cell depletion was insufficient to increase LPS-induced lipolysis or reduce inflammatory cytokines in vWAT from old mice, suggesting a driving role for B1 cells. B1 B cells from young and old vWAT were differentially activated by LPS indicating age-associated dysfunction. Our results demonstrate that endotoxemia results in immune and metabolic activation within the vWAT, both of which are dysfunctional during aging. These data reveal B cell subsets may differentially impair lipolysis and exacerbate the inflammatory response in vWAT following pathogenic challenge.
Supported by grants from NIH (R00 AG058800, R01 AG079913)
Investigating the roles of fetal-specific genes in hematopoiesis
Authors: Welsh Alia , Wilkinson Adam , Roy Anindita , Muljo Stefan Adi 
Published: August 2023

Abstract
Hematopoiesis, the process which generates blood cells, changes significantly during mammalian development. Fetal hematopoiesis primarily takes place in the fetal liver (FL), where hematopoietic stem cells (FL HSCs) are characterized by high self-renewal capacity and a distinctive program of multilineage differentiation. After birth, the main location of hematopoiesis is the bone marrow (BM), where stem cells (BM HSCs) are less proliferative and have a more restricted differentiation capacity. How exactly fetal hematopoiesis transitions to adult hematopoiesis and which cell-intrinsic properties or environmental factors aid this process have yet to be defined. This project aims to elucidate the cell-intrinsic mechanisms behind this transition. Studies show that FL and BM HSCs have distinct gene expression profiles, which may account for some of their phenotypic differences. Genes, such as LIN28B, which encodes an RNA binding protein, are highly expressed in the fetus, yet are absent in postnatal life. The re-expression of such fetal specific genes can confer fetal-like self-renewal and proliferation. Previous work in the Muljo lab demonstrated that LIN28B re-expression partially reprograms BM HSCs to undergo fetal-like lymphopoiesis, which is characterized by increased development of innate-like lymphocytes. I aim to fully reprogram adult BM HSCs to phenotypically resemble FL HSCs in their ability to generate cell types that develop early in life. FL HSCs, though clinically promising, are not readily available for therapeutic use. Reprogramming adult BM HSCs may be a suitable alternative that could improve current HSC transplantation procedures.
This work is supported by the Intramural Research Program of NIAID, NIH.
Intramural Research Program NIAID NIH
Role of walnut-derived urolithins in reducing colonic inflammation in a patient cohort elucidated by an integrated omics analysis
Authors: Moussa Marmar R , Fan Nuoxi , Nakanishi Masako , Hatano Yuichiro , Provatas Anthony , Vaziri Haleh , Birk John , Rosenberg Daniel W 
Published: August 2023

Abstract
Diet can directly affect colon health and cancer risk. For example, the polyphenolic ellagitannins (punicigalin) that are present in walnuts are converted by the microbiome to a panel of bioactive urolithin metabolites. In particular, urolithin A has been studied for its anti-inflammatory and anti-cancer properties. In this pilot clinical trial, we evaluate the effects of walnut consumption (2-oz per day) on urinary urolithins and blood serum inflammatory markers, as well as on the transcriptome of normal colon and polyp tissue in 38 healthy obese and non-obese subjects. Our in-depth computational analysis of metabolomics and proteomics data suggests that subjects with higher urolithin A formation show significantly lower levels of several key serological markers of inflammation, including C-Peptide, sICAM-1, sIL6-R, Ghrelin, TRAIL, sVEGFR2, MCP2, and Haptoglobin. Furthermore, RNA-Seq transcriptomic analysis of colon tissue taken from proximal and distal colon shows reduced inflammatory programs and activation of the KICSTOR complex in subjects with higher urolithin A formation. These studies indicate that higher urolithin A formation is linked to an anti-inflammatory response, warranting further studies to better understand the role of urolithins in the inflammatory process.
Supported by grants from American Institute for Cancer Research, California Walnut Commission, and National Cancer Institute (R01 CA252045).
Maternal high fat diet exposure results in maternal microbiome dependent increase in inflammatory cytokines and decrease in neurons in offspring brain
Authors: Tran Tuan Q , Niu Xinying , Wu Jun , Lu Dongmei , Leon Rachel , Minassian Berge , Mirpuri Julie 
Published: August 2023

Abstract

Introduction
We hypothesized that maternal high fat diet (mHFD) exposure will result in a microbiota dependent increase in inflammation and inhibition of axonal development in offspring brain.

Methods
Conventional and germ-free murine dams were exposed to 60% high fat diet (HFD) or regular diet (RD) prior to mating. Offspring brains were collected at 2-weeks of life and analyzed for inflammatory (TNF-α, IL-6, IL-17A, IL1β and TGF-β) and regulatory markers of neuronal development (Nurr1) by quantitative RT-PCR. RNA seq was performed on whole brain in conventional mice. We quantified differences in regional neurons by histology (Nissl and H&E). Behavioral studies on mHFD and RD offspring are ongoing.

