bluuebunny/crossref_metadata_2025_split huggingface dataset:
Inhibition of B lymphopoiesis mediated by adipocytes, myeloid-derived suppressor cells, and IL-1 (HEM1P.223)
Authors: Kennedy Domenick , Knight Katherine 
Published: January 2023

Abstract
B lymphopoiesis declines with age in many mammals, correlating with an increase in adipose tissue in the bone marrow (BM). We showed that adipocyte-derived factors inhibit B lymphopoiesis in vitro, and in this study, we investigated the mechanism by which this occurs. In cultures of mouse BM cells with OP9 stromal cells, we found that adipocyte conditioned medium (ACM) induces the generation of CD11b+Gr1+ myeloid cells, which when added to OP9 cultures also inhibited B lymphopoiesis. These ACM-induced CD11b+Gr1+ cells express arginase (Arg1) and iNos (Nos2), and suppress T cell proliferation, suggesting that they are myeloid-derived suppressor cells (MDSCs). Addition of arginase and iNos inhibitors to BM cultures containing ACM-induced MDSCs did not restore B lymphopoiesis, suggesting that MDSC-mediated inhibition is independent of arginase and iNos. Transwell and conditioned medium experiments showed that MDSC-mediated inhibition of B lymphopoiesis occurs through soluble factors. Using a cytokine array, we detected IL-1α and IL-1β in MDSC-conditioned medium. Addition of IL-1α/β to BM cultures resulted in the loss of B lymphopoiesis, while addition of anti-IL-1α and anti-IL-1β to BM cultures containing MDSCs restored B lymphopoiesis. These data identify IL-1 as the major inhibitory factor responsible for MDSC-mediated inhibition of B lymphopoiesis. This study identifies IL-1 as a potential therapeutic target for restoring B lymphopoiesis in aged individuals.
Sodium tanshinone IIA sulfonate inhibits cigarette smoke-induced airway inflammation via regulating cystic fibrosis transmembrane conductance regulator-mediated pathway (HUM1P.263)
Authors: Lu Wenju , Li Defu , Gong Xuefang , Wang Jian , Zhong Nanshan 
Published: January 2023

Abstract
Cystic fribrosis transmembrane conductance regulator (CFTR) is an important anti-inflammatory protein and confers to development of chronic obstructive pulmonary disease (COPD). Sodium tanshinone IIA sulfonate (STS) has been reported to be anti-inflammatory under various stimuli exposure, however, the underlying mechanisms were not fully understood. In this study, we found exposure to cigarette smoke (CS) led to COPD in mice, manifested by reduction in lung function, increases of inflammatory cell counts in bronchial alveolar lavage fluid , and alveoli enlargement; these changes were associated with reduced expression and chloride current of CFTR, greater activation of ERK1/2 and Nrf2, and greater levels of IL-6 and IL-8 in the lung. Treatment of STS aerosol (10mg·kg-1·day-1) attenuated these responses in COPD mice. In 16HBE human bronchial epithelial cells, exposure to CS extract resulted in reduced CFTR expression, activation of ERK1/2 and Nrf2, and increased IL-6 and IL-8 release; these were potentiated by rise of intracellular concentration of Cl- (70 mM), pretreatment with CFTR inhibitor inh-172 (10 mM) or Nrf2 activation, yet prevented by knockdown of Nrf2, inhibition of ERK1/2 activation, or STS (25uM) treatment. These results indicate that STS could inhibit CS-induced COPD development by preventing CS-induced CFTR reduction, thus inhibiting Cl--ERK1/2-Nrf2 mediated pro-inflammatory cytokine production in airway epithelial cells.
Meta-analysis of atopic dermatitis studies (HUM1P.269)
Authors: Bhattacharya Sanchita , Butte Atul 
Published: January 2023

