bluuebunny/crossref_metadata_2025_split huggingface dataset:
IL-1 signaling regulates skin inflammation through directly activating and indirectly chemoattracting dermal γδ T17 cells (CAM1P.147)
Authors: Cai Yihua , Xue Feng , Liu Na , Fleming Christopher , Yan Jun 
Published: January 2023

Abstract
Interleukin (IL)-1β has been demonstrated to play an important role in skin inflammation. The mechanisms by which IL-1β signaling pathway regulates skin inflammation remain elusive. Previously we have demonstrated the critical role of dermal γδ T17 cells in psoriasis pathogenesis, therefore we hypothesized that IL-1β may regulate skin inflammation through the activation of dermal γδ T cells. To test this hypothesis, we established a neonatal thymocytes reconstitution system in which IL-1R signaling is selectively deficient in dermal γδ T cells or the other cells. The reconstituted mice with IL-1R signaling specific deficiency in dermal γδ T cells showed less IL-17 production in skin compared to control mice after IMQ application, but the epidermal thickness was not significantly changed. Similar phenotype was also found in the reconstituted mice with WT dermal γδ T cells, but IL-1R deficiency in all the other cells. These results indicate that IL-1R signaling in both dermal γδ T cells and the other cells is required to induce full-fledged skin inflammation. Indeed, we found that IL-1β stimulated keratinocytes (KCs) to secrete chemokines including CCL20. Therefore, IL-1β may regulate skin inflammation at two levels: directly activating dermal γδ T17 cells and stimulating KCs to secrete chemokines which may chemoattract peripheral γδ T cells to dermis, thus amplifying the inflammatory cascade. This work is supported by a grant from National Psoriasis Foundation.
Respiratory syncytial virus infection triggers HMGB1 release from lung epithelial cells to promote inflammatory cytokine production (CAM1P.152)
Authors: Hosakote Yashoda , Garofalo Roberto , Kurosky Alexander 
Published: January 2023

Abstract
Respiratory syncytial virus (RSV) is an important cause of lower respiratory tract infections in infants and young children. Oxidative stress is shown to play an important role in the pathogenesis of lung inflammation. We have shown that RSV induces oxidative stress by rapid generation of reactive oxygen species and downregulation of antioxidant enzyme expression resulting in lung inflammation. High mobility group box 1 protein (HMGB1) is a redox-sensitive multifunction protein that serves as both a chromatin protein and an extracellular signaling molecule. Although HMGB1 has been implicated in inflammatory diseases, there has been no report on its role in RSV related lung disease. The goal of this study is to dissect the mechanisms that induce the release of HMGB1 and associated cellular signaling in response to RSV infection. Human lung epithelial cells were infected with RSV and harvested over time to analyze HMGB1 expression by Western blot, immunohistochemistry and qRT-PCR. Our studies show for the first time that RSV infection induces the translocation of HMGB1 from cell nuclei to the cytoplasm and its subsequent release to the extracellular space demonstrating a novel mechanism of HMGB1 in the activation of cells to promote inflammatory cytokine release. Understanding of HMGB1 role in the setting of viral-induced oxidative stress may lead to the development of novel strategies to treat respiratory viral infections in pediatric and elderly population.
The atypical chemokine receptor ACKR4 facilitates dendritic cell migration during inflammation by scavenging CCL19 (CCR3P.205)
Authors: Bryce Steven , Asquith Darren , Bromley Shannon , Luster Andrew , Graham Gerard , Nibbs Robert 
Published: January 2023

Abstract
The migration of dendritic cells from tissues to draining lymph nodes is a critical step in the induction of peripheral tolerance and the initiation of adaptive immune responses. This is dependent on CCR7 expression by dendritic cells. In response to the chemokine CCL21, CCR7 directs dendritic cells into lymphatic vessels in the tissue, and permits their transit from the subcapsular sinus into the lymph node parenchyma. The CCR7 ligands CCL19 and CCL21 also bind ACKR4, an atypical chemokine receptor expressed by keratinocytes in the skin and lymphatic endothelial cells lining the subcapsular sinus. In mice, ACKR4 controls interfollicular CCL21 gradients, and enhances dendritic cell entry into the lymph node parenchyma from the subcapsular sinus. Here we report that Ackr4 deficiency disrupts CCR7-dependent dendritic cell arrival at skin-draining lymph nodes during cutaneous inflammation. We show that this, at least in part, is due to the defective departure of dendritic cells from inflamed skin, and is accompanied by dysregulation of bioavailable CCL19 and CCL21 in the skin. Strikingly, genetic deletion of CCL19 completely rescues the defective inflammation-driven trafficking of dendritic cells caused by Ackr4 deficiency. Thus, by regulating CCL19, ACKR4 helps maintain CCR7-dependent dendritic cell departure from inflamed tissues.
Metabolic inhibition by inositol-tetrakisphosphate delays thymocyte β-selection and renders it Notch-dependent (HEM2P.241)
Authors: Conche Claire , Westernberg Luise , Huang Yina , Rigaud Stephanie , Siegemund Sabine , Mukherjee Sayak , Nosaka Lyn'Al , Das Jayajit , Sauer Karsten 
Published: January 2023

