bluuebunny/crossref_metadata_2025_split huggingface dataset:
Development of functionally distinct Treg subsets in the thymus
Authors: Owen David L. , Mahmud Shawn A , Williams Jason B , Jeschke Jonathan C , Aggarwal Praful , Broeckel Ulrich , Alegre Marisa , Zheng Ye , Williams Calvin B , Farrar Michael A 
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. Work from the Singer lab has 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. Further, TCR sequencing has provided evidence that these 2 progenitor populations contain largely distinct TCR repertoires. Further, we have observed differential dependence on NFκB signaling and the Foxp3 regulatory element Cns3 between the 2 progenitor populations. Our preliminary data suggests that these TRPs mediate tolerance in distinct autoimmune contexts. Our results suggest a model whereby cells are driven by high affinity or high avidity interactions with self-peptide through two discrete pathways to form a comprehensive Treg repertoire capable of protecting against sterile and musical autoimmunity.
Inhibition of properdin is more effective than other inhibitors of the complement system at preventing cell lysis in an in vitro model of atypical hemolytic uremic syndrome
Authors: Galwankar Neeti , Emch Heather N , Lad Apurva C , Cortes Claudio , Ferreira Viviana P 
Published: January 2023

Abstract
The alternative pathway (AP) of the complement system can be activated excessively in several inflammatory diseases, particularly when there is a defect in regulatory components of the complement system. For instance, defects of complement regulatory proteins such as factor H (FH) and lack of CD55 and CD59 are associated with atypical hemolytic uremic syndrome (aHUS) and paroxysmal nocturnal hemoglobinuria (PNH), respectively. Both diseases lead to severe prothrombotic pathologies in which the damage is mediated mainly by the AP. Thus, strategies to protect host cells by effectively inhibiting AP complement-mediated attack are necessary. Here we have developed and characterized monoclonal antibodies against properdin (clones 6E11A4, 3A3E1, 6E9E6, and 1G6D2), the only known positive regulator of complement, to study their effects in preventing lysis in an in-vitro model of aHUS. We determined that our antibodies recognize both human and rabbit properdin, and the non-inhibitory antibodies recognize distinct epitopes as determined in a binding competition assay. More importantly, the data indicate that the inhibitory anti-properdin monoclonal antibodies had lower IC50 values than all other complement inhibitors tested, including Soliris, which is currently used to treat patients with this disease. We have also standardized a highly sensitive sandwich ELISA, using monoclonal antibody pairs, with a lower properdin detection limit than commercially available kits (20 pg/ml). Further studies aimed at determining the therapeutic value of inhibiting properdin in human inflammatory diseases are warranted.
Functional characterization of Irakm
rΔ9–11 splice variant in mice
Authors: Rothschild Daniel E , Zhang Yao , Diao Na , Lee Christina K , Chen Keqiang , Caswell Clayton C , Slade Daniel J , Helm Richard F , LeRoith Tanya , Li Liwu , Allen Irving C 
Published: January 2023

Abstract
Ulcerative colitis (UC) and Crohn’s disease (CD) are two pathologies collectively referred to as Inflammatory Bowel Disease (IBD). While a definitive etiology is currently unknown, a complex interplay of environmental factors and genetic predispositions has been linked to IBD development. The Toll-like receptors (TLRs) are a family of pattern recognition receptors (PPRs) involved in the signaling pathways that regulate the inflammatory response, and as such, represent essential targets for therapeutic intervention of UC and CD. Interleukin receptor associated kinase M (IRAKM) is an important negative regulator of TLR signaling acting to attenuate an overzealous innate immune response. Metadata analysis of human patient samples afflicted with IBD revealed increased expression of IRAKM compared to both healthy controls and patients with inactive forms of IBD. Furthermore, our findings in murine studies have identified that commercially available Irakm−/− mice contain a spliced mRNA variant of the Irakm gene as a result of the knockout strategy; defined here to be IrakmrΔ9–11. We have found that the truncated IrakmrΔ9–11 protein robustly activates a NF-κB dependent luciferase reporter when overexpressed in mammalian cells. These results, together with data supporting the mechanistic role of this truncated protein, suggest an alternative explanation for the function of IRAK-M in TLR signaling and in modulating gastrointestinal immune homeostasis with potential therapeutic implications for IBD patients.
Deficiency in Toll-Interacting Protein (Tollip) Skews Inflamed yet Incompetent Innate Leukocytes in vivo during DSS-Induced Septic Colitis
Authors: Zhang Yao , Diao Na , Li Liwu 
Published: January 2023

