bluuebunny/crossref_metadata_2025_split huggingface dataset:
Ascorbic acid ameliorates T cell-mediated acute liver injury in gulo-/- mice (173.41)
Authors: Bae Seyeon , Kim Hyemin , Yu Yeonsil , Kim Yejin , Kim Hang-Rae , Hwang Young-il , Kang Jae Seung , Lee Wang Jae 
Published: January 2023

Abstract
Deficiency of ascorbic acid (vitamin C) is thought to be contributed to the pathogenesis of liver diseases. To clarify the role of vitamin C in protection from liver injury, we induced concanavalin A (Con A)-mediated hepatitis in vitamin C-insufficient gulo-/- mice, which cannot synthesize vitamin C like humans. In Con A-treated vitamin C-insufficient gulo-/- mice, the extensive production of pro-inflammatory cytokines, such as IFN-gamma and TNF-alpha was observed in plasma and liver. Moreover, extensive liver damage and apoptosis of hepatocytes were also found. Increased numbers of liver-infiltrating T cells in vitamin C-insufficient gulo-/- mice correlated with increase of hepatic levels of IFN-inducible factor (IP-10). Even though IL-22, a hepato-protective cytokine, was highly increased in vitamin C-insufficient gulo-/- mice, IL-22R alpha expression and STAT3 activation followed by IL-22 were not induced in hepatocyte. Finally, we confirmed that vitamin C-insufficient T cells has hyper-proliferating activity and extensive inflammatory cytokine production to Con A. Taken together, vitamin C-insufficiency in vivo causes uncontrolled production of pro-inflammatory cytokines by liver-infiltrating T cells and severe defects on STAT3 activation at the down-stream of IL-22R alpha on hepatocytes and hepatic inflammation deteriorated. It suggests that severe hepatic damages by autoimmune or chronic inflammation could be prevented by the sufficient vitamin C supplementation.
IL-7 induces rapid internalization of CD127 by clathrin mediated endocytosis, leading to subsequent degradation by the proteasome. (174.1)
Authors: Faller Elliott , Al Ghazawi Feras , MacPherson Paul 
Published: January 2023

Abstract
IL-7, a potent immunomodulatory cytokine, is currently being investigated as a potential therapy and vaccine adjuvant in the treatment of HIV infection. In order to maximize these therapeutic strategies, we must first understand how the IL-7 receptor is regulated. We show here that in pimary human CD8 T cells, IL-7 decreases surface CD127 expression on CD8 T-cells in a dose- and time-dependent manner with initial suppression as early as 20 minutes and maximal suppression at 12 hours. This decrease at the cell surface is followed by loss of total CD127 protein within the cell as demonstrated by western blot. IL-7 induces internalization of surface CD127 through endocytic vesicles. The endocytosis inhibitors Filipin, and Dynasore both prevent IL-7 induced down regulation of CD127 at the cell membrane. Consistent with this we have shown by confocal microscopy that in resting CD8 T-cells CD127 is distributed evenly throughout the cell. After treatment with IL-7, CD127 forms multiple intracellular punctae with increased co-localization with clathrin by 5 minutes followed by co-localization with the early endosomal marker EEA1 after 30 minutes. By 2 hours CD127 staining associates with the late endosome marker RAB7 and the proteasomal 20S subunit, while at the same time showing decreased colocalization with the lysosomal marker LAMP1. Interestingly, the proteasome inhibitors lactacystin and MG132 both blocked IL-7’s ability to down regulate CD127.
Macrophage migration inhibitory factor induces autophagy via reactive oxygen species generation (174.10)
Authors: Yeh Trai-Ming , Chuang Yung-Chun 
Published: January 2023

Abstract
Autophagy is an evolutionarily conserved catabolic process which maintains cellular homeostasis under stress conditions such as starvation and pathogen infection. Macrophage migration inhibitory factor (MIF) is a multifunctional cytokine that plays important roles in inflammation and tumorigenesis. Cytokines such as IL-1β and TNF-α that are induced by MIF have been shown to be involved in the induction of autophagy. However, the actually role of MIF in autophagy is still unclear. Here, we demonstrated that incubation of human hepatoma cell line Huh-7 cells with recombinant MIF (rMIF) induced reactive oxygen species (ROS) production and autophagy formation, including LC3-II expression, LC3 punctae formation and mitochondria membrane potential loss. The autophagy induced by rMIF was inhibited in the presence of MIF inhibitor, ISO-1 as well as ROS scavenger N-acetyl-L-cysteine (NAC). In addition, serum starvation-induced MIF release and autophagy of Huh-7 cells were partly blocked in the presence of NAC. Moreover, diminished MIF expression by shRNA transfection or inhibition of MIF by ISO-1 decreased serum starvation-induced autophagy of Huh-7 cells. Taken together, these data suggest that MIF is involved in autophagy through ROS generation to prevent cell death.
The two main microvesicle subtypes are significantly different in construction and have different physiological roles (174.18)
Authors: Inal Jameel , Stratton Dan 
Published: January 2023

