bluuebunny/crossref_metadata_2025_split huggingface dataset:
Anti-malarial drug Artesunate ameliorates oxidative lung damage in experimental allergic asthma (55.12)
Authors: Ho Wanxing , Cheng Chang , Peh Hong Yong , Xu Fengguo , Tannenbaum Steven , Ong Choon Nam , Wong Wai-Shiu 
Published: January 2023

Abstract
Oxidative stress is an important clinical feature of asthma, resulting in oxidative damage to lung proteins, DNA and lipids. Our previous study has shown that artesunate, an anti-malarial drug, has potent anti-inflammatory effects in a murine asthma model. As oxidative stress plays a critical role in the pathogenesis of asthma, we further investigated the effects of artesunate on oxidative lung damage in this asthma model. BALB/c mice sensitized and challenged with ovalbumin, developed airway inflammation and oxidative lung damage with increased levels of nitrotyrosine (protein), 8-isoprostane (lipid) and 8-hydroxy-2-deoxy-guanosine (DNA). Superoxide dismutase (SOD) expression and activity were increased, while catalase expression and activity were suppressed in asthmatic mice. Treatment with artesunate showed comparable anti-inflammatory effects to dexamethasone, a potent corticosteriod, significantly suppressing airway inflammation and oxidative lung damage. Mice treated with artesunate had reduced levels of nitrotyrosine, 8-isoprostane and 8-hydroxy-2-deoxy-guanosine. SOD expression and activity were returned to basal levels, while catalase gene expression and activity were promoted with artesunate treatment. Gluthathione peroxidase expression and activity were unaltered in all treatment groups. Our findings indicate that artesunate has potent anti-inflammatory effects, comparable to dexamethasone, by ameliorating oxidative lung damage in experimental allergic airways.
Multiple drug hypersensitivity: role of T regulatory cells (55.15)
Authors: Daubner Barbara , Groux-Keller Monika , Kawabata Thomas , Naisbitt Dean J. , Park Kevin B. , Thomas Wendland , Marianne Lerch , Pichler Werner J. 
Published: January 2023

Abstract
Introduction: Up to 10% of patients with severe immune-mediated drug hypersensitivity tend to develop multiple drug hypersensitivities (MDH), and react clinically and immunologically to various drugs. Objective: Evaluating the role of T regulatory (T reg) cells in drug reactions and developing an improved clinical and immunological definition of MDH. Methods: T cell reactivity to various drugs was assessed by expression analysis of activation markers and cross-reactivity of drug specific T cell clones to various drugs was analyzed. The role of T regs (Foxp3+/CD25high) was analyzed functionally in T reg depletion assays. The phenotype of reacting T cells was characterized by analysis of activation and cell exhaustion markers. Results: T regs from MDH patients are functionally highly active and suppress T cell proliferation similar to T regs from monoallergic patients and healthy controls. Removal of T regs enhances the reactivity to involved drugs, but does not facilitate an immune response to not exposed drugs in vitro. Drug reactive T cells from monoallergic patients reside in the resting CD4+CD25neg T cell fraction while in MDH patients they reside in an in vivo activated cell fraction (CD4+/CD25dim/CD38+/HLA-DR+/PD-1+). Conclusion: T regs are able to regulate drug specific immune responses. In MDH patients, the drug reactive T cells are contained in a pre-activated cell fraction. This may enhance their responsiveness to drugs and thus explain MDH.
The eicosanoid hepoxilin A3 plays critical role in transmigration of PMNs and concomitant invasion of bacteria in Streptococcus pneumoniae lung infection (56.11)
Authors: Bhowmick Rudra , Gronert Karsten , McCormick Beth , Leong John 
Published: January 2023

Abstract
The hallmark of pneumonia caused by Streptococcus pneumoniae (pneumococcus) is massive recruitment of polymorphonuclear cells (PMNs) from the circulation into lung alveolar spaces, causing considerable tissue damage. Moreover, pneumococcal translocation across lung epithelium into blood can lead to potentially lethal septicemia. The PMN influx caused by the bacterial insult, might lead to the disruption of the barrier function of the respiratory epithelium, thus contributing to the transepithelial migration of S. pneumoniae into the bloodstream. Our results show that S. pneumoniae triggered PMN migration from basolateral to apical side of polarized monolayers of lung epithelial cell line H292, and this PMN migration was associated with elevated levels of bacterial migration in the reverse direction. HPLC/MS studies of infected H292 culture supernatants showed increased levels of hepoxilin A3 (HXA3), a 12-LOX-derived eicosanoid that can act as a PMN chemoattractant. Administration of a 12-LOX inhibitor significantly reduced both pneumococcus-induced PMN migration and translocation of bacteria itself. Interestingly, 12-LOX knockout mice, or wild type mice treated with a 12-LOX inhibitor, showed diminished lung inflammation and bacteremia, and showed 100% survival in an otherwise lethal lung challenge. Our results indicate that during S. pneumoniae lung infection, HXA3 plays important roles in both pulmonary inflammation and bacterial invasion of the bloodstream.
CD73-generated adenosine is critical for immune regulation during Toxoplasma gondii infection (56.13)
Authors: Mahamed Deeqa , Mills Jeffrey , Bynoe Margaret 
Published: January 2023