Abstract
The Toll-interacting protein (Tollip) is a critical regulator of Toll-like receptor-mediated innate immune responses. However, the role and mechanism of Tollip in the defense to bacterial infection remains poorly understood. In this study, we found that Tollip deficient mice were more susceptible to DSS induced acute colon injury. Tollip deficient mice displayed higher clinical scores with higher inflammatory cytokines in the blood. Further studies showed that Tollip deficient neutrophils had decreased migratory capacity, compromised bacterial killing activity, as well as reduced potential to generate neutrophil extra-cellular trap. On the other hand, Tollip deficient neutrophils had elevated levels of CCR5, responsible for their homing to sterile inflamed tissues. Together, our data reveal a novel mechanism in Tollip alteration that underlies the inflamed and incompetent polarization of neutrophils leading to severe outcomes of colitis.
Inhibition of radiation-induced lung inflammation and NF-kB activation by soy isoflavones.
Authors: Fountain Matthew Donovan , Abernathy Lisa Marie , Cannon Alexa Christine , Joiner Michael C , Hillman Gilda Gali 
Published: January 2023

Abstract

Background
Lung cancer patients treated with radiotherapy (RT) develop late respiratory distress as a result of inflammatory responses and lung fibrosis. We previously demonstrated that soy isoflavones (SIF) inhibited RT-induced inflammation, pneumonitis and fibrosis. NF-kB is a major transcription factor responsible for driving inflammatory responses. We have now investigated the effects of SIF on histopathology and status of NF-kB in lungs and BEAS-2B normal lung epithelial line treated with RT.

Methods
C57BL/6 and BALB/c mice were treated with 10Gy thoracic RT and oral SIF given daily for up to 18 weeks. Lung tissues were processed for histology and western blot protein analysis. In-vitro BEAS-2B cells were treated with SIF and 3Gy RT. NF-kB-p65 was assessed by western blot of cytoplasmic and nuclear protein fractions.

Results
H&E and Masson’s trichrome staining for fibrosis showed SIF reduced RT-induced inflammation and collagen fiber accumulation in lung parenchyma. SIF inhibited the infiltration and activation of macrophages and neutrophils in irradiated lungs. Analysis of NF-kB-p65 subunit, a marker of NF-kB activation, showed that RT induced expression of p65 was reduced by SIF in the lungs at 1–12 weeks after RT. In-vitro studies showed that while RT caused an increase in nuclear p65 at 3 and 24 hours post-RT, treatment with SIF and RT showed reduced p65 translocation to the nucleus.

Conclusions
SIF treatment mitigated radiation-induced histopathological alterations and p65 activation in-vivo and in-vitro. These findings suggest a trend for SIF to regulated NF-kB activation and the inflammatory response after RT. Future studies will decipher the signaling pathways involved in SIF-mediated radioprotection.
Intracellular HMGB1 mediating neutrophil extracellular trap formation during liver sterile inflammation
Authors: Huang Hai , Yazdani Hamza , loughran Patricia , Tsung Allan 
Published: January 2023

Abstract
Neutrophil extracellular traps (NETs) has been recently found exacerbate sterile inflammatory injury during liver ischemia/reperfusion (I/R). High mobility group box-1 (HMGB1) released from damaged cells, mediates liver damage and inflammatory responses after I/R. However, the intracellular role of HMGB1 in NET formation remains unknown. We sought to determine the role of intracellular HMGB1 in NET formation. Myloid cells HMGB1 knockout (LysM-HMGB1 KO) and HMGB1-flox mice were subjected to a non-lethal warm liver I/R. Less NETs was identified in ischemic liver lobes of LysM-HMGB1 KO mice compared with flox mice by confocal immunofluorescence (IF) imaging. This was associated with significantly less NET markers in LysM-HMGB1 KO mice, serum level of myeloperoxidase (MPO)-DNA complexes, and tissue level of citrullinated histone H3. Absence of HMGB1 in myloid cells protected the live from I/R injury indicated by significantly decreased serum transaminases (sALT), less necrosis and inflammatory cytokines production compared to flox mice. In vitro, no NET formation was observed in HMGB1 KO neutrophils under stimulation of PMA (positive control) or extracellular HMGB1 or histones confirmed by IF imaging. Chromatin in HMGB1 KO neutrophils failed to de-condensate in response to PMA which is the key step of NET formation. Additionally, gene deletion of HMGB1 in neutrophils completely blocked citrullination of histone H3 as a key step of NET formation, compared with control neutrophils in response to various stimulations. Our study demonstrates the dominant role of intracellular HMGB1 in NET formation. Lack of HMGB1 in neutrophils leads to diminished NET formation protect the liver from organ damage and cells death after liver I/R.
Foxo3 Transcription Factor Drives Pathogenic T Helper 1 Differentiation by Inducing the Expression of Eomes
Authors: MICHIELETTO MICHAEL , STIENNE CAROLINE , BENAMAR MEHDI , CARRIE NADEGE , CADENAT ISABELLE , SAOUDI ABDEL , LIBLAU ROLAND , HEDRICK STEPHEN M , DEJEAN ANNE S 
Published: January 2023

