Browsing by Subject "ST2"

Now showing 1 - 6 of 6
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    Bcl6 and Blimp1 reciprocally regulate ST2+ Treg-cell development in the context of allergic airway inflammation
    (Elsevier, 2020) Koh, Byunghee; Ulrich, Benjamin J.; Nelson, Andrew S.; Panangipalli, Gayathri; Kharwadkar, Rakshin; Wu, Wenting; Xie, Markus M.; Fu, Yongyao; Turner, Matthew J.; Paczesny, Sophie; Janga, Sarath Chandra; Dent, Alexander L.; Kaplan, Mark H.; Pediatrics, School of Medicine
    Background Bcl6 is required for the development of T follicular helper cells and T follicular regulatory (Tfr) cells that regulate germinal center responses. Bcl6 also affects the function of regulatory T (Treg) cells. Objective The goal of this study was to define the functions of Bcl6 in Treg cells, including Tfr cells, in the context of allergic airway inflammation. Methods We used a model of house dust mite sensitization to challenge wild-type, Bcl6fl/fl Foxp3-Cre, and Prdm1 (Blimp1)fl/fl Foxp3-Cre mice to study the reciprocal roles of Bcl6 and Blimp1 in allergic airway inflammation. Results In the house dust mite model, Tfr cells repress the production of IgE and Bcl6+ Treg cells suppress the generation of type 2 cytokine–producing cells in the lungs. In mice with Bcl6-deficient Treg cells, twice as many ST2+ (IL-33R+) Treg cells develop as are observed in wild-type mice. ST2+ Treg cells in the context of allergic airway inflammation are Blimp1 dependent, express type 2 cytokines, and share features of visceral adipose tissue Treg cells. Bcl6-deficient Treg cells are more susceptible, and Blimp1-deficient Treg cells are resistant, to acquiring the ST2+ Treg–cell phenotype in vitro and in vivo in response to IL-33. Bcl6-deficient ST2+ Treg cells, but not Bcl6-deficient ST2+ conventional T cells, strongly promote allergic airway inflammation when transferred into recipient mice. Lastly, ST2 is required for the exacerbated allergic airway inflammation in Bcl6fl/fl Foxp3-Cre mice. Conclusions During allergic airway inflammation, Bcl6 and Blimp1 play dual roles in regulating Tfr-cell activity in the germinal center and in the development of ST2+ Treg cells that promote type 2 cytokine responses.
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    Diagnostic and Prognostic Plasma Biomarkers for Idiopathic Pneumonia Syndrome after Hematopoietic Cell Transplantation
    (Elsevier, 2018-04) Seo, Sachiko; Yu, Jeffrey; Jenkins, Isaac C.; Leisenring, Wendy M.; Steven-Ayers, Terry; Kuypers, Jane M.; Huang, Meei-Li; Jerome, Keith R.; Boeckh, Michael; Paczesny, Sophie; Pediatrics, School of Medicine
    Idiopathic pneumonia syndrome (IPS) is a noninfectious pulmonary complication after hematopoietic cell transplantation (HCT) and is difficult to diagnose. In 41 patients with IPS, we evaluated 6 candidate proteins in plasma samples at day 7 post-HCT and at onset of IPS to identify potential diagnostic or prognostic biomarkers for IPS. Samples at similar times from 162 HCT recipients without documented infections and 37 HCT recipients with respiratory viral pneumonia served as controls. In multivariable models, a combination of Stimulation-2 (ST2; odds ratio [OR], 2.8; P < .001) and IL-6 (OR, 1.4; P = .025) was the best panel for distinguishing IPS at diagnosis from unaffected controls, whereas tumor necrosis factor receptor 1 (TNFR1; OR, 2.9; P = .002) was the best marker when comparing patients with IPS and viral pneumonia. The areas under the curve of the receiver operating characteristic (ROC) curves for discriminating between IPS and unaffected controls at day 7 post-HCT were .8 for ST2, .75 for IL-6, and .68 for TNFR1. Using estimated sensitivity and specificity values from cutoffs determined with the ROC analysis (cutoff level: ST2, 21 ng/mL; IL-6, 61 pg/mL; TNFR1, 3421 pg/mL), we calculated positive predictive values (PPV) for a range of estimated population prevalence values of IPS. Among the 3 markers, ST2 showed the highest PPV for IPS occurrence. Based on an assumed prevalence of 8%, a positive ST2 test increased likelihood of IPS to 50%. We conclude that a prospective validation study is warranted to determine whether a plasma biomarker panel can aid the noninvasive diagnosis and prognosis of IPS.
