bluuebunny/crossref_metadata_2025_split huggingface dataset:
Sex-differences in the response to inhaled nanoparticles
Authors: Ray Jessica , Holian Andrij 
Published: January 2023

Abstract
Multi-walled carbon nanotubes (MWCNTs) are a versatile engineered nanomaterial of which the production and integration into consumer products is rapidly expanding. Unfortunately, the risk of occupational and environmental exposures continues to increase, yet long-term consequences and potentially sensitive populations remain undefined. Notably, the respiratory response to MWCNTs closely resembles that seen in asthma, including airway hyper-responsiveness (AHR), Th2-type cytokine production, and eosinophil recruitment to the airways. Based on the similarities in disease pathology and the evidence that asthma occurs most commonly in women of reproductive age, I hypothesized that female animals would be more sensitive to MWCNTs than males. Male and female C57BL/6 mice were exposed to a single dose of MWCNTs or exposed once per week for 4 weeks and harvested 8-weeks after the last exposure. Lung lavage fluid was analyzed for cytokine expression and immune cell recruitment; histology was performed on lung sections. Comparable to the results seen in asthma, female animals mounted a greater Th2-type immune response and subsequent lung pathology. At all time points airway eosinophil recruitment and IL-33 expression, key mediators in both allergic asthma and MWCNT-induced inflammation, were significantly elevated in females compared to males. Lung pathology in the repeated, long-term exposure study reflected the differences seen in the acute response and was more severe in female animals than in males. The next step in this project is to investigate the modification of alveolar macrophage phenotype through steroid hormone signaling as an explanation for the sex-differences observed. Work supported by R01 ES023209.
EGF-like repeats and discoidin I-like domain 3 (EDIL3) deficiency improves post-myocardial infarction healing via neutrophil extracellular traps (NETs) mediated pro-inflammatory macrophage polarization
Authors: Wei Xiaoqiong , Zhang Chengxin , Xie Zhonghui , Teng Xiu , Wang Zhen , Zheng Huaping , Zou Song , Huang Nongyu , Cui Kaijun , Li Jiong 
Published: January 2023

Abstract
After myocardial infarction (MI), injured cardiomyocytes recruit neutrophils, leading to extravasated monocytes polarized to inflammatory and reparative macrophages sequentially, which contribute to the healing and regenerative process. As an endogenous leukocyte-endothelial adhesion inhibitor, the role of EDIL3 in MI remains obscure. We found that serum EDIL3 level of MI patients was negatively associated with MI biomarkers, including CK-MB, cTnI and MGB. EDIL3−/− mice showed improved infarct healing with lower mortality, better cardiac function and decreased infarcted size compared with wild type (WT). Enhanced neutrophil infiltration resulted in the increase of Ly6Chi MHClo Mertk− macrophages, which we identified to be pro-inflammatory, protecting EDIL3−/− mice hearts from excessive fibrosis. A neutrophil infiltration antagonist not only eliminated the difference in cardiac function between WT and EDIL3−/− mice, but also reduced Ly6Chi MHClo Mertk− macrophage polarization. These data implied that improved cardiac healing was associated with increased infiltration of neutrophil and it mediated macrophage polarization. Notably, we confirmed that this polarization depended on NETs, which were more abundant in hearts and serum in EDIL3−/− mice than in WT. Indeed, self-DNA released from NETs primed the pro-inflammatory polarization of macrophages. The degradation of NETs by DNase I reduced this polarization and thus affected post-MI outcome, indicating the pivotal role of NETs in MI healing. Meanwhile, the pro-inflammatory macrophages induced apoptosis of neutrophils and restrained excessive inflammation. Our findings reveal a novel neutrophil–macrophage crosstalk essential to cardiac healing after MI.
Histone Deacetylase 3 regulates the ontogeny and maintenance of tissue-resident macrophages
Authors: Yao Yi , Liu Queping , Geissmann Frederic , Zhou Li , Mi Qing-Sheng 
Published: January 2023