Abstract
Several independent studies been conducted to understand the genetic and environmental factors influencing the cause of atopic dermatitis, which is an inflammatory skin disorder. To leverage the power of combining the studies we downloaded seven publicly available datasets on atopic dermatitis from ImmPort data portal (https://immport.niaid.nih.gov/). These studies include wide range of molecular and cellular measurements like ELISA, flow and complete blood count (CBC) across multiple cohort and various sample types. We have taken the meta-analysis approach to understand the factors influencing the disease phenotype by integrating the datasets measured under different conditions to find the associations between independent and combined effects. The molecular and cellular measurements were normalized such that data is comparable across studies. We have found a strong association of certain inflammatory cytokines in atopic dermatitis patients under specific conditions, and perturbations in certain cell types of these patients. We also evaluate the influence of gender, age and vaccine response in atopic dermatitis patients with respect to healthy controls.
Comparative studies connecting IFN dysregulation with pathway dysregulation in 2 autoinflammatory diseases, SAVI and CANDLE (HUM1P.274)
Authors: Marrero Bernadette , Liu Yin , Huang Yan , Almeida De Jesus Adriana , Goldbach-Mansky Raphaela 
Published: January 2023

Abstract
Type I interferon dysregulation is associated with some autoinflammatory diseases. Gain-of-function mutations in TMEM173 encoding Stimulator of Interferon Genes (STING) lead to constitutive production of Type I IFN and the clinical syndrome, STING associated vasculopathy with onset in infancy (SAVI). In another IFN mediated disease, Chronic Atypical Neutrophilic Dermatosis with Lipodystrophy and Elevated Temperature (CANDLE), disease causing mutations cause global proteasome dysfunction and increase in IFN message. The cellular source of the IFNs in blood and the dominant isoforms remain unclear. We examined the expression of 5 type I IFN genes among FACS sorted PBMCs: T-, B-, NK cells and monocytes in SAVI (n=2) and total PBMCs from CANDLE patients (n=2) by qRTPCR. We found in SAVI that monocytes expressed the highest level of type I IFN message. Among the IFN genes tested and normalized to healthy monocytes, patients’ IFNβ is over 250-fold higher than IFNα; following the notion that STING pathway activation leads to IFNβ transcription. Depleting monocytes from SAVI PBMCs reduced 90% of the IFN message, confirming that monocytes not dendritic cells are the main source of IFNs. In contrast, CANDLE patients’ IFN alpha and beta genes are comparably upregulated. Although IFN dysregulation is identified in blood, determining the cellular origin of the IFN production and the pathways that drive IFN dysregulation will allow us to develop better targets for therapy.
The role of IL-22 signaling in the pathogenesis of necrotizing enterocolitis (HUM1P.314)
Authors: Good Misty , Ma Congrong , Kumar Pawan , Pociask Derek , Ozolek John , Kolls Jay 
Published: January 2023

Abstract
Necrotizing enterocolitis (NEC) is the leading cause of death from gastrointestinal disease in premature infants and the specific molecular mechanisms responsible for NEC development remain unclear. NEC is characterized by intestinal epithelial barrier disruption and impaired mucosal healing. Recent evidence suggests a critical role for IL-22 in the regulation of intestinal epithelial barrier integrity and gut inflammation in inflammatory bowel disease. Thus, we hypothesized that IL-22 signaling plays an important role in NEC pathogenesis. To test this, we subjected wild type and IL-22Ra1 intestinal specific knock out mice (villin-cre X IL22ra1fl/fl) to an experimental model of NEC using gavage formula feeds and intermittent hypoxia. NEC severity was assessed by intestinal mucosal cytokines and a NEC severity score assigned by a blinded pathologist. We discovered the IL-22Ra1 intestinal specific knock out mice demonstrated earlier NEC-related mortality than WT mice. Further, histology on the IL-22Ra1 intestinal specific knock out mice demonstrated disruption in the intestinal mucosal architecture and upregulation of pro-inflammatory cytokines. Taken together, these data suggest that IL-22 signaling may play an important role in attenuating the immune response in NEC pathogenesis. These findings raise the possibility for novel therapeutic approaches in the management of this devastating disease by exploring the efficacy of IL-22 treatment for NEC and the mechanisms involved.
Understanding the hygiene hypothesis mechanism (HYP2P.331)
Authors: Johnson Jenny , Jones Mark , Cobb Brian 
Published: January 2023