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    Elevated Plasma Soluble ST2 Levels are Associated With Neuronal Injury and Neurocognitive Impairment in Children With Cerebral Malaria
    (Case Western Reserve University, 2022-06-23) Fernander, Elizabeth M.; Adogamhe, Pontian; Datta, Dibyadyuti; Bond, Caitlin; Zhao, Yi; Bangirana, Paul; Conroy, Andrea L.; Opoka, Robert O.; John, Chandy C.; Pediatrics, School of Medicine
    Background: Murine experimental cerebral malaria studies suggest both protective and deleterious central nervous system effects from alterations in the interleukin-33 (IL-33)/ST2 pathway. Methods: We assessed whether soluble ST2 (sST2) was associated with neuronal injury or cognitive impairment in a cohort of Ugandan children with cerebral malaria (CM, n=224) or severe malarial anemia (SMA, n=193). Results: Plasma concentrations of sST2 were higher in children with CM than in children with SMA or in asymptomatic community children. Cerebrospinal fluid (CSF) sST2 levels were elevated in children with CM compared with North American children. Elevated plasma and CSF ST2 levels in children with CM correlated with increased endothelial activation and increased plasma and CSF levels of tau, a marker of neuronal injury. In children with CM who were ≥5 years of age at the time of their malaria episode, but not in children <5 years of age, elevated risk factor-adjusted plasma levels of sST2 were associated with worse scores for overall cognitive ability and attention over a 2-year follow-up. Conclusions: The study findings suggest that sST2 may contribute to neuronal injury and long-term neurocognitive impairment in older children with CM.
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    IL-1 receptor like 1 protects against alcoholic liver injury by limiting NF-κB activation in hepatic macrophages
    (Elsevier, 2017) Wang, Meng; Shen, Guannan; Xu, Liangguo; Liu, Xiaodong; Brown, Jared M.; Feng, Dechun; Ross, Ruth Ann; Gao, Bin; Liangpunsakul, Suthat; Ju, Cynthia; Medicine, School of Medicine
    Background & Aim Alcohol consumption increases intestinal permeability and causes damage to hepatocytes, leading to the release of pathogen- and damage-associated molecular pattern molecules (PAMPs and DAMPs), stimulating hepatic macrophages and activating NF-κB. The resultant inflammation exacerbates alcoholic liver disease (ALD). However, much less is known about the mechanisms attenuating inflammation and preventing disease progression in most heavy drinkers. Interleukin (IL)-33 is a DAMP (alarmin) released from dead cells that acts through its receptor, IL-1 receptor like 1 (ST2). ST2 signaling has been reported to either stimulate or inhibit NF-κB activation. The role of IL-33/ST2 in ALD has not been studied. Methods Serum levels of IL-33 and its decoy receptor, soluble ST2 (sST2) were measured in ALD patients. Alcohol-induced liver injury, inflammation and hepatic macrophage activation were compared between wild-type, IL-33−/− and ST2−/− mice in several models. Results Elevation of serum IL-33 and sST2 were only observed in patients with severe decompensated ALD. Consistently, in mice with mild ALD without significant cell death and IL-33 release, IL-33 deletion did not affect alcohol-induced liver damage. However, ST2-deletion exacerbated ALD, through enhancing NF-κB activation in liver macrophages. In contrast, when extracellular IL-33 was markedly elevated, liver injury and inflammation were attenuated in both IL-33−/− and ST2−/− mice compared to wild-type mice. Conclusion Our data revealed a dichotomous role of IL-33/ST2 signaling during ALD development. At early and mild stages, ST2 restrains the inflammatory activation of hepatic macrophages, through inhibiting NF-κB, and plays a protective function in an IL-33-independent fashion. During severe liver injury, significant cell death and marked IL-33 release occur, which triggers IL-33/ST2 signaling and exacerbates tissue damage. Lay summary In mild ALD, ST2 negatively regulates the inflammatory activation of hepatic macrophages, thereby protecting against alcohol-induced liver damage, whereas in the case of severe liver injury, the release of extracellular IL-33 may exacerbate tissue inflammation by triggering the canonical IL-33/ST2L signaling in hepatic macrophages.