Abstract
Tissue-resident macrophages (TRMs) are essential for tissue homeostasis, immune-surveillance, and resolution of inflammation, and contribute to the pathogenesis of cancer, autoimmune, and inflammatory diseases. Most adult TRMs are derived from embryonic yolk sac erythro-myeloid progenitors and self-maintain independently from adult hematopoiesis. A few genes have been recently identified to be required for TRM tissue-specific development. However, the master regulator that centrally controls TRM ontogeny remains a mystery. Using a fate-mapping strategy, here we report that conditional deletion of histone deacetylase 3 (HDAC3) in mice essentially abrogates epidermal Langerhans cells and TRMs in dermis, lung, kidney, and heart at embryonic stage and after birth. In contrast, HDAC3 deletion promotes liver TRM ontogeny, while without significant effects on brain TRM microglia. Using lung TRM alveolar macrophage (AM) as a model, we further indicate that HDAC3 controls metabolism and cell death, at least by directly targeting PPAR-γ during AM embryonic development. Moreover, single-cell RNA sequencing identifies four distinct AM sub-clusters and lack of HDAC3 dysregulates AM functions in a cluster-specific manner. Overall, this is the first study to demonstrate that HDAC3 serves as a key epigenetic regulator of embryonic TRM ontogeny and maintenance in a spatial- and tissue-specific manner. Not only do these findings provide a new conceptual framework for our understanding of epigenetic regulation in TRM ontogeny and homeostasis, they also shed light on HDAC3 as a potential therapeutic target for TRM-based intervention in cancer and autoimmune diseases.
IL-27 Receptor Signaling potentiates Angiotensin II induced myelopoiesis and promotes Abdominal Aortic Aneurysm
Authors: Aghayev Turan , Peshkova Iuliia , Fatkhullina Aliia , Makhov Petr , Eguchi Satoru , Tan Yin Fei , Kossenkov Andrew , Sykes Stephen , Koltsova Ekaterina 
Published: January 2023

Abstract
Abdominal Aortic Aneurysm (AAA) is a vascular disease, where aortic wall degradation is in part mediated by the accumulation of immune cells leading to aortic wall rupture and bleeding which is often fatal for the patient. Smoking, age, male gender, hypertension and atherosclerosis are major risk factors, however the mechanism of AAA development is still elusive. Though cytokines regulate the inflammatory milieu within the aortic wall, their possible role in systemic regulation of this disease, particularly in the control of hematopoietic stem cell proliferation, myeloid cell differentiation and their subsequent accumulation in AAA remains poorly defined.
Here we report an unexpected pathogenic role of IL-27R signaling in the development of AAA. We found that in an animal model of AAA, prolonged infusion of Angiotensin (Ang) II robustly induces AAA formation in hyperlipidemic Apoe−/− and Apoe−/−Il27ra+/− mice but not in IL-27R deficient Apoe−/− mice. This mitigation of AAA formation in Apoe−/−Il27ra−/− mice is associated with a blunted accumulation of myeloid cells in suprarenal aortas due to a reduction of Ang II-induced hematopoietic stem and progenitor cell (HSPCs) expansion. We found that the absence of IL-27R signaling engages transcriptional programs that promote HSCs self-renewal program and suppress myeloid lineage differentiation, resulting in decreased mature myeloid cell production and thus a concomitant lack of Ang II-induced myeloid cell accumulation in the suprarenal aortas.
Collectively, these data demonstrate that IL-27R signaling influences AAA development by potentiating Ang II induced myelopoiesis and may represent a molecular point of therapeutic intervention in AAA.
CCCTC-binding factor regulates the development and function of dendritic cells
Authors: Yang Bobae , Kim Tae-Gyun , Kim Sueun , Kim Hyoung-Pyo 
Published: January 2023

Abstract
Dendritic cells (DCs) are professional antigen presenting cells, which present antigen to cognate T cells. DC activation through diverse toll-like receptors is prerequisite for triggering efficient immune responses to foreign antigens. CCCTC-binding factor (CTCF) is a DNA binding protein that regulates 3D genome structure which is believed to be important to control of gene expression. Here we described that CTCF is required for development and function in DCs. CTCF is critically required for the FLT3L-dependent CD11c+ DCs (FL-DCs) development, unlike for those in the GM-CSF-dependent CD11c+ DC (GM-DCs) development. However, the resultant CTCF-deficient DC number was decreased by 50% in both FLT3L- and GM-CSF-supplemented culture conditions. Although CTCF was required for bone marrow (BM) progenitor proliferation in both FLT3L-and GM-CSF-supplemented cultures, CTCF-deficient GM-DCs showed normal cellular apoptosis rate and higher CD11c+ DC differentiation. Upon TLR4 ligation, CTCF-deficient DCs showed higher expression levels of surface MHCII and co-stimulatory molecules compared to those WT DCs. Thus, our data indicate that CTCF plays a critical role in the overall differentiation, survival, and maturation of DCs.
The DNA-binding protein ARID3a is Required for Human Erythrocyte Lineage Differentiation using the K562 Model Cell Line
Authors: Garton Joshua W , Chapman Brittany , Shankar Malini , Rose Kira , Webb Carol 
Published: January 2023

