bluuebunny/crossref_metadata_2025_split huggingface dataset:
Targeting CD44 in SEB-induced acute respiratory distress syndrome (54.13)
Authors: McKallip Robert , Bridges Christy , Law Gabriela , Sun Jingping 
Published: January 2023

Abstract
Exposure to bacterial superantigens, such as staphylococcal enterotoxin B (SEB), can lead to the induction of acute lung injury/acute respiratory distress syndrome (ALI/ARDS). In the current study we investigated the role of CD44 in ALI/ARDS. Intranasal exposure of CD44 wild type (CD44 WT) mice to SEB led to a significant increase in the expression of CD44 on lung mononuclear cells. CD44 knockout (CD44 KO) mice developed significantly reduced SEB-induced ALI/ARDS, compared to similarly treated CD44 WT mice. Deletion of CD44 did not have a significant effect on lymphocyte activation, apoptosis or inflammatory cytokine production. However, mononuclear cell migration to the lungs of SEB-exposed CD44 KO mice was significantly reduced when compared to mononuclear infiltration in the lungs of SEB-exposed CD44 WT mice. Mechanistically, deletion of CD44 led to reduced ability of SEB-exposed spleen cells to bind to lung epithelial cells. Finally, treatment of SEB-exposed mice with anti-CD44 mAbs led to a significant reduction in vascular permeability, prevented inflammatory cells infiltration in the lungs and reduced the ability of SEB-exposed splenocytes to adhere to epithelial cells. Together, these results demonstrate an important role of CD44 in SEB-induced lung injury and suggest the possibility of targeting CD44 for the treatment of SEB-induced ALI/ARDS.
Glycogen synthase kinase-3 facilitates IFN-γ-mediated phorbol ester-induced skin inflammation (54.25)
Authors: Hsieh Chia-Yuan , Chen Chia-Ling , Tsai Cheng-Chieh , Huang Wei-Ching , Tseng Po-Chun , Lin Yee-Shin , Chen Shun-Hua , Wong Tak-Wah , Lin Chiou-Feng 
Published: January 2023

Abstract
Activation of glycogen synthase kinase (GSK)-3 facilitates IFN-γ signaling, and IFN-γ generation is positively correlated with disease severity in inflammatory skin diseases, such as psoriasis and atopic dermatitis. In this study, we investigated a pathogenic role for GSK-3 in phorbol ester (12-O-tetradecanoylphorbol-13-acetate; TPA)-induced IFN-γ-mediated skin inflammation. TPA induced acute skin inflammation in the ears of C57BL/6 mice, including edema, the infiltration of granulocytes but not T cells, and the deregulation of adhesion molecule CD54 expression, in an IFN-γ receptor (IFNGR) 1-regulated manner. TPA/IFN-γ induced GSK-3 activation and caused the activation and expression of signal transducers and activators of transcription 1 in a GSK-3-regulated manner. Inhibiting GSK-3 through either pharmacological inhibition or a genetic approach using lentiviral-based short hairpin RNA reduced acute TPA-induced skin inflammation, but not T cell infiltration. Notably, inhibiting GSK-3 decreased the TPA-induced IFN-γ production as well as the nuclear translocation of T-box transcription factor Tbx21, a transcription factor of IFN-γ, in CD3+ T cells. In chronic TPA-induced skin inflammation, inhibiting GSK-3 attenuated epidermis hyperproliferation and dermis angiogenesis. These results demonstrate the dual and indispensable role of GSK-3 in TPA-induced skin inflammation by facilitating IFN-γ signaling.
Contribution of an aging environment towards a proinflammatory tumor-like milieu (54.4)
Authors: Mirza Noweeda , Hoelzinger Dominique , Myers Cheryl , Pollock Kevin , Dominguez Ana , Lustgarten Joseph , Cohen Peter , Gendler Sandra 
Published: January 2023