Abstract
Microvesicles or MVs exist as two distinct sub-types, cMVs and sMVs, which exhibit radically different sizes and calcium contents. The further characterisation of these sub-types was needed to assess significant differences in their biological roles as hitherto reported in the literature. cMVs are heavier then sMVs, containing many proteins reminiscent of the parent cell, including an abundance of surface receptors. They have high carbohydrate levels and have been shown to contain DNA sequences. Conversely, sMVs are lighter, and whilst containing a representative assortment of receptors and surface proteins, contain fewer proteins from their parental cells. They contain low carbohydrate levels and contain very little DNA. Furthermore, whereas cMVs may have various specific roles, sMV release acts as a mechanism to postpone apoptosis by exporting stress agents from the cell, allowing the cell to recover. Furthermore, sMVs have a tendency to offer protection against complement-mediated lysis for both mammalian and bacterial cell types.
The E3 ubiquitin ligase adaptor Ndfip1 regulates TH17 differentiation by limiting the production of pro-inflammatory cytokines (175.11)
Authors: Beal Allison , Ramon Hilda , Worthen George , Oliver Paula 
Published: January 2023

Abstract
Ndfip1 is an adaptor that promotes polyubiquitylation by the E3 ubiquitin ligase Itch. Mice that lack either Ndfip1 or Itch develop a severe TH2-mediated inflammatory disease at sites of environmental antigen exposure, including the lung. Here we demonstrate that lungs from Ndfip1-/- mice showed increased numbers of neutrophils and TH17 cells. This was not because Ndfip1-/- T cells are intrinsically biased towards TH17 differentiation. In fact, fewer Ndfip1-/- T cells differentiated into TH17 cells in vitro due to the overproduction of IL-4 production. Rather, TH17 differentiation in vivo was increased in Ndfip1-/- mice due to elevated numbers of IL-6 producing eosinophils. Interestingly, mice lacking both Ndfip1 and IL-4 had levels of IL-6 comparable to WT controls and these Ndfip1-/- IL-4-/- mice had fewer TH17 cells in their lungs compared to Ndfip1-/- IL-4+/+ mice. These results indicate that TH2 inflammation, such as that observed in Ndfip1-/- mice, can increase TH17 differentiation by recruiting IL-6 producing eosinophils into secondary lymphoid organs and tissues. This may explain why TH17 cells develop within an ongoing TH2 inflammatory response, such as asthma.
Transcriptional profiling of steady-state and inflamed lymph node stroma reveals potential hematopoietic-stromal cross-talk pathways and suggests an active role for stroma during ongoing immune responses. (176.22)
Authors: Malhotra Deepali , Fletcher Anne , Astarita Jillian , Lukacs-Kornek Veronika , Elpek Kutlu , Turley Shannon , (ImmGen) Immunological Genome Project Consortium 
Published: January 2023

Abstract
Lymph node stromal cells (LNSCs) closely regulate immunity and self-tolerance, yet key aspects of their biology remain poorly illuminated. Little is known about what factors these cells produce beyond a short list of critical molecules, or how these subsets respond to inflammation. Comparative transcriptomic analyses of steady-state murine LNSC subsets revealed expression of important immune mediators and growth factors. Further, pairwise analyses of ligand and cognate receptor expression by hematopoietic and stromal subsets suggested a complex web of cross-talk. Transcriptional profiling of steady-state LNSC subsets also suggested a readiness of these cells to respond to inflammatory and infectious triggers. Accordingly, fibroblastic reticular cells (FRCs), blood endothelial cells (BECs), and lymphatic endothelial cells (LECs) isolated from inflamed lymph nodes upregulated expression of numerous genes involved in the acute phase response, immune cell recruitment, and the MHC II antigen processing and presentation pathway, among others. Flow cytometric analysis demonstrated elevated levels of surface MHC II on FRCs, BECs, and LECs isolated from skin-draining lymph nodes 18 hours after the onset of inflammation. LNSC subsets from inflamed lymph nodes also produced the antimicrobial molecule lipocalin 2. Together these data offer insight into the transcriptional identities of murine LNSC subsets, while suggesting that they may be active players during ongoing inflammation.
Uric acid acts as a natural adjuvant by promoting Th17 cell differentiation via an inflammasome-dependent mechanism (176.28)
Authors: Mortellaro Alessandra , Conforti-Andreoni Cristina , Spreafico Roberto , Ricciardi-Castagnoli Paola 
Published: January 2023