Results
mHFD offspring had a significant increase in the inflammatory cytokines IL-17A and IL-6 when compared to controls. Nurr1 was increased 50-fold in mHFD offspring. In germ-free mHFD offspring, there was no difference. Quantification of neurons by Nissl staining demonstrated a decrease in neuron cell count in the cortex (20% decrease), and in hippocampal regions (22% in CA2 and 32% in CA3). Preliminary RNAseq analysis showed upregulation of specific genes involved in immunoregulation, neuron development and migration, and apoptosis in mHFD offspring.

Conclusion
mHFD exposure resulted in increased inflammatory cytokines and reduced neurogenesis in the offspring brain. This change was ameliorated in germ free mice, demonstrating a microbiome dependent diet effect. RNAseq findings demonstrate changes in specific immunoregulatory pathways which warrant further exploration. We speculate that maternal diet interacts with the maternal microbiome to increase immune activation in the fetal brain which affects neurogenesis.

Supported by grants from NIH (R01 1K12HD068369) and Children’s Medical Center Research Grant
Itaconic acid underpins hepatocyte lipid metabolism in non-alcoholic fatty liver disease
Authors: Weiss Jonathan M , Palmieri Erika M , Gonzalez-Cotto Marieli M , Bettencourt Ian A , Megill Emily L , Snyder Nathaniel W , McVicar Daniel W 
Published: August 2023

Abstract
Itaconate, the product of the decarboxylation of cis-aconitate, regulates numerous biological processes. We and others have revealed itaconate as a regulator of fatty acid beta-oxidation, generation of mitochondrial reactive oxygen species and the metabolic interplay between resident macrophages and tumors. In the present study, we show that itaconic acid is upregulated in human non-alcoholic steatohepatitis and a mouse model of non-alcoholic fatty liver disease. Mice deficient in the gene responsible for itaconate production (Immunoresponsive gene /Irg-1) have exacerbated lipid accumulation in the liver, glucose and insulin intolerance and mesenteric fat deposition. Treatment of mice with the itaconate derivative, 4-OI, reverses dyslipidemia associated with high fat diet feeding. Mechanistically, itaconate treatment of primary hepatocytes reduces lipid accumulation and increases their oxidative phosphorylation in a manner dependent upon fatty acid oxidation. We propose a model whereby macrophage-derived itaconate acts in trans upon hepatocytes to modulate the liver’s ability to metabolize fatty acids.
This research was supported, in part, by the Intramural Research Program of the NIH, National Cancer Institute, CCR, CIL. RNA sequencing and initial data analysis were conducted at the Frederick National Laboratory for Cancer Research at the CCR Sequencing Facility, NCI Frederick. Human specimens were provided by the Clinical Biospecimen Repository and Processing Core of the Pittsburgh Liver Research Center (supported by National Institutes of Health grant 1P30DK120531). Acyl-CoA analysis was supported by R01GM132261 to NWS.
D-2-hydroxyglutarate decreases allergic sensitization in asthma
Authors: Del Carmen Camarena Maria , Tharakan Anuj , Conrad Daniel , Martin Rebecca 
Published: August 2023

Abstract
Allergic asthma is a chronic inflammatory disease affecting the lungs which is mediated by allergen-specific IgE and type 2 cytokines. IgE and type 2 cytokine production require Tfh13 cell and Th2 cell polarization, respectively, which must first be primed by dendritic cells (DC). Recent studies demonstrate that cellular metabolic perturbations critically regulate DC activation and subsequent T cell priming. To characterize DC metabolic mechanisms which may regulate allergic sensitization, we analyzed GWAS data to identify metabolism-related genes that are associated with asthma risk. We identified 384 single nucleotide polymorphisms (SNPs) in the D2HGDH locus that are significantly associated with childhood-onset asthma. Further, expression quantitative trait loci analysis of the 10 most significant SNPs revealed that these SNPs promote reduced expression of D2HGDH mRNA. D2HGDH is an enzyme which catalyzes the conversion of D-2-hydroxyglutarate (D-2HG) to α-ketoglutarate (aKG). D-2HG is a potent inhibitor of aKG-dependent epigenetic enzymes. Bone marrow-derived dendritic cells (BMDCs) stimulated with the fungal allergen Alternaria exhibited a significant increase in the ratio of aKG/D-2HG compared to mock or LPS treated BMDCs. Further, in vivo studies revealed that intranasal administration of cell-permeable D-2HG prior to intranasal exposure to Alternaria significantly reduced Th2 and Tfh13 polarization, impaired IgE+ germinal center B cell differentiation, and induced T follicular regulatory cell polarization in mice. Our results suggest a mechanism whereby D-2HG suppresses epigenetic modifications in DCs, which are necessary for allergic sensitization and polarization of Th2 and Tfh13 cells.
VCU CTSA UL1TR002649 as well as funding from NIAID R56AI139658
Sterol isolated from Sargassum horneri attenuated particulate matter-exacerbated allergic asthma through the Th17 response
Authors: Jin Kim Hyo , Yang Jiwon , Udayanganie Olupathage Indrachapa , Ko Mi-Ok , Jeon You-Jin , Kim Hyun Jung , Jee Youngheun 
Published: August 2023