Abstract
Chronic inflammation associated with aging is termed inflamm-aging. It manifests as a rise in many proinflammatory mediators and contributes to a decline in immune function. Unregulated inflammasome activation initiates an inappropriate inflammatory response. It is particularly imperative to understand inflammasome dysregulation in the elderly (&gt;65 yrs), since it is a likely basis of immune dysfunction. Analyses of freshly isolated memory CD4+ and CD8+ splenic T cells demonstrated that even without further activation, inflammasome genes were already significantly up-regulated in old mice compared to young, including factors critical to myeloid-derived suppressor cell (MDSC) expansion including S100a8, S100a9, IL-1β, IL-13 and IL-6. A corresponding 2-3 fold increase in CD11b+Gr1+cells was observed in the spleens of old naïve mice compared to young. Importantly, cells with the CD11b+Gr1+ phenotype from old mice, unlike young, were functionally MDSCs and suppressed T cell proliferation. Therefore, the immunosuppressive environment of the tumor-bearing host also appears to be operative in aging, even in the absence of tumor. We hypothesize that constituitive activation of inflammasome complex results in a chronic inflammatory state, altering immune responses in the elderly similarly to the tumor-bearing state. Preemptive reversal of inflammasome-induced MDSCs may enhance T cell immunosurveillance in the elderly, a population with a heightened susceptibility to malignancy.
Phospholipase A2 plays a key role in PMN transepithelial migration during S. pneumoniae infection (55.18)
Authors: Bhowmick Rudra , Leong John , McCormick Beth 
Published: January 2023

Abstract
Streptococcus pneumoniae lung infection is characterized by a massive alveolar infiltration of neutrophils (PMNs). Using an in vitro model of lung epithelium and human PMNs, we have shown that S. pneumoniae-induced PMN transepithelial migration is mediated by hepoxilin A3 (HXA3), an arachidonic acid (AA)-derived eicosanoid. Generation of AA is thought to be the rate-limiting step in generation of eicosanoids. Therefore, we studied the role of phospholipase A2 (PLA2), which generates AA from membrane phospholipids, on S. pneumoniae-elicited PMN transpeithelial migration. We found that pneumococcal infection of in vitro lung epithelium resulted in release of AA. This event was partially inhibited by pan-PLA2 inhibitors ONO-RS-082 and ACA, and also by diacylglycerol (DAG) lipase inhibitor RHC 80267. However, while the pan-PLA2 inhibitors significantly reduced S. pneumoniae-induced PMN transmigration, RHC 80267 had no effect on this event. We found that, cytosolic PLA2 (cPLA2) and calcium-independent PLA2 (iPLA2) are important for generation of free AA and inhibition of these enzymes lead to dramatic reduction in PMN transepithelial migration. On the other hand, secretory PLA2 (sPLA2) did not seem to pay a key role in this event. We observed that S. pneumoniae infection caused an increase in the phosphorylation of cPLA2, suggesting a mechanism whereby S. pneumoniae activates PLA2 to generate free AA that may ultimately be converted to the PMN chemoattractant HXA3.
NNovel phosphoantigen for human Vγ2Vδ2 T cells produced by Staphylococcus aureus and other Gram-positive cocci using the mevalonate isoprenoid pathway (55.21)
Authors: Morita Craig , Workalemahu Grefachew 
Published: January 2023