Abstract
As an obligate intracellular pathogen, the apicomplexan parasite Toxoplasma gondii evades immune system-mediated clearance by undergoing stage differentiation to persist indefinitely in susceptible hosts. Previously, we found that mice deficient in the ecto-enzyme CD73, which generates adenosine in the extracellular matrix, were significantly resistant to acute and chronic toxoplasmosis after oral infection with the T. gondii type II ME49 strain. Resistance in CD73-knockout mice was due to a reduction in immune-mediated pathology in the intestine, and a delay in parasite differentiation in the CNS. To further clarify the role of CD73 and extracellular adenosine in T. gondii pathogenesis, we infected wildtype and CD73KO mice with ME49 cysts by the intraperitoneal (IP) route. In contrast to oral infection, IP-infected CD73KO mice were highly susceptible to immune-mediated pathology, with significantly increased infiltration of neutrophils and T cells into the peritoneal cavity. Peritoneal exudate cells from infected CD73KO mice generated higher levels of the inflammatory mediators nitric oxide, TNFα, and IL1β, without enhanced parasite killing or clearance. In addition, mice deficient in the adenosine receptors A1 or A2A were more susceptible to immunopathology during intraperitoneal infection with T. gondii, compared to wildtype mice. Thus extracellular adenosine is a key molecule that regulates the immune response to an intracellular pathogen and promotes host survival.
Increased neutrophil migration rescues impaired function and susceptibility to Pseudomonas pneumonia after burn injury (56.25)
Authors: Neely Crystal , Wolfgang Matthew , Vadlamudi Sivaram , Maile Robert , Cairns Bruce 
Published: January 2023

Abstract
Bacterial lung infection is a major cause of mortality late after burn injury. Neutrophil dysfunction is implicated in the susceptibility of wound infection with Pseudomonas aeruginosa. We hypothesized that burn-induced impaired neutrophil migration and function within the lungs would increase susceptibility to intratracheal P. aeruginosa infection. Female C57BL/6 mice were anesthetized and subjected to a 20% full thickness contact burn or sham injury. Fourteen days later, mice were inoculated with 1x106 CFU of P. aeruginosa. After 24 hours, pulmonary bacterial load was evaluated. Flow cytometric analysis was used to quantify neutrophils and evaluate their function by dihydrorhodamine (DHR) oxidation. Contrary to our hypothesis, burn mice had a significant increase in bacterial clearance compared to sham. This correlated with an increased percentage and absolute number of lung neutrophils in burn mice (mean±SEM, burn: 2.5±1.4x108, sham: 2.7±0.8x107cells, p=0.007). However, these neutrophils had reduced reactive-oxygen production compared to sham (burn: 1044±21, sham: 51431±182 MFI of oxidized DHR, p=0.0131). As predicted, lung neutrophil function was significantly impaired after burn injury. However, burn mice exhibited a larger neutrophil influx than sham. The net result was that burn mice cleared the infection quicker than sham mice. This implies a fine balance exists between neutrophil migration and function after burn injury.
Development of functionally active recombinant form of mouse IL-35 (57.11)
Authors: Lee Hyun-Ku , Pascual David , Sehy David , Chitta Sriram , Singh Gita , Quintel Payton , Andrew Kody , Wardle Lauren , Rosenberg Jonathan , Singh Sujay 
Published: January 2023