Abstract
Non-microbial molecules released from damaged cells act as natural adjuvants capable of promoting an efficient immune response mediated by innate cells, including macrophages and dendritic cells (DCs). Among these molecules, uric acid (UA) in its crystallized form has been found to trigger inflammation through the activation of NLRP3 inflammasome, which leads to secretion of the proinflammatory cytokines IL-1β and IL-18. UA modulation of innate immune responses has been extensively studied, but the impact of this damage-associated molecular pattern on adaptive responses remains largely undocumented. As one of the most ubiquitous sterile danger signals in mammals, and in view of the key role played by UA in alum adjuvanticity, we sought to determine how UA crystals shape adaptive immune responses. In the present study, we focused on adaptive CD4+ T cell polarization since adjuvants that are able to direct appropriately polarized responses will be key to the success of next-generation vaccination strategies. In the presence of NF-κB signaling delivered by muramyl dipeptide, UA crystals were capable of stimulating DCs to promote the release of cytokines associated with Th17 polarization. Accordingly, UA crystals potently induced Th17 responses both in vitro and in vivo. These effects were dependent on the inflammasome-related cytokines IL-1α/β and IL-18, as well as on ASC and caspase-1. Accordingly, NLRP3 deficiency significantly impaired Th17 polarization, at least in vitro.
Effect of AhR activation by TCDD on the immunosuppressive CTLA-4 - IFNγ - IDO pathway (176.5)
Authors: Rohlman Diana , Pennington Jamie , Bradford Sam , Kerkvliet Nancy 
Published: January 2023

Abstract
The aryl hydrocarbon receptor (AhR) is a promising target for the treatment of immune-mediated diseases. Activation of AhR by 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD) results in potent immunosuppression in a murine graft versus host (GVH) model, concurrent with a CD4+ regulatory phenotype characterized by increased expression of CTLA-4. CTLA-4 is associated with induction of indoleamine 2,3-dioxygenase (IDO) via IFNγ, resulting in decreased T-cell proliferation and immunosuppression. Treatment with TCDD has also been shown to induce IDO, suggesting that the TCDD-mediated up-regulation of CTLA-4 on donor cells may be responsible for the induction of IDO. Our results show that increased expression of CTLA-4 on donor CD4+ T-cells was concurrent with increased IFNγ, and significant up-regulation of the genes encoding IDO, Ido and Ido2. However, antibody blockade of CTLA-4 did not prevent the suppression of the CTL response by TCDD, suggesting that increased expression of CTLA-4 was not essential for the immunosuppressive effects. A direct role for increased IDO expression in TCDD-mediated immunosuppression is currently under investigation.
Chronic IL-33 exposure induces a hypo-responsive mast cell phenotype (177.13)
Authors: Jung Mi-Yeon , Smrz Daniel , Desai Avanti , Bandara Geethani , Ito Tomonobu , Kang Jeong-Han , Beaven Michael , Metcalfe Dean , Gilfillan Alasdair 
Published: January 2023

Abstract
Antigen-mediated mast cell (MC) activation, and the ensuing release of inflammatory mediators, is a pivotal event in the initiation of such conditions as asthma and anaphylaxis. IL-33 is elevated in asthmatic lungs and thus has been hypothesized to play a role in the pathogenesis of atopic diseases. However, we observed that IL-33 by itself did not induce anaphylaxis in a mouse model. Indeed, peritoneal mast cells taken from chronically IL-33-treated mice, appeared less sensitive to antigen challenge. We therefore examined the direct effects of IL-33 on mouse and human MCs in culture. Cells exposed to IL-33 for &gt;72 h had dramatically reduced antigen-mediated degranulation and generation of specific cytokines. This was not a consequence of reduced expression of the high affinity IgE receptor, FcϵRI, or KIT but reflected altered signaling in the IL-33-treated cells. In this respect, the required antigen-mediated calcium signal and cytoskeletal reorganization were diminished in IL-33-treated mast cells, and this was respectively associated with IL-33-dependent down-regulation of PLCγ1 and Hck expression. These data thus reveal that MCs can be reprogrammed to produce a hypo-responsive phenotype and furthermore suggest that IL-33 may have a protective, rather than a causative role, in allergic disorders. The ability to manipulate MC activation in this manner may provide novel opportunities for therapeutic intervention of MC-driven disease.
The unfolded protein response induces the resistance of hepatoma cells to NK cells’ cytotoxicity (178.13)
Authors: Chen Lihua , Gong JiuYu , Liu Rongrong , Fang Liang , Zhuang Ran , Zhang Yun , Jin Boquan 
Published: January 2023