Abstract
Vγ2Vδ2 T cells are innate lymphocytes that use their TCRs to recognize nonpeptide antigens thereby bridging innate and adaptive immunity and expand to large numbers during a variety of infections. Vγ2Vδ2 T cell responses to Apicomplexan protozoa and many Eubacteria are due to TCR recognition of (E)-4-hydroxy-3-methyl-but-2-enyl pyrophosphate (HMBPP), a metabolite unique to the 2-C-methyl-D-erythritol 4-phosphate (MEP) isoprenoid pathway. However, Staphylococcus aureus, Streptocococcus spp., and most other Gram-positive cocci (GPC) using the mevalonate isoprenoid pathway also stimulate Vγ2Vδ2 T cells. We now report that this stimulation is due to the production of a novel phosphoantigen distinct from HMBPP, isopentenyl pyrophosphate, and other mevalonate and MEP pathway intermediates when analyzed by ion-pairing reverse phase chromatography. Moreover, production of this phosphoantigen does not require mevalonate pathway enzymes. Although S. aureus and other GPC do not secrete the phosphoantigen, exposure to live S. aureus, Streptococcus pyogenes, and Enterococcus faecalis bacteria expands Vγ2Vδ2 T cells in vitro. In contrast, non-pathogenic Staphylococcus carnosus lack detectable bioactivity and minimally expand Vγ2Vδ2 T cells. Thus, rather than responding only to MEP pathogens, Vγ2Vδ2 T cells also respond to GPC using the mevalonate pathway and likely play roles in human immunity to this important class of pathogens.
Differential c-type lectin receptor expression correlates with the magnitude of pathology in murine schistosomiasis (55.4)
Authors: Ponichtera Holly , Shainheit Mara , Larkin Bridget , Stadecker Miguel 
Published: January 2023

Abstract
In murine schistosomiasis, immunopathology and cytokine production in response to schistosome eggs is uneven and strain dependent. Infected CBA mice develop severe hepatic egg-induced granulomatous inflammation associated with prominent Th17 and Th1 cytokine responses, whereas in BL/6 mice milder lesions develop in a Th2-dominant cytokine environment. The pathogenic Th17 response in CBA mice is largely dependent on IL-1β and IL-23 produced by schistosome egg-stimulated dendritic cells (DC); by comparison, this pro-inflammatory cytokine pathway fails to materialize in low-pathology BL/6 mice. Whereas requirements for Th17 cell differentiation elicited by CBA DC are apparent, the reason for such a strain difference in APC reactivity to live eggs is not known. Initial gene profiling disclosed a significant difference in C-type lectin receptor (CLR) expression between CBA and BL/6 bone marrow derived DC. CLR are pattern recognition receptors capable of binding carbohydrates, including those secreted by schistosome eggs. A significant increase in CLR expression, particularly murine homologues of human DC-specific ICAM-3-grabbing non-integrin (DC-SIGN), was documented by real-time PCR and flow cytometry on tissues from infected CBA mice, including liver, spleen and granuloma cells. Current work is aimed at elucidating the functional implications of differential CLR expression on T cell subset differentiation, activation and pathogenicity during the schistosome infection.
Mouse macrophage galactosa-type lectin (mMGL) is critical for the host resistance against Trypanosoma cruzi infection (55.7)
Authors: Rodriguez-Sosa Miriam , Vazquez Alicia , Juarez Imelda , Gomez-Garcia Lorena , Calleja Elsa , Camacho Griselda , Chavez Ana , Terrazas Luis 
Published: January 2023

Abstract
The C-type lectin receptor mMGL is expressed exclusively by myeloid APC such dendritic cells and macrophages (MΦ), mediates binding to glycoproteins carrying terminal N-acetylgalactosamine (GalNAc) residues. Parasite glycosylated molecules are recognized by mMGL. T. cruzi parasite expresses large amounts of mucins (TcMUC)-like glycoproteins, here we show by Jacalin lectin-blot that GalNAc moieties are also expressed on their surface. Then, our goal was to study the impact of mMGL in T. cruzi infection. Male mMGL knockout (KO) and wild-type (WT) C57BL/6 mice were infected via intraperitoneal (i.p.) with 10-5 trypomastigotes of T. cruzi (Queretaro strain). Following i.p. T. cruzi infection, mMGL-KO mice developed higher parasitemia load and higher mortality associated with poor production of Nitric Oxide (NO), IL-12 and TNF-α by MΦ in response to total soluble T. cruzi antigens compared to WT. Interestingly, whereas heart from WT mice infected with T. cruzi did not present amastigotes nest, mMGL-KO mice did. We conclude that mMGL have an important role during the invasion of T. cruzi to the host cell, also induce inflammatory cytokines and NO production by macrophages.
Lack of IL-21R on donor cells attenuates chronic GVHD but promotes humoral autoimmunity in acute GVHD (56.11)
Authors: Rus Violeta , Nguyen Vinh , Tegla Cosmin , Luzina Irina , Chen Qing , Rus Horea 
Published: January 2023