Abstract
As a novel heterodimeric cytokine and one of the IL-12 family members, IL-35 is composed of IL-12p35 subunit and Epstein-Barr virus-induced gene 3 (EBI3) protein. IL-35 is known to play an essential role in immune regulation of the CD4+CD25+ Treg cells, alleviating inflammatory responses. We have developed the recombinant fusion construct of mouse IL-35 (mIL-35)-hIgG1 Fc (hFc), in which EBI3 and IL-12p35 are joined by a flexible linker of (Gly4Ser)3. The mIg k-chain leader sequence at the amino terminus also allows secretion of the fusion protein. The mIL-35 construct was stably expressed in HEK 293 cells, and culture supernatants of single clones were screened by ELISA using a combination of anti-hFc and anti-mEBI3 antibodies, among which the most positive clone 35-5 was selected and adapted in a serum-free culture system. Functional activity of the secreted mIL-35 from this clone was tested using the [3H]thymidine-based cell proliferation assay. When CD4+ T cells purified from TCR-transgenic DO11.10 mice were stimulated with a combination of syngeneic irradiated APCs and OVA peptide in the presence of the mIL-35 culture supernatants, the mIL-35 significantly suppressed CD4+ T cell proliferation. Furthermore, the mIL-35-mediated inhibition of CD4+ T cell proliferation was reversed by anti-mIL-35 antibody. Taken together, these results demonstrate that the recombinant mIL-35 is functionally active and can be a useful research tool to study T cell-based immune regulations.
Progesterone, IL-10 and TGF-β act in synergy to impair plasmacytoid dendritic cell functions in cord blood (57.19)
Authors: Harnois Michael , Charrier Emily , Cordeiro Paulo , Herblot Sabine , Duval Michel 
Published: January 2023

Abstract
Plasmacytoid dendritic cells (pDC) are specialized dendritic cells, also known as IFN-α producing cells. pDC are key inducers of immune responses upon viral infections; the environment although modulate their phenotype and functions. We have shown that cord blood (CB) pDC are unable to produce IFN-α after stimulation while they retain the capacity to maturate in antigen presenting cells. To get insights into the mechanisms of pDC regulation in CB, we first investigated the levels of immune regulators secreted by the placenta in CB. We show that progesterone (PG), IL-10 and TGF-β are present at high levels in CB as compared to adult blood. Using in vitro differentiated pDCs we analysed the effect of these molecules, separately or in combination, on pDC differentiation and activation. We reveal that physiological concentrations of these three factors individually have low impact on pDCs while in combination they inhibit pDC differentiation and IFN-α production. Higher concentrations of PG, IL-10 or TGF-β are also able to inhibit IFN-α production, but these conditions are not relevant to physiological levels in CB. Our results therefore shed new light on the synergy of immune regulators secreted by the placenta that have an impact on foetal and neonatal immune responses.
EFNB1 and EFNB2 physically bind to IL-7R-alpha and retard its internalization from the cell surface (57.2)
Authors: Luo Hongyu , Qi Shijie , Wu Zenghui , Han Bing , Wang Xuehai , Wu Jiangping 
Published: January 2023

Abstract
IL-7 plays vital roles in thymocyte development, T cell homeostasis and the survival of these cells. IL-7 receptor alpha (IL-7R-alpha) on the thymocytes and T cells is rapidly internalized upon IL-7 ligation. Ephrins (EFN) are cell surface molecules and are ligands of the largest family of receptor kinases, Eph kinases. We discovered that T cell-specific double deletion of EFNB1 and EFNB2 (double KO) in mice led to reduced IL-7R-alpha expression in thymocytes and T cells, and that IL-7R-alpha downregulation in double KO CD4 cells upon IL-7 treatment was accelerated. On the other hand, EFNB1 and EFNB2 overexpression in T cell line EL4 cells retarded IL-7R-alpha downregulation. The EFNB1/EFNB2 double KO T cells manifested compromised homeostatic proliferation, which is an IL-7-dependent process. Using fluorescent resonance energy transfer (FRET), we demonstrated that EFNB1 and EFNB2 physically interacted with IL-7R-alpha. Such interaction likely retarded IL-7R-alpha internalization, as EFNB1 and EFNB2 were not subjected to internalization. Therefore, we revealed a novel function of EFNB1 and EFNB2 in stabilizing the IL-7R-alpha expression at the post-translational level, and a previously unknown modus operandi of EFNBs in the regulation of the expression of other vital cell surface receptors.
Type I interferon inhibits expression of the alternative GATA3 transcript in human Th2 cells (57.22)
Authors: Huber Jonathan , Farrar J. 
Published: January 2023