Abstract
CD4 T cell differentiation is a process finely controlled by specific transcriptional programs leading to the acquisition of specific T helper effector functions. Up to now, the functions of Foxo3 in CD4 T cells have not been investigate. Here, we described for the first time the critical role of the transcription factors Foxo3 in Eomes expression and their involvement in pathogenic T Helper 1 differentiation.
First, we showed that TCR triggering resulted in a dose-dependent upregulation of Foxo3 in CD4 T cells with an increased expression over time. We next addressed Foxo3 functions in CD4 T cells and we observed a decreased production of the Th1 related cytokines IFN-g and GM-CSF by Foxo3 KO CD4 T cells, with no impact survival, proliferation or other lineages differentiation. We then compared the transcriptome of WT and Foxo3 KO CD4 T cells and found that Foxo3 deficiency resulted in a decreased expression of genes related to the IFN- g/IFN-g response pathway and that the most downregulated gene in this pathway is Eomes. We showed, using ChIP and luciferase experiments, that Foxo3 binds and induces the expression of Eomes through direct DNA binding within the eomes locus. Using lentivirus experiments we showed overexpression of Eomes in Foxo3 KO CD4 T cell restored the proportion of IFN-g and GM-CSF producing cells, thus comforting Eomes role’s in the pathogenicity of CD4 T cells. In addition to this defect of differentiation, Foxo3-deficient mice developed a less severe Experimental Autoimmune Encephalomyelitis (EAE) as compared to WT mice, thus emphasizing the role of Foxo3 and Eomes in the development of autoimmunity. Altogether, we described here a new pathway whereby Foxo3 and Eomes drive CD4 T cells pathogenicity and neuro-inflammation.
Regulation of gene expression in Th17 cells by cyclic AMP Response Element Binding protein
Authors: Hernandez Jeniffer B , Cave Si 
Published: January 2023

Abstract
The CREB/CRTC2 pathway has emerged as an important regulator of immune function. We have previously shown that the CREB/CRTC2 pathway modulates autoimmune disease by promoting differentiation of the pro-inflammatory T cell, Th17. Although Th17 cells protect us against specific pathogens, Th17 cells have been found to cause destruction of tissue in patients with autoimmune diseases. Using RNAseq analysis, we have identified several genes that may be regulated by CREB in Th17 cells. Of these potential CREB targets, the G protein coupled receptor 65 is uniquely expressed in Th17 cells and mice deficient in GPR65 are resistant to autoimmunity. Blockade of GPR65 may lead to inhibition of pathogenic Th17 cells while simultaneously leaving non-pathogenic Th17 cells untouched.
Lumican Inhibits the pathogenicity of murine encephalitic TH17 cells
Authors: Yang Xuexian , Castillo Eliseo F , Zheng Handong , Cabanlong Christian , Dong Fei , Luo Yan , Yang Yi , Liu Meilian , Kao Winston 
Published: January 2023