Abstract
IL-21 enhances CD8 maturation into cytotoxic T lymphocytes (CTL), promotes the differentiation of T follicular helper cells (TFH) cells and Th17 cells, downregulates Tregulatory (Treg) cells and exerts stimulatory activities on B cells, suggesting a complex role for IL-21 in promoting autoimmunity. To assess the role of IL-21/IL-21R interaction on CD4 and CD8 T cells in promoting lupus-like disease we used the parent-into-F1 model of acute and chronic graft versus host disease (GVHD) using IL-21R KO and wild type B6 mice as donors. cGVHD induced with CD8 depleted splenocytes from IL-21R KO mice exhibited an attenuated disease phenotype characterized by significant decrease in the number of donor (d)CD4 and dTFH cells, impaired help for B cells as determined by anti-ssDNA antibody levels and less severe lupus-like glomerulonephritis. However the balance between IL-17 producing dTh17 cells and FoxP3 dTreg cells was not altered. Acute GVHD induced with IL-21R KO splenocytes resulted in an attenuated disease phenotype as indicated by a significant decrease in dCD4 and CD8 engraftment, decreased host B cell elimination (90%±0.3) compared to wt injected mice (57%±6; p=0.03), decreased anti-host CTL activity and increased anti-ssDNA Ab levels. These results suggest that IL-21/IL-21R interaction on T cells promotes lupus-like cGVHD by sustaining TFH cell number yet it downregulates the humoral component in aGVHD by enhancing host B cells elimination by CTL.
Inhibition of Calcium/calmodulin-dependent protein kinase IV suppresses the autoimmunity in lupus-prone mice. (56.4)
Authors: Ichinose Kunihiro , Kawakami Atsushi , Tsokos George 
Published: January 2023

Abstract
OBJECTIVE: Systemic lupus erythematosus (SLE) is a chronic inflammatory disease associated with abnormal immune cell function.SLE T cells express high levels of calcium/calmodulin-dependent protein kinase IV (CaMKIV). We have shown previously that pharmacologic (Arthritis Rheum. 2011) or genetic silencing of Camkiv (J Immunol. 2011) suppresses lupus nephritis in lupus-prone mice. The purpose of this study was to determine whether pharmacologic inhibition of CaMKIV would improve immune function abnormalities. METHODS: We treated MRL/lpr mice with KN-93, a CaMKIV inhibitor, starting at week 8 of age through week 16 and evaluated the presence of CD4+, CD8+, CD3+CD4-CD8- (double negative, DN) and CD62Llow T cells and proinflammatory cytokine production. We also determined the effect of inhibition of CaMKIV on proinflammatory cytokine production by human T cells and macrophages. RESULTS: CaMKIV inhibition in MRL/lpr mice resulted in significant suppression of DN and CD62Llow of T cells population and IFN-γ production by T cells. In human activated T cells and macrophages, pharmacologic inhibition of CaMKIV resulted in suppression of IFN-γ production and CD69 expression by T cells and IL-1β, IL-6 and TNF-α by macrophages. CONCLUSION: We conclude that pharmacologic inhibition of CaMKIV suppresses cell activation and cytokine production in lupus-prone mice. Our data justify the development of small-molecule CaMKIV inhibitors for the treatment of patients with SLE.
Combined Treatment with Neutralizing Antibodies to IL-1α / β and TNFα / PGE2 in a Late Therapeutic Mode Ameliorates Inflammation and Inflammatory Bone Loss in a mouse Collagen Induced Arthritis (mCIA) model of Rheumatoid Arthritis (56.6)
Authors: Syed Farhan , Bryant Shaughn , Mario Regina , Mathieu Suzanne , O'Connor Elizabeth , Erickson Jamie , Waegell Wendy , Murtaza Anwar , Wang Li Chun , Kamath Rajesh , Gu Jijie , Olson Lisa , Annette Schwartz 
Published: January 2023