Abstract
As the western world becomes increasingly sterilized, the rate of allergic diseases, such as asthma, have increased dramatically. Alternatively, children born vaginally, raised on a farm, or with older siblings have a reduced risk of developing a multitude of allergic conditions. This phenomenon, known as the hygiene hypothesis, has become well established; however, the cellular mechanism by which this exposure protects the individual remains unclear. We have found that the commensal bacterium B. fragilis, in particular the capsular polysaccharide PSA, can protect against airway inflammation characteristic of asthma. The population of CD4+ T cells responding to PSA treatment was found to be clonal in nature, with a CD4+Foxp3-CD45RblowCD44+CD62L- (TEM) phenotype. These cells show potent inhibition of asthma in an IL-10-dependent fashion upon transfer to naïve recipients. Additionally, analysis of top clones revealed increased prevalence of zwitterionic motifs in the CDR3 loop sequences of PSA experienced T cells, which corresponds to a need for a similar motif in PSA itself for MHCII presentation. Collectively these data show that a polysaccharide antigen induces clonal expansion of effector T cells which act to suppress asthmatic inflammation, thereby adding further evidence to the beneficial effects of commensal flora on immune homeostasis as predicted by the hygiene hypothesis.
Crucial role for CD11c+ interstitial macrophages in the development of TSLP-mediated allergic airway inflammation (HYP2P.321)
Authors: Lai Jen-Feng , Thompson Lucas , Ziegler Steven 
Published: January 2023

Abstract
Allergic asthma is a common chronic Th2-driven airway inflammatory disease. TSLP is an epithelial-derived cytokine recognized as a potent factor in the development of asthma. TSLP is known to influence the ability of dendritic cells to enhance Th2 T cell responses, however many of the mechanisms underlying TSLP-induced airway inflammation remain undefined. In addition to dendritic cells, the lung tissues include other MHC class II-expressing phagocytic populations that may influence T cell responses. Here we demonstrate that pulmonary CD11c+ interstitial macrophages (IM) (CD11cintF4/80+Nur77+CD11b+CX3CR1hiCCR2loMHCII+/-) express high levels of TSLPR and recruited to the lung tissue in response airway priming in the context of TSLP and antigen. TSLP-mediated eosinophilic allergic airway inflammation is attenuated by ablation of CD11c+ IM or by selective deficiency of TSLPR signaling in these cells. More importantly, CD11c+ IM are sufficient for the development of this response in the absence of DC. These findings indicate a crucial role for CD11c+ IM in the development of TSLP-mediated allergic airway inflammation. By elucidating the cellular mechanisms of airway inflammation, these data may contribute to more effective therapeutic approaches for treatment of asthmatic disease.
Macrolide therapy suppresses key features of experimental steroid-sensitive and steroid-insensitive asthma (HYP2P.342)
Authors: Essilfie Ama-Tawiah , Horvat Jay , Kim Richard , Mayall Jemma , Pinkerton James , Beckett Emma , Starkey Malcolm , Simpson Jodie , Foster Paul , Gibson Peter , Hansbro Philip 
Published: January 2023