Abstract
TH17 cells play an essential role in the development of both human multiple sclerosis and animal experimental autoimmune encephalomyelitis (EAE). Nevertheless, it is not well understood how the pathogenicity of TH17 cells is controlled in the autoimmune neuro-inflammation. In vitro, we found Lumican (Lum), an extracellular matrix (ECM) protein, is selectively expressed by TH17 cells among tested murine TH subsets. Lum-deficiency leads to earlier onset and enhanced severity of experimental autoimmune encephalomyelitis. This enhanced disease in Lum-deficient mice is associated with increased production of IL-17 and IL-21 and decreased TH17 cell apoptosis. Dysregulation in cytokine production appears to be specific to TH17 cells as TH1 and TH2 cell polarization and/or cytokine production were unaltered. Furthermore, adoptive transfer of MOG-specific TH17 cells derived from Lum-deficient mice led to earlier onset and increased severity of disease compared to controls highlighting a TH17 cell-intrinsic effect of Lum. Taken together, our results suggest that Lum negatively regulates encephalitic TH17 cells, implicating a potential therapeutic pathway in TH17 cell-mediated autoimmune and inflammatory diseases.
BAMBI, a new molecular target in autoimmunity
Authors: Alvarez Pilar , Augustín Juan Jesús , Tamayo Esther , Iglesias Marcos , Merino Jesús , Merino Ramón 
Published: January 2023

Abstract
We have previous demonstrated that BAMBI (BMP and Activin Membrane Bound Inhibitor) negatively regulates the functional differentiation of CD4 T cells into tolerogenic regulatory T-cells (Tregs) and positively the differentiation into pro-inflammatory TH17 cells. Accordingly, mice deficient in BAMBI are resistant against the development of collagen type II-induced arthritis (CIA). To analyze the therapeutic effects of BAMBI inhibition in normal mice in the development of autoimmunity, we developed new inhibitory mouse anti-mouse BAMBI mAbs. Treatment of B10RIII wild type (WT) mice with a high dose of a mouse IgG1 anti-mouse BAMBI mAb (clone B101.37; 2 mg/mice/week), but not with a low dose of B101.37 (0.3 mg/mice/week) or a high dose of an irrelevant IgG1 mAb (2 mg/mice/week), inhibited the development of CIA as efficiently as observed in B10RIII.BAMBI-KO mice.
We further explore the therapeutic potential of B101.37 in experimental models of psoriasis (Ps) and psoriasis arthritis (PsA). A single ip injection of mannan from Saccharomyces cerevisiae induces an acute inflammation resembling human Ps and PsA in B10RIII.WT but with a reduced severity in B10RIII.BAMBI-KO mice. Again, treatment of WT mice with B101.37, but not with an irrelevant IgG1 antibody, protects the animals against mannan-induced PsA and Ps by a Treg- and TGFβ-dependent mechanism. B101.37 also exhibits a therapeutic activity against mannan-induced PsA and Ps once the disease has been established. Similar results have been observed in a model of Ps induced after the topic administration of the TLR-7 agonist imiquimod. Altogether, our results demonstrate the beneficial effects of BAMBI inhibitors in the treatment of autoimmune skin and joint diseases.
The transcription factor Bhlhe40 is a switch of inflammatory versus anti-inflammatory Th1 cell fate determination
Authors: yu fang , Sharma Suveena , Jankovic Dragana , Su Pan , Rieder Sadiye , Porcella Stephen , Sun Bing , Zhu Jinfang (Jeff) 
Published: January 2023

Abstract
Type 1 T helper (Th1) cells play a critical role in host defense against intracellular pathogens and in autoimmune diseases by producing a key inflammatory cytokine interferon (IFN)-γ; some Th1 cells can be anti-inflammatory through producing IL-10. However, the molecular switch for regulating the differentiation of inflammatory and anti-inflammatory Th1 cells is still elusive. Here we show that Bhlhe40-deficient CD4 Th1 cells produced less IFN-γ but substantially more IL-10 than wild type Th1 cells. Bhlhe40-mediated IFN-γ production was independent of transcription factor T-bet regulation. Mice with conditional deletion of Bhlhe40 in T cells succumbed to Toxoplasma gondii infection and blockage of IL-10 signaling during infection rescued these mice from death. Thus, our results demonstrate that transcription factor Bhlhe40 is a molecular switch for determining the fate of inflammatory and anti-inflammatory Th1 cells.
CD001, an active compound from Astragalus membranaceus, downregulates TH17 cells differentiation and attenuates collagen-induced arthritis through inhibition of IL-6/IL-6R signaling
Authors: Yen Hung-Rong , Pai Fu-Tzu , Lu Cheng-You , Song Ying-Chyi , Wu Mei-Yao , Yu Sheng-Jie , Huang Ming-Cheng 
Published: January 2023