Abstract
Rheumatoid Arthritis is characterized by chronic inflammation and synovial hyperplasia which leads to the destruction of cartilage and bone. We have shown earlier (Wu et al, 2007) that blocking IL1α/β provides better efficacy than monotherapy in a CIA model when treatment begins at first clinical sign of inflammation but not necessarily bone loss (therapeutic mode). These studies describe a late therapeutic mCIA treatment mode designed to evaluate the efficacy of anti-inflammatory drugs on inflammation and bone in animals with established bone lesions. To define the kinetics of bone loss, male DBA1/J mice with established arthritis were sacrificed at days 5, 7, 9 and 11 after onset of first clinical signs of disease. Day 7 was selected as the optimal point to begin treatment based on 28% decrease in tarsal bone volume and 27% increase in erosion by microCT and correlating bone histomorphometry endpoints. The efficacy of two pairs of anti-inflammatory mAbs was evaluated: 1) Anti-TNF alone and in combination with anti-PGE2 and 2) anti-IL1β alone and in combination with anti-IL1α. Treatment was initiated on day 7 and was continued for 2 weeks. For both antibody sets, the paired combination significantly reduced inflammation (by 40%) and maintained bone volume to a greater extent than anti-TNF or anti-IL1β dosed alone (37% and 22% increase). Our data demonstrate that a late therapeutic mCIA mode can be used to evaluate effects of anti-inflammatory drugs on bone loss.
Gingiva-derived mesenchymal stem cells-mediated therapeutic intervention for experimental arthritis through Foxp3+ Tregs (56.7)
Authors: Zheng Song Guo , Chen Maogen , Su Wenru , Wang Julie , Brand David , Ryffel Bernhard , He Xiaoshun , Le Anh 
Published: January 2023

Abstract
Current approaches are unable to cure rheumatoid arthritis. Accumulated evidence has revealed that manipulation of bone-marrow mesenchymal stem cells (BMSCs) has a potential promise to treat these diseases. Nonetheless, isolation and expansion of BMSCs for therapeutic usage is less feasible in the clinic. Here, we demonstrate that use of gengival-derived mesenchymal stem cells (GMSCs), mostly sharing similar phenotypic and functional characteristics with BMSCs, resulted in significantly therapeutic effects on the established collagen induced arthritis (CIA). Infusion of GMSCs to DBA/1J mice at day 0, 14 or day 28 after CII/CFA immunization significantly decreased the severity of arthritis and pathology scores, down-regulated inflammatory cytokine (IFN-γ, IL-17A). The role of GMSCs in controlling the diseases may partially depend upon the induction of CD4+Foxp3+ Tregs, and CD39/CD73 signals. Strikingly, GMSCs increase CD4+Foxp3+ cells in naïve and CIA inflammatory mice. GMSCs significantly inhibit humanized xeno-GVHD model, suggesting that GMSCs have clinical relevance. GMSCs can function as an immunomodulatory and anti-inflammatory component of the immune system in vivo and use of GMSC may provide a promising approach for the treatment of rheumatoid arthritis and other autoimmune diseases.
Pin1 attenuates Fas-mediated apoptosis through binding to FADD in activated eosinophils. (57.1)
Authors: Oh Jiyoung , Malter James 
Published: January 2023