Abstract
In β-selection, surface-expression of a pre-T cell receptor (pre-TCR) induces thymocyte metabolic activation, proliferation, survival and differentiation. This pivotal αβ T cell fate-determining event requires co-stimulatory Notch signals. Here, we show that this Notch dependence is enforced through antagonistic signaling by inositol-trisphosphate 3-kinase B (Itpkb) and phosphoinositide 3-kinase (PI3K). Itpkb produces soluble inositol-tetrakisphosphate which competes with the PI3K lipid-product PIP3 for binding to the effector-kinase Akt. Itpkb-/- thymocytes are pre-TCR hyperresponsive, hyperactivate Akt, downstream mTOR and metabolism, undergo an accelerated β-selection and can develop to CD4+CD8+ cells without Notch. This is reversed by inhibition of Akt, mTOR or glucose-metabolism. Thus, Itpkb restricts pre-TCR induced metabolic activation to enforce coincidence-detection of pre-TCR expression and Notch-engagement, and to prevent premature thymocyte maturation.
Development of regulatory T cells in the thymus: two paths to the same goal? (HEM2P.237)
Authors: Owen David , Mahmud Shawn , Farrar Michael 
Published: January 2023

Abstract
Mature thymic regulatory T cells (Tregs) are defined by dual expression of Foxp3 and CD25 on CD4SP thymocytes. However, the cellular pathways by which CD4 thymocytes differentiate into Tregs remain incompletely understood. Previous reports demonstrated that Treg development occurred via a two-step process. In step one, strong TCR signaling induces expression of CD25 leading to a CD25+Foxp3- Treg progenitor (TRP). In step two, exposure of this TRP to IL2 results in conversion to a CD25+Foxp3+ Treg. Recently, work by Singer and colleagues have defined a CD25-Foxp3lo TRP that can also be converted by IL2 into CD25+Foxp3+ Tregs. A key question is why two distinct cellular pathways involving distinct TRP populations are needed to reach the same endpoint. Using a combination of maturation marker analysis and RAG2-GFP reporter mice we observed that CD25+Foxp3- TRP arise more rapidly than the CD25-Foxp3lo TRP following positive selection. Analysis of Nur77-GFP reporter mice revealed that these two progenitor populations also display distinct affinity spectrums for self-peptide. The CD25+Foxp3- TRP have a high and relatively narrow range of TCR affinities for antigen, while the CD25-Foxp3lo TRP have a lower but broader range of TCR affinity for antigen. Our results suggest that these two different Treg developmental pathways generate Tregs with distinct TCR repertoires that may have distinct function in protecting against autoimmunity and reactivity to commensal organisms.
Human resistin, a neutrophil-derived metabolic and inflammatory mediator correlates with decreased lung function and NETosis in cystic fibrosis airway disease (HUM1P.261)
Authors: Forrest Osric , Chopyk Daniel , Ingersoll Sarah , Yoo Dae-goon , Brown Milton , Tangpricha Vin , Tirouvanziam Rabindra , Rada Balazs 
Published: January 2023