Abstract
Background Steroid-insensitive endotypes of asthma are an important clinical problem requiring effective treatments. They are associated with non-eosinophilic inflammatory responses and bacterial infections. Macrolide therapy is effective in steroid-insensitive endotypes, such as non-eosinophilic asthma, however the mechanisms of how they work is unknown. Objectives To determine the efficacy of macrolide and non-macrolide antibiotic treatments in infection-induced, severe, steroid-insensitive allergic airways disease (SSIAAD). Methods Mouse models of Chlamydia and Haemophilus lung infection-induced SSIAAD were used to investigate the effects of clarithromycin and amoxicillin treatment on immune responses and AHR in steroid-sensitive AAD and SSIAAD compared to dexamethasone treatment. Results Amoxicillin and clarithromycin had similar anti-microbial effects on infection. Amoxicillin did not suppress either form of AAD, but restored steroid sensitivity in SSIAAD by reducing infection. In contrast, clarithromycin alone widely suppressed inflammation and AHR in both steroid-sensitive and SSIAAD. This occurred through reductions in both Th2 responses that drive steroid-sensitive, eosinophilic AAD, and TNF-α and IL-17 responses that induce neutrophilic SSIAAD. Conclusions Macrolides have broad anti-inflammatory effects that are independent of their anti-microbial effects. The specific responses suppressed are dependent upon the responses that dominate during disease
Severe asthma, airway re-modelling and induced bronchial associated lymphoid tissue produced using novel dust mite specific CD4 T cell receptor transgenic mice (HYP2P.327)
Authors: Kemeny David , Chua Yen , Liong Ka , Koh Hui , Tang Yafang , Zhou Qian , Wong Hok Sum , Huang Chiung-Hui , Wong Wai Shiu Fred , Chua Kaw 
Published: January 2023

Abstract
Patients with severe asthma are very difficult to manage are present a major medical challenge. Development of clinical asthma requires many years of patient exposure to allergens. Mouse asthma models require weeks and are normally transitory and do not lead to allergen-induced dyspnea. We have followed an alternative approach to conventional immunization through the transfer highly polarized CD4 T cell receptor transgenic T cells specific for the dust mite allergen Blo t 5 followed by thrice weekly intranasal recombinant challenge with recombinant allergen to induce persistent high levels of eosinophilia (4 million/mouse lavage) and serum IgE (40,000 ng/ml) and specific IgG1 (30,000 ng/ml). Intranasal challenge of these mice with 25ug of allergen is well tolerated, but a fourfold increase to 100ug induces respiratory symptoms within 15 minutes. These mice show evidence of mucus plugging, increased collagen deposition, mucus hypersecretion and the formation of bronchial associated lymphoid structures (iBALT). Neutralization of IL-4 or IL-13 with monoclonal antibody reduced the response and a combination of these two was most effective. Many drugs reduce respiratory inflammation in mice yet fail to benefit asthmatic patients. We hope that the model described here may help identify new/better drugs for the treatment of patients with severe asthma.
A West Nile virus NS4B P38G mutant induces MAVS-dependent type 1 interferon and the host anti-viral responses (INC1P.353)
Authors: Luo Huanle , Xie Guorui , Diamond Michael , Gale Michael , Barrett Alan , Wang Tian 
Published: January 2023

Abstract
The nonstructural (NS) proteins of West Nile virus (WNV) are important determinants of viral pathogenesis. WNV NS4B-P38G mutant, which has a P38G substitution in the NS4B protein is highly attenuated in mice, but induces stronger type 1 interferon (IFN) and T cell responses than the wild-type WNV. Here, we investigated mice lacking the RIG-I-like receptor adaptor gene Mavs, and found increased viremia and lethality following WNV NS4B-P38G infection. MAVS-/- mice had a reduced IFNβ production and impaired primary T cell response after infection. WNV NS4B-P38G also induced lower levels of type 1 IFNs and cell surface expression of MHC class II and co-stimulatory molecules on MAVS-/- dendritic cell (DC)s. IRF-3, -5, and -7 are the key transcription factors responsible for mediating the type I IFN and ISG response in mDCs during wild-type WNV infection. PCR array analysis showed a significantly decreased expression of IFNβ and most IFN stimulated gene (ISG)s, except IRF3 and IRF5 in WNV NS4B-P38G-infected MAVS-/- DCs compared to the wild-type group. Moreover, DCs of IRF3-/- x IRF7-/- double knockout or Irf3-/-×Irf5-/- ×Irf7-/- triple knockout mice had either unaffected or a higher IFNβ expression after WNV NS4B-P38G infection. Collectively, our results suggest that MAVS signaling is essential for the induction of type 1 IFN and T cell responses upon WNV NS4B-P38G mutant infection and this could occur through an IRF-3 and IRF-5-independent pathway.
Influenza induces GM-CSF deficiency: lung-specific overexpression after infection confers protection (INC1P.355)
Authors: Halstead Eric , Guo Weichao , Yang Linlin , Hu Sanmei , Umstead Todd , Hartshorn Kevan , White Mitch , Chroneos Zissis 
Published: January 2023