Abstract
Pin1 is widely expressed peptidyl-prolyl isomerase (PPIase) that plays a key role in a variety of events including cell cycle progression, response to viruses, expression of cytokines and cell death. Eosinophils (Eos) rely on Pin1 to mediate prosurvival signaling induced by IL-5 or GM-CSF by binding to and inhibiting pro-apoptotic Bax. Here we show Pin1 also participates in Fas-mediated apoptosis of Eos. Fas activation suppressed Pin1 activity despite co-treatment with IL-5. This was accompanied by phosphorylation of Pin1 at Ser16 and increased nuclear, rather than plasma membrane localization. Anti-Fas alone or in combination with IL-5 rapidly triggered FADD phosphorylation at Ser194. Interestingly, only the combination of agonists induced a stable interaction between P-FADD and Pin1. These results suggested Ser194-Pro195 was the Pin1 binding site in FADD. Consistent with this, phospho-mimic Ser194Glu FADD mutants preferentially interacted with Pin1 in vitro compared to WT or Ser194Ala mutants. Introduction of FADD Ser194Glu mutants significantly accelerated Eos apoptosis compared to WT or S194A. Therefore, our data suggest that Pin1 participates in extrinsic apoptosis via an interaction with FADD at P-Ser194-Pro195.
A critical role for the kainate receptor in both IgE production and IgE mediated allergic lung inflammation (57.8)
Authors: Sturgill Jamie , Brooks Keith , Conrad Daniel 
Published: January 2023

Abstract
According to the American Lung Association, approximately 34.1 million Americans have been diagnosed with asthma. Despite the extremely high prevalence of this disease, there is still no preventative measure, only treatments to alleviate the symptoms. Thus, novel treatments for asthmatic disease are certainly warranted. Recently, our laboratory has discovered that glutamate signaling through the kainic acid receptor (KAR) leads to enhanced ADAM10 activity and as a result leads to increased production of soluble CD23 and IgE production in the human in vitro culture system. This finding is critical because it is one of the first to highlight the importance of a neurotransmitter receptor on B cells and that signaling by this receptor may play a role in IgE mediated disease. We have extended these studies to demonstrate that in the murine in vitro system, the KAR is also critical for the in vitro production of IgE and that signaling through this receptor also leads to increased ADAM10 activity, production of soluble CD23 release, and subsequent IgE production. Furthermore, we determined in vivo relevance for this receptor. Mice deficient in the KAR post antigen challenge produce significantly less IgE and display significantly reduced airway hyperreactivity in a murine model of allergic airway disease. Thus, KARs may serve as an innovative pharmacological target for the treatment of asthma and other IgE mediated disease.
High Throughput Sequencing of the Human Antibody Repertoire in Response to Influenza Vaccination (58.14)
Authors: Jiang Ning , He Jiankui , Weinstein Joshua , Penland Lolita , Saaki Sanae , He Xiaosong , Dekker Cornelia , Wilson Patrick , Greenberg Harry , Davis Mark , Fisher Daniel , Quake Stephen 
Published: January 2023

Abstract
Despite the many advances in personal genome analysis, the immunoglobulin repertoire of the genome, while central to human health, is in practice extraordinarily challenging to measure and analyze. There are several reasons for this, including the facts that each B cell contains a distinct antibody sequence encoded in its genome, that the antibody repertoire is not constant but changes over time, and the high similarity between antibody sequences. We have addressed this challenge by using high-throughput long read sequencing to perform immunogenetic characterization of expressed human antibody repertoires. Informatic analysis of large numbers of antibody heavy chain sequences from individual subjects allowed us to perform global characterizations of isotype distributions, clonal lineage structure of the repertoire and age-related mutational activity. With influenza vaccination as a specific stimulus, we used lineage analysis to measure the clonal structure and mutational distribution of individuals’ repertoires; analysis of this data showed that elderly subjects have a decreased number of lineages but an increased pre-vaccination mutation load in their repertoire and that some of these subjects have an oligoclonal character to their repertoire in which the diversity of the lineages is greatly reduced relative to younger subjects. These analyses may ultimately be useful as metrics to measure vaccine response and to further understand impaired immune function in aging.