Abstract
The GATA3 transcription factor contributes to multiple immune processes, including the differentiation of T helper type 2 (Th2) cells. Th2 cells regulate many aspects of allergic disorders and express GATA3 in response to IL-4 signaling. Subsequently, GATA3 promotes transcription of the Th2 cytokines while also creating a feed-forward loop that stabilizes Th2 commitment. A previous study in mice has shown that Th2 commitment is accompanied by increased utilization of an alternate first exon (exon 1A) in the GATA3 transcript via an upstream promoter. The resulting transcript contains the same protein coding sequence but permits cell-specific control of expression levels. We previously demonstrated that the antiviral cytokine type I interferon (IFN-α/β) suppresses GATA3 mRNA and protein levels both in developing Th2 cells and in fully committed Th2 cells, leading to a decrease in Th2 cytokine expression. Here, we show that IL-4 significantly enhances utilization of exon 1A in the GATA3 transcripts in human Th2 cells. IFN-α/β preferentially inhibits expression of the exon 1A transcript, suggesting that IFN-α/β can regulate Th2 cells without affecting the basal levels of GATA3 required for other immune processes. Thus, IFN-α/β suppresses GATA3 in human Th2 cells and may be useful as a novel therapeutic for asthma and allergy.
SUMOylation of chromosomal protein HMGN2 negatively influences its binding to nucleosomes (57.24)
Authors: Wu Jie , Kwak Man , Shin Jeon-Soo 
Published: January 2023

Abstract
The high mobility group-17 (HMG-17, HMGN2) is a small and unique non-histone protein that partakes in many key cellular processes, such as architectural element, transcription regulation and DNA repair. Recently, more functions of HMGN2 have been suggested, including antimicrobial activity, homing to special cells, cytokine release. The biochemical properties of HMGN2 protein are regulated by post-transcription modification like acetylation and phosphorylation, but it is unknown whether HMGN2 properties can also be affected by SUMOylation. In the present study, we showed for the first time that HMGN2 is modified by the covalent attachment of small ubiquitin-related modifier (SUMO)-1 and we identified the major SUMOylated lysine residues, located at HMGN2 nucleosome binding domain. Using a basal SUMOylation system in Escherichia coli, we were able to successfully separated sumo-conjugated HMGN2. Finally, we demonstrated that SUMOylated HMGN2 decreases binding ability to nucleosome particle core in comparison to its unSUMOylated form. These observations potentially provide a new perspective for a better understanding of the functions of HMGN2.
STING regulates IFN-β expression during endoplasmic reticulum stress (57.4)
Authors: Smith Judith , Tian Austin , Zeng Ling , Gutman Delia , Barber Glen , Liu Yi-Ping 
Published: January 2023

Abstract
STING (TMEM173, MPYS,MITA) located in the endoplasmic reticulum (ER), plays a critical role in type I IFN responses to intracellular DNA. STING activates TBK1, resulting in phosphorylated IRF3 that regulates IFN-β transcription. Our previous work showing markedly enhanced LPS-induced IFN-β during ER stress implicated increased IRF3 recruitment to the ifnb1 promoter. In this study, utilizing STING-/- mouse embryonic fibroblasts (MEFs) and RNAi (in MEFs and macrophages) we determined that STING was essential for synergistic induction of IFN-β mRNA in response to LPS and ER stress (thapsigargin/TPG treatment). TPG treatment alone induced re-localization and clustering of STING and TBK1 in MEFs. Although ER stress resulted in nuclear translocation of IRF3 in a STING-independent manner, TPG and TPG+LPS-induced IRF3 phosphorylation (as detected by immunofluorescence and western blot respectively) depended upon STING. In comparison, STING was not required for LPS or LPS+TPG induced NF-κB phosphorylation. These results indicate that ER stress alone results in IRF3 nuclear translocation and phosphorylation. In mice, treatment with the ER stress inducer tunicamycin was sufficient for induction of serum-detectable IFN-β, comparable with low dose LPS. Our results also suggest that the synergistic IFN-β responses during LPS and ER stress involve STING-dependent IRF3 phosphorylation.
An essential role of invariant natural killer T cells in the pathogenesis of eosinophilic esophagitis (59.1)
Authors: Mishra Anil , Rajavelu Priya , Rayapudi Madhavi , Zhu Xiang 
Published: January 2023

Abstract
Experimental eosinophilic esophagitis (EE) is a recently described chronic allergic inflammatory disorder whose basic pathogenesis is not well understood. Herein, we focus on the hypothesis that iNKT cell responses are essential for the initiation and progression of EE. We show that iNKT cells and their specific chemokine CXCL16 are induced in human and experimental EE. CXCL16 is primarily derived from esophageal epithelial cells and correlates with the levels of esophageal eosinophils. Notably, iNKT cell-deficient CD1d-null mice are protected from the induction of experimental EE; whereas, NK cell depleted mice exhibit full disease following allergen challenge. Interestingly, in vivo activation of human iNKT cells by the α-galactosylceramide analog PBS57 is sufficient to induce esophageal eosinophilia. Mechanistically, PBS57 exposed human iNKT cells produce IL-5 and IL-13 via STAT5 activation. Taken together, these findings provide evidence that iNKT cells have an essential pathogenic role in the initiation and progression of human and experimental EE, providing new opportunities for therapeutic strategies.
Specific comensal bacteria modulate epithelial glycosylaion (59.5)
Authors: Goto Yoshiyuki , Umesaki Yoshinori , Benno Yoshimi , Kiyono Hiroshi 
Published: January 2023