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    IL-33 Mediated Th2 Effector Functions are Suppressed in Tregs by Bcl6 and Regulated by Sex
    (2024-08) Lee, Kyu Been; Dent, Alexander; Richer, Martin; Robinson, Christopher; Yang, Kai
    Allergic airway inflammation (asthma) is a prevalent and uncurable disease worldwide, affecting many individuals’ quality of life. Although asthma does not form from a singular cause, one primary mediator comes from the exposure to environmental allergens and the improper activation of the T cell subset: T helper 2 (Th2) cells. Th2 cells produce pro-inflammatory cytokines and promote the activation and recruitment of various pro-inflammatory cells into the lung, causing greater damage and inflammatory responses in the organ. Th2 cell’s activation is regulated by another T cell subset, Regulatory T (Treg) cells, by expressing anti-inflammatory cytokines and downregulating the inflammatory response. On the contrary, the release of interleukin-33 (IL-33) from damaged lung epithelial cells transitions Tregs into Th2-like Tregs (ST2+ Tregs) which release both pro-and anti-inflammatory cytokines and cannot suppress the inflammatory disease. However, transcriptional repressor protein B cell lymphoma 6 (Bcl6) provides Tregs a stable follicular phenotype and suppresses the ST2+ Treg transition. Preliminary data revealed that Bcl6 repressive function is dependent on mouse sex, in which Tregs of male mice are more resistant to the ST2+ Treg phenotype than those of female mice. However, the removal of Bcl6 also removed the sex-dependent suppression against the ST2+ Treg transition. The project therefore sought to further confirm and answer whether Bcl6 suppressed the ST2+ Treg phenotype in a sex-dependent manner, ultimately leading to a sex-biased asthma prevalence and severity. We utilized quantitative polymerase chain reaction (qPCR) and next-generation sequencing techniques to uncover which genes Bcl6 regulates, how IL-33 affects chromatin accessibility/gene expression, and what relation sex hormones have with Bcl6 in the expression of Th2 cytokines from Tregs. Currently, we have discovered that estrogen-like chemicals in common cell culturing media may be acting on the estrogen receptor of Tregs and causing differential gene expressions based on media conditions. We also determined that Bcl6 is acting independently of mouse sex to suppress Th2 genes in Tregs, contrary to preliminary findings. Overall, we have obtained insight on the role of the estrogen receptor and Bcl6’s mechanism of suppression in relation to sex.
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    ST2/MYD88 signaling is a therapeutic target alleviating murine acute graft-versus-host disease sparing T regulatory cell function
    (2018-01-10) Griesenauer, Brad; Paczesny, Sophie; Dent, Alexander L.; Kaplan, Mark H.; Kapur, Reuben
    Acute graft-versus-host disease (aGVHD) hinders the efficacy of allogeneic hematopoietic cell transplantation (HCT). Plasma levels of soluble serum stimulation-2 (sST2) are elevated during human and murine aGVHD and are correlated to a type 1 T cell response. Membrane-bound ST2 (ST2) on donor T cells has been shown to be protective against aGVHD. ST2 signals through the adapter protein myeloid differentiation primary response 88 (MyD88). The role of MyD88 signaling in donor T cells during aGVHD remains unknown. We found that knocking out MyD88 in the donor T cells protected against aGVHD independent of interleukin 1 receptor (IL-1R) and toll-like receptor 4 (TLR4) signaling, both of which also signal through MyD88, in two murine HCT models. This protection was entirely driven by MyD88-/- CD4 T cells, leading to a decreased type 1 response without affecting T cell proliferation, apoptosis, or migration. In our aGVHD models, loss of intrinsic MyD88 signaling is not responsible for the observed protection. However, transplanting donor MyD88-/- T conventional cells (Tcons) with wild type (WT) or MyD88-/- T regulatory cells (Tregs) ameliorated aGVHD severity and lowered aGVHD mortality. Transcriptome analysis of sorted MyD88-/- CD4 T cells from the intestine ten days post-HCT showed lower levels of Il1rl1 (gene of ST2), Ifng, Csf2, Stat5, and Jak2, among others. Decreased sST2 was confirmed at the protein level with less secretion of sST2 and more expression of ST2 compared to WT T cells. Transplanting donor ST2-/- Tcons with WT or ST2-/- Tregs mirrored observations when using donor MyD88-/- Tcons. This suggests that Treg suppression from lack of MyD88 signaling in Tcons during alloreactivity uses the ST2 but not the IL-1R or TLR4 pathways. The results of our study confirm that ST2 represents an aGVHD therapeutic target that spares Treg function.