Abstract
GM-CSF is an essential cytokine for normal lung immune homeostasis. In the current studies we examined the role of GM-CSF and its lung-specific conditional overexpression on the host immune response to influenza. Transgenic tet-GM+/+ mice were intranasally infected with A/PR8/34 H1N1 IAV, BALF was collected and single cell lung suspensions were generated using collagenase/DNase digestion. IAV infection induced a prolonged period of GM-CSF deficiency in the lung environment. "Early" (3 days prior to infection) induction of GM-CSF led to protection characterized by significantly enhanced weight recovery as compared to non-induced mice, as well as increased numbers of CD11c+ cells, including CD11b+ and CD11b- dendritic cells as well as enhanced recovery of CD11c+ Siglec-F+ AMs. Interestingly, the weight recovery curves for "late" (3 days post-infection) as compared to "early" GM-CSF overexpression were similar suggesting that GM-CSF may have a role in the resolution of inflammation. Indeed, local GM-CSF restoration caused decreased the frequencies of inflammatory Ly-6C+ monocytes/macrophages and Ly-6G+ neutrophils. Lastly, "late" GM-CSF overexpression accelerated secretion of anti-IAV IgA antibody in BALF. These results indicate viral-induced GM-CSF deficiency impairs recovery from influenza infection, yet can be corrected with exogenous administration of GM-CSF.
Intracellular activation of complement 3 mediates intestinal tissue damage during mesenteric ischemia (INC1P.356)
Authors: Kannan Lakshmi , Tsokos Maria , Dalle Lucca Jurandir , Tsokos George 
Published: January 2023

Abstract
Ischemia of the intestine followed by reperfusion leads to significant local and remote organ injury (IRI) attributed to inflammatory elements acting during the reperfusion phase. Whether ischemia contributes to IRI has not been addressed. Careful evaluation of intestinal tissue following ischemia we noticed significant local injury, which was associated by increased production of complement 3 (C3) by intestinal epithelial cells. C3-deficient mice failed to exhibit similar injury and while cobra venom factor pre-treatment, which depleted all complement in the circulation, eliminated all IRI, but it failed to mitigate injury during the ischemia phase. C3 was activated within the epithelial cells during ischemia as indicated by immunocytochemistry and Caco2 (colon epithelial cancer cells) produced C3a after LPS stimulation. Production of C3a was decreased in the presence of cathepsin inhibitors. In conclusion, intestinal epithelial cells when subjected to ischemia can produce and activate C3 and initiate intestinal damage, which is amplified during the reperfusion phase.
HMGB1 increases IL-8 secretion under hypoxic condition in human nasal epithelia (INC1P.358)
Authors: Min Hyun Jin , Yoon Joo-Heon , Kim Chang-Hoon 
Published: January 2023