Abstract
Our previous studies demonstrated that AT-rich interacting domain 3a (ARID3a), a DNA-binding protein associated with increased immunoglobulin heavy chain transcription and chromatin accessibility, is required for normal hematopoiesis in mice and in human cells. ARID3a knockout mice exhibited low numbers of erythrocytes and died due to failed erythropoiesis between days 9 and 12 of gestation. The role of ARID3a in human erythropoiesis has not been studied. Stimulation of the human K562 cell line with hemin induces fetal globin synthesis and erythrocyte differentiation. K562 cells constitutively express ARID3a, so we used this cell line to determine if ARID3a is important for human erythrocyte differentiation. Knockdown of ARID3a with shRNA in hemin-stimulated K562 cells resulted in &gt;75% inhibition of globin. To identify genes affected by ARID3a loss, we performed RNA-seq experiments at various times after hemin stimulation with and without ARID3a. ARID3a shRNA-inhibited cells confirmed inhibition of globin gene products, including HBA1, HBA2, and HBZ. Erythroid specific transcription factors were also inhibited in samples treated with ARID3a shRNA while myeloid surface markers were induced. Several critical upstream regulators of ARID3a were also identified in these analyses. These data suggest that ARID3a is important for cell fate decisions in erythropoiesis in human cells and identifies potential important targets of ARID3a in this process.
An Nfil3-Zeb2-Id2 pathway imposes Irf8 enhancer switching during cDC1 development
Authors: Bagadia Prachi 
Published: January 2023

Abstract
Classical type 1 dendritic cells (cDC1) are required for anti-viral and anti-tumor immunity, motivating a need to understand their development. We recently discovered that the development of the cDC1 progenitor requires an E protein-dependent +41 kb Irf8 enhancer, but its maturation instead requires a BATF3-dependent +32 kb Irf8 enhancer. To identify the genetic circuitry underlying this switch, we performed single-cell RNA-sequencing of the multipotent common dendritic cell progenitor (CDP). We found a cluster of cells within the CDP that already expressed transcription factors influencing cDC1 development, including Nfil3, Id2, and Zeb2. Genetic epistasis between these factors revealed a hierarchy of action in which Nfil3 expression is required for a transition from Zeb2hi and Id2lo CDPs into Zeb2lo and Id2hi CDPs, which represent the earliest committed cDC1 progenitors. This genetic circuit blocks E protein activity to exclude pDC potential within this progenitor and also explains the switch in Irf8 enhancer usage during cDC1 development.
Sargassum horneri ethanol extract down-regulates the Th2 polarization via STAT5 in ovalbumin sensitized murine splenocytes
Authors: Mihindukulasooriya Suyama Prasansali , Herath Kalahe Hewage Iresha Nadeeka Madushani , Kim Areum , Kim Hyo Jin , Ko Mi-Ok , Jeon You-Jin , Youngheun Jee 
Published: January 2023

Abstract
Sargassum horneri, a brown marine algae distributed across East Asian countries, is known to exhibit several health promoting effects such as anti-virus, anti-inflammation, and anti-oxidation. In this study, we aimed to clarify the anti-allergic effect of S. horneri ethanol extract (SHE). BALB/c mice were first sensitized with intraperitoneal injection of ovalbumin (OVA; 20 μg) and alum (Days 0 and 14; 2 mg). After the final administration, splenocytes were obtained and challenged with OVA (100 μg/mL) in the presence or absence of SHE. SHE was not cytotoxic on murine splenocytes at any of the concentrations tested. Furthermore, SHE exhibited suppressive effect on the proliferation of murine splenocytes. SHE treatment decreased the population of CD3+CD4+ helper T cells in OVA-sensitized and OVA-challenged splenocytes compared with the SHE non-treated controls. We also discovered that the increase in the population of CD45+Gr-1+ granulocytes due to OVA challenge was subdued significantly through SHE treatment. Importantly, SHE simultaneously attenuated Th1 and Th2 responses: it reduced the production of both Th1 (INF-γ, TNF-α) and Th2 (IL-4, IL-5, IL-13) cytokines induced through the OVA challenge. Also, SHE mitigated OVA induced activation of STAT5. The down-modulation of IL-13 and STAT5 activation was abrogated when a STAT5 inhibitor (CAS 285986-31-4) was applied. Our results suggest that SHE can mitigate OVA induced allergic immune responses through the attenuation of OVA induced TH2 polarization probably via STAT5 pathway and be therapeutically useful for alleviating symptoms in allergen mediated immune diseases. This research is a part of the project (No. 20150306) funded by Ministry of Oceans and Fisheries, Korea.
Bacillus subtilis-mediated suppression of house dust mite allergic airway inflammation
Authors: Swartzendruber Julie A , Negris Olivia , Incrocci Ryan , Knight Katherine L 
Published: January 2023