Abstract
Resistin, a protein initially cloned from mouse adipocytes, is a strong antagonist of insulin signaling. In humans, it is located in both the azurophil and specific granules of PMNs and as a result can be elevated in metabolic and PMN-driven inflammatory disorders. Cystic fibrosis (CF) combines PMN-dominated airway inflammation with profound metabolic anomalies, but the presence of resistin in CF patients has not been studied thus far. Methods: We measured resistin levels using an ELISA on platelet-free plasma and airway fluid from CF patients and measured the presence of neutrophil extracellular traps (NETs) a marker of neutrophil activation in CF airway fluid. Results: Resistin levels in platelet-free plasma were significantly higher in CF subjects than in HC subjects. Resistin levels in expectorated CF sputum were 2 to 3 orders (100-500 fold) of magnitude higher than in plasma. Interestingly, we found a strong negative correlation between sputum resistin and lung function (Spearman Rho=-0.81, P&lt;10-4). Similarly resistin was also shown to positively correlate with NETs in CF sputum. Conclusions: Resistin levels are abnormal in CF plasma and strikingly elevated in CF airway fluid during chronic disease. These results show, as also suggested by prior studies, that extracellular resistin is associated with PMN-driven CF airway inflammation, including NET release. Mechanistic studies looking at the precise impact of resistin on metabolism and inflammation in CF are warranted.
ICOS deficiency results in defective ILC2 expansion, impaired Th2 responses, and increased mortality after bleomycin-induced lung injury (HUM1P.264)
Authors: Hrusch Cara , Casaos Joshua , Bonham Catherine , Blaine Kelly , Bryazka Dana , Jaffery Mohammad , Takahashi Stephenie , Noth Imre , Sperling Anne 
Published: January 2023

Abstract
Idiopathic pulmonary fibrosis (IPF) is a progressive lung disease causing irreversible lung scarring and loss of pulmonary function. RNA analysis has shown that patients with IPF have reduced ICOS expression in peripheral blood mononuclear cells. We now show that ICOS surface expression on CD4 T cells positively correlates with lung function in patients with IPF. However, whether decreased ICOS is a result of disease progression or playing a role in the pathogenesis is unclear. Therefore, using bleomycin to induce pulmonary fibrosis in mice, we found that ICOS was decreased in peripheral CD4 T cells similar to our findings in patients. In contrast, ICOS was increased on lung CD4 T cells by 3d post-bleomycin and remained elevated through 21d at the height of collagen deposition. Compared to wild-type B6 mice, ICOS-deficient mice had increased weight loss and mortality after bleomycin challenge, suggesting a protective role for ICOS. Strikingly, ILC2s expanded in the lung at 3d post-bleomycin in B6 mice, but not in ICOS-deficient mice. In B6 mice, ILC2 expansion was associated with CD4 T cell infiltration at 5d and Th2 cytokine production in the draining lymph nodes at 21d. However, ICOS-deficient mice that survived the initial bleomycin insult failed to recruit T cells to the lungs and had less IL-13 in the draining lymph nodes. Overall, these results indicate that ICOS expression promotes lung tissue repair by promoting both innate and adaptive type-2 immune responses.
Staphylococcal superantigens trigger rapid human IL-17A production by a novel population of memory T cells (HUM1P.268)
Authors: Szabo Peter , Goswami Ankur , McCormick John , Haeryfar S. M. 
Published: January 2023

Abstract
Toxic shock syndrome (TSS) is a life-threatening illness characterized by fever, hypotensive shock and multi-organ failure within hours of onset. TSS is caused by exposure to bacterial toxins known as superantigens (SAgs), which are produced by common Gram-positive bacteria such as Staphylococcus aureus. During infection, SAgs can activate of up to 20% of all T cells, resulting in massive and rapid release of pro-inflammatory cytokines, systemic intravascular coagulation, organ damage and death. However, the exact cellular mechanisms underlying the rapidity of this potentially fatal inflammatory reaction are far from clearly understood. In our preliminary experiments, human peripheral blood mononuclear cells (PBMCs) stimulated with SAgs in vitro showed immediate up-regulation (up to 2000-fold) of mRNA for the pro-inflammatory cytokine IL-17A. SAg-stimulated PBMCs also produced substantial amounts of IL-17A protein within hours of activation. The cells responsible for the rapid production of IL-17A were identified as a subset of memory T cells exhibiting a novel phenotype. Furthermore, neutralizing IL-17A at the onset significantly reduced both morbidity and mortality in a humanized mouse model of TSS. Our results reveal a critical role for memory T cells in TSS and define a novel contribution by IL-17A to the initiation and pathogenesis of the syndrome.
Repeated challenge with the hapten oxazolone provokes persistent vulvar mechanical sensitivity, labiar mast cell accumulation and nerve overgrowth in previously sensitized ND4 mice (HUM1P.270)
Authors: Chatterjea Devavani , Landry Jasmine , Dhanwada Jyothi , Mengistu Hanna 
Published: January 2023