Abstract
Particulate matter (PM) has become a serious health issue causing pulmonary diseases such as asthma. Due to the side effects and non-specificity of conventional drugs, it is a need to develop alternative treatment using natural product. Sargassum horneri (S. horneri) is an edible species of large brown algae inhabiting the coasts of northeastern Asia extensively. S. horneri has sterols and has been used in oriental medicine to treat allergic condition. Therefore, we investigated if sterol isolated from S. horneri ethanol extract (SHE-sterol) could mitigate the PM-exacerbated allergic asthma. To establish a mouse model of asthma, BALB/c mice were sensitized with ovalbumin (OVA, 10 mg) and challenged with PM (5 mg/m3) for 7 days consecutively. SHE-sterol (50, 200 mg/kg), Prednisone (5 mg/kg). In SHE-sterol, fucosterol was specially identified as 0.701 μg/mL. SHE-sterol attenuated the PM-aggravated granulocytes infiltration. Moreover, SHE-sterol further attenuated PM-exacerbated eosinophil infiltration in the lung, trachea, and BALF. In addition, SHE-sterol markedly mitigated the activation of mast cells and the IgE level in serum. Concomitantly, SHE-sterol further restrained the Th17 cell response in PM-exposed allergic mice through attenuating expression of relevant effector cytokine IL-17A. This resulted in mitigated neutrophil infiltration in the lung. Also, SHE-sterol significantly suppressed PM-exacerbated hypersecretion of mucus in asthmatic mice. Taken together, these results suggest that sterol isolated from SHE has therapeutic potential for treating PM-exacerbated allergic asthma.
This research was funded by the Ministry of Education (2019R1A6A1A10072987 and 2022R1I1A1A01072505).
NOX2-Deficient Pulmonary Neutrophils and Macrophages Have Lower PD-L1 Expression and May Aggravate Allergic Lung Inflammation through Affecting ILC Populations
Authors: Ling Lun-Ling , Shieh Chi-Chang 
Published: August 2023

Abstract
Redox balance plays an important role in the pathogenesis of allergic asthma. We previously reported that NADPH oxidase 2 (NOX2)-derived ROS may modulate tissue inflammation through affecting neutrophil programmed cell death 1 ligand 1 (PD-L1) expression. To reveal the role of NOX2 in regulating PD-L1 expressions on pulmonary neutrophils and macrophages and in ILC differentiation, we established an allergic asthma model using NOX2-deficient (Cybb−/−) mice stimulated with the Dermatophagoides pteronyssinus (Der p) extract along with LPS. We first found that NOX2 deficiency led to increased group 2 innate lymphoid cell (ILC2) in Der p extract induced lung inflammation. The cell numbers of neutrophil, eosinophil and alveolar macrophage (AM) also increased in the stimulated Cybb−/− mice when compared with WT mice. The AM in Cybb−/− mice expressed higher levels of CD11b and the M2 marker CD163 and produced more TNF-α. Moreover, the Cybb−/− neutrophils and AMs had low PD-L1 expressions while ILC2s had significant levels of programmed cell death 1 (PD-1) expression in the inflammatory lungs. Altogether, these results indicated that NOX2 deficiency may lead to downregulation of PD-L1 expression on neutrophils and AMs while eliciting the M2 phenotype and inducing higher amounts of pro-inflammatory cytokine production. Our results suggested that the lowered PDL1 on NOX2-deficient neutrophils and AMs may aggravate allergic Inflammation through affecting ILC populations in the lung.
c-Kit signaling modulated group 3 innate lymphoid cell functions in mouse neutrophilic asthma model
Authors: Shao Jheng-Syuan , Chi Po-Yu , Chang Ya-Jen 
Published: August 2023