Abstract
The incidence of allergic diseases is increasing, with house dust mite allergy, afflicting up to 20% of the population in developed countries. House dust mites (HDM) are a common allergen that can be difficult to avoid and can trigger allergic reactions, including wheezing and shortness of breath. We recently showed that two pretreatments with Bacillus subtilis, a gram-positive bacterium, can prevent murine HDM-induced allergic lung inflammation. We assessed infiltration of eosinophils in bronchial alveolar lavage fluid and found significantly reduced eosinophils following B. subtilis treatment. Our current work addresses the capacity of B. subtilis to provide long-term protection from HDM challenge. Following pretreatment with B. subtilis, we found protection from HDM challenge, determined by quantifying infiltrating eosinophils for two weeks, but lost protection after three weeks. These data suggest a transient protection elicited by B. subtilis and support the need for frequent dosing to maintain suppression of allergic airway inflammation.
Clearance of Apoptotic cells by Lung Macrophages Prevents Development of House Dust Mite-induced Asthmatic Lung Inflammation
Authors: Miki Haruka , Gracias Donald Tom , Croft Michael 
Published: January 2023

Abstract
Allergen inhalation can cause epithelial damage and induce cell death while driving asthmatic lung inflammation. It has been suggested that patients with severe asthma may have a defect in clearance of apoptotic cells, of significance as apoptotic cell phagocytosis is thought important to maintain tissue homeostasis. Previously we have reported that lung resident macrophages in a non-inflamed lung generate regulatory T cells (Tregs) and can promote airway tolerance, and hypothesized that this ability was related to uptake of apoptotic cells. We investigated this by infusing apoptotic thymocytes into the lungs to determine their impact on macrophage function and allergic asthma. We found that lung macrophages were the primary cell to engulf apoptotic cells and this was not modified with intranasal exposure to House Dust Mite (HDM) allergen challenge. The uptake of apoptotic cells by alveolar macrophages in vivo or in vitro resulted in increased expression of RALDH1 and RALDH2, enzymes that drive retinoic acid production. When apoptotic cells were transferred into the lung during sensitization with HDM, eosinophilic airway inflammation, and Th2 cytokine production in the BALF and lung, were significantly reduced compared to mice given viable cells. This was accompanied by an increase in the frequency of antigen-specific Treg in the lung draining lymph nodes. These results indicate that apoptotic cell clearance by lung macrophages is important to maintain airway tolerance and prevent induction of allergic asthma.
Ly-6C+CD11b+conventional dendritic cells accumulate in inflamed lung and differentiate into type 2 dendritic cells
Authors: Izumi Gentaro , Nakano Keiko , Thomas Seddon Y , Whitehead Gregory , Grimm Sara A , Nakano Hideki , Cook Donald N 
Published: January 2023

Abstract
Allergic asthma is a complex inflammatory disease characterized by airway obstruction and airway hyperresponsiveness. Pulmonary dendritic cells are critical for allergic sensitization as they take up inhaled allergens and direct differentiation of allergen-specific helper T cell lineages in lung-draining lymph nodes. In this study, we used mass cytometry to study lung DC subsets that increase in frequency after allergen inhalation. This approach revealed a novel cell population displaying Ly-6C, in addition to surface markers routinely used to identify type 2 conventional DCs (cDC2), including CD11b and CD26. These Ly-6C+ cells had dendrites, lacked monocyte/macrophage markers such as F4/80 and CD115, and were absent in the mice lacking FMS-like tyrosine kinase 3ligand (FLT3L), a growth factor essential for cDC differentiation. Based on these observations, we conclude that this novel population represents bona fide cDCs. Their numbers in the lung were low at steady state, but increased dramatically after allergic sensitization. Cultured DC precursors (preDCs) displayed Ly-6C, but lost that marker by time. Ly-6C+CD11b+cDCs freshly isolated from mouse lung also lost Ly-6C expression after ex vivo culture. Together, these results suggest that Ly-6C+CD11b+cDCs are the precursor of cDC2. Given that the number of these DCs increase dramatically in the lung after allergen inhalation, they might play important roles in allergic sensitization and the induction of allergic asthma.
Critical role for IL-33 in orchestrating group 2 innate lymphoid cell and natural killer cell function in the lungs
Authors: Ferrini Maria M , Jaffar Zeina , Roberts Kevan 
Published: January 2023