Abstract
Vulvodynia is a chronic vulvar pain condition affecting up to 8-16% of 18-60 year-old women. Epidemiological studies have associated an increased risk of developing vulvodynia with a history of seasonal and insect allergies. We have previously demonstrated that acute labiar exposure to the hapten allergen oxazolone provokes increased vulvar mechanical sensitivity in ND4 Swiss mice. Here, we show that repeated oxazolone challenge produces persistent vulvar mechanical sensitivity in sensitized mice for at least12 days after 10 allergen exposures. This persistent sensitivity is accompanied by mast cell accumulation and overgrowth of cutaneous neurites both of which persist for at least 14 days after the final allergen exposure. These changes are accompanied by an early and transient increase in mRNAs encoding CADM1 - an adhesion molecule that facilitates nerve-mast cell synapses - in the skin and mRNAs encoding the inflammatory cytokine IL-6 in the spinal cord. Taken together, these neuroimmune biomarkers may serve as potential diagnostic/therapeutic targets for specific allergy-driven subsets of chronic vulvar pain.
FcγR3A genotype influences the inhibition of activated T cell proliferation by infliximab and adalimumab (HUM1P.313)
Authors: Casinghino Sandra , Cole Susan , Bono Christine , Al-Derzi Mazin 
Published: January 2023

Abstract
The anti-tumor necrosis factor (TNF) antibodies, infliximab and adalimumab are efficacious in Crohn’s disease (CD) patients but their relevant mechanism(s) of action (MOA) are not fully elucidated. Neutralization of TNF activity is a key efficacy mechanism, but may not be the only relevant MOA for efficacy in CD. Fc receptor-mediated dampening of the immune response has been proposed as one of the alternative hypotheses. Two FcγR3A-158 polymorphisms (158V and 158F) have been shown to influence binding affinity of IgG1 antibodies, and CD patients with V/V genotypes have increased biological responses to infliximab. Previous work by others showed that in a mixed lymphocyte reaction (MLR), infliximab and adalimumab induced formation of immunosuppressive macrophages in an Fc region-dependent manner and that these macrophages inhibited proliferation of activated T cells. We ran MLRs with FcγR3A genotype-matched donor pairs to determine if Fc receptor genotype influenced the anti-inflammatory response by infliximab and adalimumab. Our results showed that regulatory macrophages were induced regardless of FcγR3A genotype but that decreases in T cell proliferation were more pronounced with V/V donor pairs than with V/F or F/F genotypes. In conclusion, our work suggests that infliximab and adalimumab may be more effective at inducing an anti-inflammatory state in individuals with the 158V polymorphism of FcγR3A.
Effects of the Bruton’s tyrosine kinase inhibitor ibrutinib on humoral immunity in patients with chronic lymphocytic leukemia (HUM1P.258)
Authors: Sun Clare , Lee Yuh Shan , Lipsky Andrew , Farooqui Mohammed , Herman Sarah , Salem Dalia , Stetler-Stevenson Maryalice , Yuan Constance , Aue Georg , Wiestner Adrian 
Published: January 2023

Abstract
Chronic lymphocytic leukemia (CLL) is characterized by immune dysregulation, often including hypogammaglobulinemia. Ibrutinib, a covalent inhibitor of Bruton’s tyrosine kinase (BTK), is highly active in B cell malignancies, including CLL. Inactivating mutations in BTK cause X-linked agammaglobulinemia. We evaluated the impact of ibrutinib on immunoglobulin (Ig) levels in CLL patients (pts) treated at NIH. Consistent with previous reports, IgG remained stable during the first 6 months, but decreased from a median of 707 mg/dL at baseline to 611 mg/dL at 24 months (17% reduction, n=25, p&lt;0.0001). In contrast, there was a sustained increase in IgA and a transient increase in IgM. Next, we assessed serum free light chains (FLCs) to distinguish the effects on clonal from non-clonal B cells. In κ-clonal CLL cases, the clonal (κ) FLC decreased from a median of 6.71 to 1.42 mg/dL after 6 months (n=39, p&lt;0.0001). Interestingly, the non-clonal (λ) FLC increased, suggesting the recovery of normal B cell function. Consistently, we found an increase in normal B cells in blood and bone marrow, including early B cell precursors. In comparison, CLL pts (n=16) treated with anti-CD20-based chemoimmunotherapy also showed a decrease in IgG at 24 months (12% reduction, p=0.0052), and surprisingly, an improvement in IgA levels, suggesting that the latter effect is not drug-specific but due to tumor reduction. The consequences of long-term BTK inhibition on immune function require further study.
Dendritic cells are functionally relevant targets of IL-25 in allergic lung inflammation (HYP2P.320)
Authors: Siebenlist Ulrich , Claudio Estefania , Tassi Ilaria , Wang Hongshan 
Published: January 2023