Abstract
NK cells, as a critical components of anti-tumor immunity, recognize and kill malignant cells through the specific NK cell activating receptors. CD226 and NKG2D are known as important NK cell activating receptors whose ligands are CD112, CD155 and MICA/B, respectively. It has been proven that CD112, CD155 and MICA/B highly express on a series of tumors and directly affect the cytotoxicity of NK cells to the malignant cells. Here we showed that the unfolded protein response induced by tunicamycin could decrease the expression levels of CD112, CD155 and MICA/B on hepatoma cells via the ATF6 and IRE1 pathway and induce the resistance of hepatoma cells to NK cells’ cytotoxicity. Furthermore, the IRE1 pathway increased the expression of the ER associated degradation (ERAD) related molecule HRD1 and facilitated the degradation of CD112, CD155 and MICA/B. Moreover, we demonstrated that the expression levels of CD112, CD155 and MICA/B in hepatoma tissues were inversely correlated with the expression level of GRP78 and the TMN grade of hepatocellular carcinoma in vivo. The results suggest that the production of HRD1 is up-regulated to facilitate the hepatoma cells escape from the NK cells’ cytotoxicity by degrading the ligands expression of the NK cells’ activating receptors.
Oral administration of Capsaicin, a ligand of VR1, can modulate dendritic cell population and induces CD4+FoxP3- Tr-1 cells in the GALT (178.14)
Authors: Acharya Nandini , Basu Sreyashi 
Published: January 2023

Abstract
VR1 is a non-selective cation channel, highly expressed by sensory neurons and cells of the immune system e.g. dendritic cells (DCs) and macrophages. Capsaicin (CP), the pungent component of chili peppers is a chemical ligand of VR1. We have recently reported that oral administration of CP inhibits proliferation and activation of auto-reactive T cells and protects mice from development of Type-1 diabetes (T1D) in a dose dependent manner. Here we demonstrate that orally administered CP can lead to an increase in IL-27 producing DCs, and IL10 producing CD4+/FoxP3- T cells (Tr1) but decrease in the frequency of CD4+/IL17+ T cells (TH17) in the pancreatic lymph node (PLN). We also demonstrate that splenocytes and PLN cells when adoptively transferred from capsaicin fed mouse to a naïve NOD mouse leads to protection of the recipient mouse from T1D. Our results thus demonstrate that engagement of VR1 on immune cells can have profound effect on gut mediated immune tolerance and autoimmunity.
The Cytomegalovirus mimic of Herpesvirus entry mediator avoids CD160 and inhibits IL-2 signaling through B and T lymphocyte attenuator restricting Natural Killer cell function (178.20)
Authors: Sedy John , Bekiaris Vasileios , Smith Wendell , Nemcovicova Ivana , Norris Paula , Benedict Chris , Zajonc Dirk , Ware Carl 
Published: January 2023

Abstract
Natural killer (NK) cells express multiple activating receptors that, upon engagement, result in the rapid release of cytolytic and antiviral effectors required for host defense, notably against herpesviruses. The host is protected from the powerful inflammatory mediators produced by NK cells through the action of inhibitory receptors that typically associate with major histocompatibility class I proteins. To develop into fully functional effector cells and to maintain homeostasis, NK cells depend upon common γ chain signaling. Here, we show that the ORF UL144 mimic of herpesvirus entry mediator (HVEM, TNFRSF14) from the β-herpesvirus cytomegalovirus (CMV), binds exclusively to B and T lymphocyte attenuator (BTLA) but not to CD160, resulting in inhibition of IL-2-mediated activation of NK cells. HVEM and the two Ig-superfamily member receptors that bind HVEM, CD160 and BTLA, are all expressed on NK cells. Mechanistically, UL144 association with BTLA results in dephosphorylation of JAK1 and STAT5, resulting in decreased strength and duration of IL-2 receptor signaling. Subsequently, inhibition of IL-2 receptor signaling by UL144-BTLA suppresses NK cell activation and the ability of NK cells to express antiviral cytokines. Taken together, our results show a novel mechanism by which CMV can control the activation of NK cell antiviral effector functions via UL144-BTLA interactions that result in inhibition of IL-2 receptor signaling.
Competing positive and negative feedbacks mediated by PH domain ligand interactions regulate Itk activation kinetics in T Cells (178.3)
Authors: Das Jayajit , Mukherjee Sayak , Rigaud Stephanie , Seok Sang-Cheol , Fu Guo , Prochenka Agnieszka , Dworkin Michael , Gascoigne Nicholas , Vieland Veronica , Sauer Karsten 
Published: January 2023