Abstract
The alarmin, IL-33, acting via ST2 receptors initiates innate immunity to inhaled allergens and environmental particulates. IL-33 belongs to the IL-1 family and is largely derived from epithelial cells, endothelial cells and fibroblasts. The cytokine plays a critical role in underpinning type 2 immunity at mucosal sites and the IL-33/ST2 axis has been implicated in bronchial asthma and virus-induced exacerbations of allergic airway disease. In this study, we found that IL-33 instillations into the airways of C57BL/6 mice, for 3 days over a 7 day period, induced a marked increase in the number of group 2 innate lymphoid cells (ILC2s) and their production of type 2 cytokines IL-13 and IL-5 and this was associated with a pronounced pulmonary eosinophilic inflammation and airway mucus production. Interestingly, IL-33 administration also resulted in an increase in the number of CD11b+CD11C+MHCII+ dendritic cells and evoked a marked expansion of Th2 cells in the lung mucosa. Concomitant with this response, there was a significant reduction in IFN-γ production by pulmonary CD3−CD19−DX5+NK1.1+ NK cells. Flow cytometry revealed that ST2 expression was predominantly expressed by pulmonary ILC2s rather than NK cells, raising the possibility that ILC2s, either directly or indirectly, regulate the NK cell response. These findings reveal that IL-33 plays critical roles in both initiating pulmonary innate and adaptive immune responses, thus providing an essential axis for rapid immune responses and tissue homeostasis in the lung as well as influencing the development of chronic airway inflammation and remodeling.
CIS inhibits Treg-intrinsic TH2 program and suppresses allergic airway inflammation
Authors: Yang Xuexian O , Zheng Handong , Wu Xiang , Jiang Ruo-Lan , Castillo Eliseo , Chock Cameron , Zhou Qin , Liu Meilian , Dong Chen 
Published: January 2023

Abstract
Maintenance of regulatory T (Treg) cells is crucial for the regulatory function of Treg cells in immune homeostasis and self-tolerance; however, the detailed mechanisms remain elusive. In this study, we found that the cytokine suppressor CIS is required for maintenance of Treg identity. Mice with Treg specific Cis-deficiency displayed aggravated experimental allergic asthma and in adulthood, developed splenomegaly, lymphadenopathy and spontaneous eosinophilic airway inflammation, accompanied by accumulation of memory T helper (TH) cells. Cis-deficiency led to decreased expression of Foxp3 and suppressive function of Treg cells. Cis-deficient Treg cells expressed TH2 signature genes, Gata3, Irf4 and Il4, and excessive IL-4-STAT6 signals resulted in repressive chromatin modification in the Foxp3 locus and permissive modification in the Il4 loci. In vitro, blockade of IL-4 restored expression of Foxp3 and suppressive function of iTreg cells. Thus, we identified a novel feedback loop in stabilization of Treg cells and inhibition of TH2 type inflammation.
In vivo induction of T regulatory cells with recombinant mouse IL-2_anti-mouse IL-2 antibody complex
Authors: Soto Hortensia , Moyron-Quiroz Juan , Moya Zoila R , Tam Miguel , Love James M , Yang Xifeng , Nguyen Dzung , Zhou Jie 
Published: January 2023

Abstract
T regulatory cells (Tregs) control peripheral tolerance, and their immunosuppressive function is essential to maintain a balanced immune system. Tregs constitutively express IL-2Rα (CD25) and the transcription factor FoxP3. IL-2 is a pleiotropic cytokine and is vital for the development of Tregs. IL-2 binds to the trimeric receptor formed by IL-2Rα, IL-2Rβ (CD122), and the common gamma chain IL-2Rg (CD132). In this study we induced in vivo Treg (CD25bright, FoxP3+, CD4+) expansion by injecting a complex made of recombinant mouse IL-2 and anti-mouse CD25 (clone JES6-1A12). The mice were injected for four consecutive days with different concentrations of IL-2_JES6-1A12 complex, as well as IL-2_JES6-1A12 complex plus an excess of IL-2, or IL-2 alone. There was a significant induction of Tregs in mice that received the complex as compared to animals that received only a comparable dose of IL-2 alone. The ratio Tregs/effector cells (defined as CD8+,CD44+, CD122+) was approximately two fold in mice that received the complex. Mice injected with the complex plus an excess of IL-2 showed similar proportions of Tregs and effector cells. Previous studies showed that the use of a different IL-2 neutralizing clone (clone S4B6, recognizes and block CD122) preferentially induced effector cells. This experimental model will facilitate the study of diseases or immune mechanisms where Tregs mediate an immune response or immune system dysregulation.