Abstract
Asthma is a chronic inflammatory disease of the airways, typically triggered by allergens and often associated with type 2 responses. Skewing towards type 2 inflammation is due to release of one or more of the cytokines IL-33, TSLP and IL-25 by epithelial cells upon encounter with allergens or helminthes or when stressed. All three cytokines stimulate innate lymphoid cells type 2 (ILC2) to rapidly produce the classic inflammatory type 2 cytokines IL-13 and IL-5, and administration of any one of these cytokines into lungs initiates a strong inflammatory asthma-like response. IL-25 is the only member of the IL-17 cytokine family involved in type 2 responses. To understand its contributions to allergic lung inflammation, we first investigated for mechanisms by which IL-25 initiates responses on its own. In addition to ILC2s, we unexpectedly found that lung resident dendritic cells (DCs) rapidly responded. To assess the relevance of this finding, we made use of mice in which IL-25 cannot signal DCs. Activation of DCs by IL-25 was required for production of IL-9 by T cells, a cytokine linked to asthma as well. Importantly, IL-25-mediated activation of DCs was also required for IL-9 production by T cells in the context of house dust mite (HDM)-induced pulmonary inflammation, a physiologic inducer of asthma in patients. Our findings identify lung resident DCs as novel and functionally relevant targets of IL-25, even in the context of the broadly acting HDM allergens.
IκBζ regulates human lung epithelial cytokine responses to house dust mite antigens (HYP2P.330)
Authors: Sundaram Kruthika , Wewers Mark 
Published: January 2023

Abstract
Rationale: Asthma is a chronic lung disease characterized by inflammation of bronchial epithelium. House dust mite (HDM) is a common allergen that triggers asthma. IκBζ is a newly recognized member of the NFκB family that is induced in lung epithelial cells to regulate their production of cytokines. We hence analyzed how IκBζ might modulate HDM‘s induction of IL-6 and GMCSF in lung epithelial cells. Methods: We co-cultured primary human bronchial epithelial cells or BEAS2B cells with HDM alone or with HDM-treated human monocytes, macrophages or dendritic cells and measured GMCSF, IL-6 and IκBζ protein expression. Results: Bronchial epithelial cells expressed IκBζ and released IL-6 and GMCSF only when co-cultured with HDM treated monocytes. However, these epithelial cells did not respond to direct HDM stimulation when cultured alone or to co-culture with HDM-treated macrophages or dendritic cells. The monocyte co-culture response correlated with its IL-1β release and was blocked by IL-1 receptor antagonist and the TLR4 antagonist Rhodobacter sphaeroides LPS. GFP tagged IκBζ accumulated in the nucleus of epithelial cells and si-IκBζ suppressed the epithelial release of IL-6 and GMCSF. Conclusions: Monocytes release IL-1β in response to HDM thus inducing the lung epithelial cell IκBζ-mediated expression of asthma associated inflammatory cytokines. We propose that control of IκBζ expression deserves future study as a key regulator of HDM induced asthma.
PARP inhibition blocks chronic asthma symptoms in a house dust mite asthma model and differentially modulates human CD4+T cell function (HYP2P.332)
Authors: Ghonim Mohamed , Pyakurel Kusma , Ibba Salomi , Wang Jeffery , Rodriguez Paulo , Lammi Matthew , Zea Arnold , Mansy Moselhy , Ochoa Augusto , Boulares Hamid 
Published: January 2023

Abstract
Asthma incidence is on the rise. In the United States alone, more than 20 million individuals suffer from the disease. A sizable portion of these asthmatics do not respond to the existing drugs. Accordingly, the need for new therapies is an immediate a necessity. One of the most essential goals for treatment is the identification of drugs that block the release or effects of Th2 cytokines. Using HDM-based chronic model, we show that a single administration of olaparib, a PARP inhibitor, was effective in decreasing lung eosinophilia. Two additional administrations of the drug provided better protection and significantly reduced airway hyper-responsiveness. These results were confirmed using similarly exposed PARP-1−/− mice. Such protective effects may be mediated by a significant reduction in Th2 cytokines and a concomitant increase in T-regulatory cells. In addition, we show that PARP is highly activated in lung tissues and PBMCs from asthmatics demonstrating the relevance to the human disease. Using human CD4+T cells, we show that PARP inhibition significantly reduced GATA-3 expression, Th2 cytokine production without affecting production of IFN-γ, T cell proliferation, or the overall numbers of Th1 or Th2 cells. However and similarly to our animal studies, PARP inhibition markedly increased the number of human T-regulatory cells. Our results provide an additional support to the potential of PARP inhibition as a novel strategy for the treatment of asthma