Abstract
Inositol phosphate second messengers often regulate crosstalk between receptor signaling and lipid metabolic networks critically affecting cell decision processes, however, molecular mechanisms underlying such cross-regulation are poorly understood. Pairing mathematical modeling and experiments we elucidate these mechanisms in thymocyte activation initiated by T cell receptor (TCR) and antigen interactions. Thymocyte activation is carefully controlled by transient activation kinetics of the Tec-family protein tyrosine kinase Itk generated by TCR signaling, and, production of the membrane lipid phosphatidylinositol(3,4,5)trisphosphate (PIP3) and soluble inositol(1,3,4,5) tetrakisphosphate (IP4). By combining PLC-g (substrate of active Itk) activation kinetics in experiments with maximum entropy based computational approaches we show multiple possible in-silico models describing different modes of molecular interactions between Itk, PIP3, and IP4, can be distinguished. We show that models displaying maximum robustness share a cooperative-allosteric mode of Itk regulation by IP4 involving oligomeric Itk PH domains which induces dueling positive and negative feedbacks in Itk activation. Models lacking the feedbacks or containing monomeric Itk are significantly less robust. We also elucidate key mechanisms regulating the "shape" of the transient Itk kinetics that can be manipulated in experiments for developing therapeutic strategies targeting TCR signaling.
Src and Syk family kinases phosphorylate distinct tyrosines of RIAM (178.4)
Authors: Sari Duygu , Patsoukis Nikolaos , Boussiotis Vassiliki 
Published: January 2023

Abstract
RIAM is a novel adaptor involved in actin polymerization, cell adhesion and PLC-γ1 activation. RIAM contains two coiled-coil regions in the N-terminus, a small proline-rich N-terminus region, a Ras-association (RA) domain, a pleckstrin homology (PH) domain and a large proline-rich C-terminus region. Via its domains RIAM mediates distinct interactions and serves different functions. It was previously determined that RIAM is a substrate of the TCR proximal Src family kinases Fyn and Lck and the Syk family kinase ZAP-70. In the present study we sought to determine the precise tyrosine(s) of RIAM, which are phosphorylated by these kinases, by co-expressing RIAM deletion mutants (N-terminus, RA-PH, and C-terminus) along with active forms of each kinase in COS cells. Immunoprecipitations and immunoblot assays revealed that Src family kinases mediated robust and selective tyrosine phosphorylation of RIAM within the RA-PH domain. Mass spectrometry identified that tyrosine 340 within the PH domain was the specific and predominant target of Fyn and Lck. In contrast, ZAP-70 did not mediate phosphorylation in the RA-PH domain but, instead, induced robust phosphorylation in RIAM C-terminus downstream of the PH domain. The distinct tyrosine phosphorylation of RIAM mediated by Src family kinases and ZAP-70 suggests unique roles of these kinases in regulating RIAM interactions and functions. The role of the distinct phosphorylation events in these outcomes will be discussed.
Proto-oncoprotein ZBTB2 represses transcription activation of RELA gene by Sp1 (178.6)
Authors: Hur Man-Wook , Kim Min-Young 
Published: January 2023

Abstract
Recently, we found that ZBTB2, a POK family transcription factor, is a proto-oncogenic control gene of the p53 pathway and is a transcription repressor of the p21 by inhibiting p53 and Sp1. NF-κB is a protein complex that controls the transcription. NF-kB is found in almost all animal cell types and is involved in cellular responses to stimuli such as stress, cytokines, free radicals, and ultraviolet irradiation. Incorrect regulation of NF-kB has been linked to cancer, inflammatory diseases, viral infection, and improper development. Surprisingly little is known how transcription of the genes encoding p65or p50 is regulated. Interestingly, we found that ZBTB2 represses transcription activation of pNF-kB-Luc reporter by NF-kB, and knock-down of ZBTB2 expression derepresses transcription. Our data suggested that ZBTB2 represses transcription of NF-kB responsive gene by repressing expression of the genes encoding NF-kB subunit p65. Sp1 plays a key role in the expression of RELA gene and ZBTB2 repressed transcription of the gene by acting on the three proximal Sp1 binding elements. Co-IP/western blot and GST fusion protein pull-down assays revealed direct protein-protein interaction between Sp1 and ZBTB2. EMSA, ChIP, and oligonucleotide pull-down assays revealed that ZBTB2 represses transcription of RELA gene by inhibiting Sp1 binding by protein-protein interaction. Functional significances and the details of regulatory mechanism are under investigation..