Abstract
Objectives High Mobility Group Box 1 (HMGB1) is a nuclear protein. It has been found that HMGB1 can be secreted into extracellular area via various mechanisms, and extracellular HMGB1 have a potential to mediate proinflammatory signaling. The aim of the present study was to investigate the role of HMGB1 in upper airway epithelial cells under hypoxic condition. Materials and Methods We cultured normal human nasal epithelial cells (NHNE). Cells were incubated in hypoxic condition and evaluated whether HMGB1 was secreted into extracellular area. Next, we harvested human nasal mucosa samples and nasal lavage fluids which were supposed to be hypoxic and non-hypoxic condition. We compared the expression of HMGB1 in human nasal mucosa samples by immunohistochemistry and the amount of HMGB1 in lavage fluids using ELISA assay. Results We found that hypoxia induced translocation of HMGB1 into extracellular area in NHNE cells and it was ROS dependent. We identified that secreted HMGB1 protein was participating in up-regulation of IL-8. In addition, much more cytoplasmic HMGB1 was identified in hypoxic conditioned human sino-nasal mucosa compared to control. The amount of HMGB1 in nasal lavage fluids was also increased in hypoxic conditioned patients compared to control Conlcusion: These findings suggest that HMGB1 plays a role in the pathogenesis of hypoxia-mediated inflammation in upper airway epithelium.
CD6 is a novel positive regulator of natural antibody producing B-1a cells (INC1P.401)
Authors: Enyindah-Asonye Gospel , Li Yan , Singer Nora , Gupta Neetu , Fung John , Lin Feng 
Published: January 2023

Abstract
Although CD6 has recently been identified as a risk gene for multiple sclerosis, its biological function remains unclear, partially due to the lack of CD6 gene engineered animals. It is established that CD6 is present on all T cells in both humans and mice; however, it is believed that mouse B cells do not express CD6. B-1a B cells are the primary source of natural antibodies (Nabs), which provide the first line of defense against infection and facilitate the clearance of oxidized lipoproteins that contribute to the pathogenesis of atherosclerosis. By studying CD6 knockout (KO) and WT mice, we found that CD6 is basally expressed selectively on splenic B-1a B cells. CD6 KO mice exhibit smaller B1a B cell population in the spleen concomitant with lower titers of Nabs in the serum than those in WT mice. Interestingly, B-1a-cell-specified progenitors also express CD6 and the frequencies of these progenitors are significantly reduced in the CD6 KO mice. B cell receptor (BCR) signaling is critical for B1a B cell development and T-independent immunoglobulin response. CD6 KO B1a B cells displayed impaired BCR-induced JNK activation and elicited impaired T-independent antibody responses to NP-Ficoll. These findings suggest a positive role for CD6 in regulating B1a B cell homeostasis and immune response.
West Nile Virus infected human dendritic cells induce natural killer T cells to produce anti-inflammatory cytokines (INC1P.406)
Authors: Kovats Susan , turner sean , Simmons Amie , Alberola-Ila Jose 
Published: January 2023

Abstract
West Nile Virus (WNV) infection is an emerging mosquito-borne zoonosis in the U.S. WNV initially replicates in keratinocytes and skin resident dendritic cells (DCs). Infected DCs in the skin or cutaneous lymph nodes are likely to interact with Invariant Natural Killer T cells (iNKTs), an innate effector cell type important for control of pathogen infections. Bidirectional interactions between DCs and iNKTs amplify the innate immune response to viral infections, thus controlling viral load and regulating adaptive immunity. iNKTs can be activated indirectly by inflammatory cytokines or stimulated by lipid antigens presented by CD1d. To assess the DC-iNKT interaction upon WNV infection, we infected human monocyte-derived DCs with WNV and studied their innate immune responses and their ability to activate isolated blood iNKTs. Infected DCs synthesized viral Envelope mRNA and protein, and upregulated costimulatory molecules but showed decreased expression of CD1d. Infected DCs secreted type I interferon, but not IL-12, IL-23, IL-18 or IL-10. Unexpectedly, the WNV-infected DCs stimulated human iNKTs to upregulate CD69 and produce IL-10, but not proinflammatory cytokines. In contrast, incubation of DCs with the TLR3 ligand polyIC did not lead to iNKT IL-10 production, suggesting that DC activation by viral RNA alone does not trigger this iNKT response. In sum, WNV-infected human DCs producing type I interferon induce iNKTs to secrete IL-10 but not proinflammatory cytokines.