Abstract
Group 3 innate lymphoid cells (ILC3s) are involved in air pollution- and bacterial infection-associated neutrophilic asthma. Studies showed that asthmatic patients have higher stem cell factor (SCF) expression in airway and sera. Of note, ILC3s express SCF receptor, c-Kit, suggesting a potential role of SCF/c-Kit signaling in ILC3 functions and neutrophilic asthma. In this study, we aimed to determine whether SCF/c-Kit signaling could modulate ILC3 functions and neutrophilic asthma. Wild-type (WT) and c-Kit deficient mice (Kitw-sh) were intranasally treated with IL-1β/IL-23 or particulate matter (PM) 2.5 to induce neutrophilic asthma. While IL-1β/IL-23 or PM2.5 caused increases in neutrophil infiltration to bronchoalveolar lavage fluid (BALF) and airway hyperreactivity (AHR) in WT mice, Kitw-sh mice had decreased infiltration of neutrophils and ameliorated AHR. Concomitantly, flow cytometry results showed a decreased number of IL-17+ ILC3 in the lung of Kitw-sh mice compared to WT mice, which may be due to the reduced proliferation of c-Kit-deficient ILC3. In addition, we showed SCF enhanced IL-17 secretion from ILC3s in vitro. Based on re-analysis of published mouse whole lung cells scRNAseq data, we hypothesized fibroblasts are the source of SCF. Indeed, mice with SCF knockout in fibroblast exhibited decreased neutrophil infiltration and reduced IL-17+ ILC3 number in response to IL-1β/IL-23. Finally, administration of imatinib, a FDA-approved drug targeting c-Kit signaling, ameliorated AHR and ILC3 activation in the mouse neutrophilic asthma model. Taken together, our data suggested that inhibition of ILC3 activation by targeting c-Kit signaling may provide a potential therapeutic management for neutrophilic asthma.
The role of protease activity and monocyte subsets in initiating a Th2 response following allergen exposure
Authors: Meloun Audrey Rae , León Beatriz 
Published: August 2023

Abstract
Allergy diseases are primarily caused by aberrant T helper 2 (Th2)-driven immune responses to allergens. During the primary sensitization phase, allergen specific Th2 cells are activated and become central players in orchestrating the subsequent development of allergic inflammation following secondary exposure to the same allergen. Still, the mechanisms by which the innate immune system detects allergens and initiates Th2 responses remain unclear. Protease activity is a feature common to many allergens, including house dust mite (HDM) and papain, a protein-digesting enzyme found in latex and papaya. Using models of Th2 airway inflammation induced by the allergens HDM and papain, we show that protease activity on allergens is required for the stimulation and clonal expansion of antigen specific T cells and their polarization towards a Th2 cell profile. Mechanistically, we found that protease activity was, in particular, required for enhanced migration of allergen-carrying dendritic cells (DCs) from the lung to draining lymph nodes and the subsequent activation of T cells throughout both phases of allergic disease. Our results suggest this occurs through CCR7 and CD86 expression. Further, we observed a decrease in monocytes and monocyte derived DCs when no protease activity was present within the allergens. Our results determine the early events involved in innate immune recognition of allergens and highlight a potential role for monocytic cells in initiating Th2 responses to allergens containing protease activity.
Supported by National Institutes of Health grant 2R01AI116584 to B. León.
Chemokine CCL19 promotes type 2 helper T cell differentiation and allergic airway inflammation
Authors: Nakano Hideki , Lyons-Cohen Miranda R , Nakano Keiko , Wilkinson Christina L , Izumi Gentaro , Grimm Sara A , Whitehead Gregory S , Cook Donald N 
Published: August 2023

Abstract
Allergic asthma is largely driven by the actions of allergen-specific CD4+type 2 T helper (Th2) cells. Following allergen inhalation, these cells are induced by the interaction of naïve CD4+ T cells with antigen-bearing dendritic cells (DCs) in lung-draining lymph nodes (LNs). The molecular mechanisms underlying the induction of T helper cells have been well studied and include the migration of allergen-bearing DCs from the lung to regional LNs in a manner dependent on the chemokine receptor, CCR7. Previous studies have demonstrated that CCL21, a CCR7 ligand, is required for the accumulation of naïve T cells and activated DCs in the LNs, but the function of another ligand, CCL19, has been unknown. In the present study, we investigated the role of CCL19 in allergic airway inflammation using CCL19-deficient mice. In a mouse model of asthma, eosinophils and lymphocytes were significantly reduced in airways of CCL19-deficient mice compared with those of wildtype (WT) animals, and production of IL-4 and IL-13 in the lung was significantly diminished, suggesting that CCL19 is required for type 2 immune responses. Co-cultures of naïve WT CD4+ T cells with CCL19-deficient DCs produced less type 2 cytokines than did T cells co-cultured with WT DCs. Further, fibroblastic reticular cells (FRCs) from CCL19-deficient mouse LNs produced less Th2 cytokine production compared with WT FRCs. Addition of recombinant CCL19 to the culture of naïve CD4+ T cells increased phosphorylation of STAT5 and gene expression of Il2, Il2ra, Il2rb, Il2rg, Sta5a, Stat5b and Stat6. Together, our findings suggest that CCL19 produced by DCs and FRCs promotes Th2 differentiation through the activation of STAT5-signaling, and that this promotes allergic airway inflammation.
This work was supported by Intramural Research Program of NIEHS, NIH (ZIA ES102025-09).