Abstract
Commensal bacteria constantly reside in our mucosal sites, especially in the intestine and create a mutually beneficial condition of symbiosis with the host. The physical and molecular crosstalk between host and gut microbiota is established at the surface of intestinal epithelial layer. It has been reported that specific epithelial carbohydrate chains, fucoses, are involved in the attachment of bacteria and viruses and ablation of these fucoses seems to be associated with the onset of Crohn’s disease. In spite of this important role, the mechanism of the induction and regulation of epithelial fucoses is not fully understood. Here, we show that specific commensal bacteria, segmented filamentous bacteria (SFB), physiologically induce fucoses on the ileal epithelial cells. To analyze the role of commensal bacteria in the induction of fucosylated epithelial cells (F-ECs), we firstly checked germfree mice. F-ECs were not found in germfree mice, while a large number of F-ECs were observed in the ileum of SPF mice. When we analyzed the ileal bacterial population to identify bacteria responsible for the induction of F-ECs, SFB were dominant in the ileum. Mono-colonization of SFB led to the development of F-ECs in germfree mice. Furthermore, F-ECs were abolished in SFB deficient mice bred in Jackson laboratory, indicating that SFB physiologically induce F-ECs. Our findings provide the basis of mutually beneficial system between the host and commensal bacteria.
Increased expression of HSP70, HSP90 and P53 in tissue of patients with periodontal and gingivitis deseases (59.6)
Authors: Sanchez-Rodriguez Sergio , López-Martínez Lucio , Hernandez-Rodriguez Alejandra , Ramirez-Santoyo Rosa , Barbosa-Cisneros Olga , Aguilera-Galaviz Luis , Lopez-Luna Maria 
Published: January 2023

Abstract
Periodontal disease (PD) is a degenerative and progressive inflammatory disease induced by supragingival plaque bacteria, which affects the tooth supporting tissue such as periodontal ligament, cementum and alveolar bone. The host response to infection by periodontal bacteria may be related to a process of acute humoral response or cellular response. The expression of heat shock proteins (Hsp) and P53 is important in apoptosis, cell cycle control in cellular homeostasis and stress are overexpressed. The baseline of this study was to determine the expression of Hsp70, Hsp90 and P53 in the tissue of patients with chronic periodontal disease and gingivitis. The oral tissues were obtained by surgery, and quantified the amount of protein and characterized by SDS-PAGE, Western blot. To detect the expression of Hsp70, Hsp90 and p53 were using monoclonal antibodies. Hsp 70 detecction by RT-PCR were performed using Super ScriptTM One-Step and densitometric analysis. Results: There was an increase of Hsp70 and 90, and a slight increase in p53 levels. By PCR Hsp70 expression was increased in initial and progresive periodontitis and in a low level in advanced.
In vitro and in vivo role of SIgA in the interaction of commensals bacteria with the intestinal epithelium (59.9)
Authors: Rol Nicolas , Mathias Amandine , Favre Laurent , Benyacoub Jalil , Corthesy Blaise 
Published: January 2023

Abstract
The precise mechanisms underlying the interaction between intestinal bacteria and the host epithelium lead to multiple consequences that remain poorly understood at the molecular level. Deciphering such events can provide valuable information as to the mode of action of commensal microorganisms in the gastrointestinal environment. Using human intestinal epithelial Caco-2 cell grown as polarized monolayers, we found that association of a Lactobacillus or a Bifidobacterium with nonspecific secretory IgA (SIgA) enhanced probiotic adhesion, increased the level of nuclear translocation of NF-kappaB and production of epithelial polymeric Ig receptor as compared to bacteria alone, whereas transepithelial electrical resistance remained stable. Following administration in mouse ligated ileal loops containing a Peyer’s patch, it was found that SIgA bound to Lactobacillus or Bifidobacterium is involved in translocation to underlying dendritic cells residing in the subepithelial dome (SED) region. This phenomenon was mediated by passage across M cells, and required exogenously delivered or endogenous SIgA, as free bacteria was not observed in the SED region. These findings add to the multiple functions of SIgA and underscore a novel role of the antibody in its complex cross-talk with the intestinal epithelium.