Abstract
Rheumatoid arthritis is a common autoimmune disease affecting approximately one percent of the worldwide population. It causes not only life-long discomfort but also disabilities of the patients. Despite the fact that conventional therapies and biological agents are used to modulate the dysregulated immune response and inflammation; there are still some unmet needs and concerns. We aimed to develop a pharmaceutical agent for targeting IL-6 receptor, which is involved in the differentiation of TH17 and pathogenesis of rheumatoid arthritis. Here we demonstrated an active compound, CD001, from Astragalus membranaceus, inhibited TH17 cells differentiation in a concentration-dependent manner in vitro. To further determine its efficacy in vivo, we administered CD001 in a murine model of collagen-induced arthritis. CD001 ameliorated paw edema and disease incidence as well as the production of IL-17, IL-22 and TNF-a in vivo. Molecular docking revealed that CD001 could couple into the binding site of IL-6 receptor. We further confirmed that CD001 interrupted the binding of IL-6 and IL-6 receptor in an in vitro binding assay. CD001 inhibited the downstream signaling pathways of IL-6 receptor, including JAK/STAT3, ErK1/2, and AKT, in TH17 cells. Our data fit the niche that is required to block IL-6 receptor signaling and inhibit TH17 for immunotherapy. We suggest that, to treat autoimmune disease, administering CD001 could be a promising pharmacologic approach to achieve the goal.
Evaluation of HPV-16 and HPV-18-specific Antibody Measurements in Saliva Collected in Oral Rinses and Merocel® Sponges
Authors: Parker Katherine H , Kemp Troy , Pan Yuanji , Giuliano Anna , Pinto Ligia A 
Published: January 2023

Abstract
Currently, there is some evidencing suggesting that HPV L1 VLP vaccines protect against HPV-16 and HPV-18 infection at the oral cavity in females and males. Although correlates of protection have not been identified, HPV specific antibodies at sites of infection are thought to be the main mechanism of protection afforded by vaccination. Oral sampling has gained increased attention as a potential alternative to serum in monitoring immunity to vaccination and understanding local immunity. The aim of this study was to evaluate if the HPV-16 and HPV-18 ELISAs currently used in sero-epidemiological studies of immunogenicity of HPV vaccines could be used to detect HPV-16 and HPV-18-specific antibodies in saliva following vaccination, using two different oral sampling methods. Data presented here demonstrate that HPV-16 and HPV-18 specific antibodies are detectable in saliva from vaccine recipients, from both mouthwash and Merocel® sponges using L1 VLP-based ELISAs.
Cross-Species Comparison Reveals Molecular and Functional Novelty of Porcine Interferon-Omega Subtype
Authors: Sang Yongming , Liu Qinfang , Lee Jinhwa , Miller Laura C. , Ma Wenjun , Blecha Frank 
Published: January 2023

Abstract
Innate immune interferons (IFNs), particularly type I IFNs, are primary mediators regulating antiviral immunity. These antiviral cytokines have evolved remarkable molecular and functional diversity to confront ever-evolving viral threats. We have annotated IFN gene families across 155 animal genomes, and show that pigs have the largest and an expanding type I IFN family consisting of nearly 60 functional genes that encode seven IFN subtypes including multigene subtypes of IFN-α and -ω. Whereas subtypes such as IFN-α and -β have been widely studied, the unconventional IFN-ω subtype has barely been investigated. We have evolutionarily defined the porcine IFN family, and preliminarily showed that porcine IFN-ω subtype has evolved several novel features including, (1) a signature multi-gene subtype expanding particularly in bats and ungulates, (2) emerging isoforms that have much higher antiviral potency than typical IFN-α, (3) cross-species high antiviral (but little antiproliferative) activity in cells of humans and other mammalian species, and (4) potential action through noncanonical signaling pathways. This study is focused on antiviral potency of porcine IFN-ωs investigating their evolutionary and functional diversity, signaling specificity, and optimization of novel antivirals against devastating viral diseases. This project will, for the first time in an animal species, establish state-of-the-art procedures for efficient characterization of the molecular and functional spectrums of unconventional IFNs, which will further IFN-based novel antiviral design.
Supported by grants from USDA (NIFA AFRI 2013-67015-21236 and NIFA AFRI 2015-67015-23216)