bluuebunny/crossref_metadata_2025_split huggingface dataset:
The contribution of autoantibody-inducing CD4+ T cell (aiCD4 T cell) help to the B cell maturation and possible autoantibody in Systemic Lupus Erythematosus
Authors: Sakurai Keiichi , Tsumiyama Ken , Shiozawa Shunichi 
Published: January 2023

Abstract

INTRODUCTION
Autoantibody-inducing CD4 T (aiCD4 T) cell seems indispensable for the self-organized criticality theory that induces Systemic Lupus Erythematosus (SLE). We previously found that the aiCD4 T cell belongs to CD45RBlo122lo CD4 T cell subpopulation. We here analyze the B cell population and CD19+ splenic B cell receptor (BCR) repertoire, and test our contention whether aiCD4 T cell helps B cell maturation.

METHODS
BALB/c mice were immunized with OVA twelve times and SLE was induced. Cell surface markers of B cell were detected with flow cytometry. CD19+ splenic B cells were sorted and BCR repertoires of these cells were analyzed on next generation sequencer.

RESULTS
After twelve times immunization of mice with OVA, follicular B (Fo B) cell and germinal center B (GC B) cell were significantly increased(P&lt;0.05), whereas marginal zone B cell was decreased. Activation markers of the B cell were increased and in particular, CD80 was significantly increased (P&lt;0.05). In addition, the number of clonotypes of CD19+ splenic B cells in OVA immunized mice was increased. Among these repertoires, the same pairs of V and J usage were frequently found in OVA immunized mice.

CONCLUSION
Fo B cell and GC B cell and the activation markers of B cell, as well, were significantly increased in OVA immunized mice, and the result of BCR repertoire analysis suggested that somatic hyper mutation occurred frequently in OVA-stimulated mice, which is compatible with the contention that aiCD4 T cells helps the maturation of B cells into germinal center B cells to enhance autoantibody formation thereby inducing SLE.
Stage specific requirement of TCF-1 for restraining Th17 immunity
Authors: Zhang Jing , He Zhiheng , Sun Zuoming 
Published: January 2023

Abstract
Besides the positive and negative selection for shaping T cell repertoire that only for attacking foreign antigens, central immune system also control the type and scale of immune responses in the periphery. T cell factor 1 (TCF-1) is highly expressed in the early thymic progenitors and has been shown to restrain Th17 responses in the periphery. However, it is not well understood which specific T cell developmental stage is critical for TCF-1 to determine the magnitude of Th17 immunity in the periphery. Here we showed that conditional deletion of TCF-1 early at hematopoietic, but not CD4+CD8+ double positive (DP) stage, resulted in severe reduction of thymic cellularity, enhanced Th17 differentiation and more aggravated experimental autoimmune encephalomyelitis (EAE). We also observed abnormal IL-17 expression in developing CD4−CD8− double negative (DN) thymocytes. Expression of wild-type TCF-1 in CD4−CD8− DN thymocytes, but not peripheral mature T cells, inhibited IL-17 expression. We also demonstrated that TCF-1 binds to IL-17 promoter region to perform its histone deacetylase (HDAC) function and hence restrain IL-17 expression in thymus. Our study first demonstrated the stage specific requirement of TCF-1 to restrain peripheral Th17 responses and thus provide an additional way to develop treatment for autoimmune diseases.
CD28 suppresses IL-23- and IL-1β-driven human Th17 development
Authors: McGeachy Mandy J. , Revu Shankar , Wu Jing , Rittenhouse Natalie , Menk Ashley , Delgoffe Greg M. , Poholek Amanda C. 
Published: January 2023

Abstract
Th17 cells drive autoimmune disease but also control commensal microbes. A common link between antigens from self-proteins or commensal microbiota is relatively low activation of T cell receptor and costimulation signaling. Indeed, strong TCR/CD28 stimulation suppressed Th17 cell differentiation from human naïve T cells, but not effector/memory cells. CD28 suppressed the classical Th17 transcriptional program, while inducing known Th17-regulators, and acted through an Akt-dependent mechanism. Th17 cells differentiated without CD28 were not anergic: they showed robust proliferation and maintained Th17 cytokine production following restimulation. IL-23 and IL-1β promoted glucose uptake and increased glycolysis. Although modestly increased compared to CD28 costimulation, glycolysis was necessary to support Th17 differentiation, indicating that cytokine-mediated metabolic shifts were sufficient to obviate the classical requirement for CD28 in Th17 differentiation. Together these data propose that in humans, strength of TCR/CD28/Akt activation serves as a rheostat tuning the magnitude of Th17 development driven by IL-23 and IL-1β.
Identifying novel mechanisms regulating the expression of the inflammatory chemokine IP-10
Authors: Richard Mara Lennard , Caldwell Tomika , Nowling Tamara K. , Gilkeson Gary S. , Zhang Xian 
Published: January 2023

Abstract
In response to the innate immune signals, mammalian cells produce inflammatory cytokines and chemokines to activate the immune system, and their expression is tightly regulated. IFN-gamma Inducible Protein (IP-10), also known as C-X-C motif chemokine 10 (CXCL10), is an inflammatory chemokine belonging to the CXC chemokine family. IP-10 is chemotactic for neutrophils, and altered expression of IP-10 is associated with many inflammatory diseases. Fli-1 belongs to the ETS transcription factor family. We have demonstrated that the Fli-1 transcription factor is a novel regulator in modulating the expression of many inflammatory mediators, including monocyte chemotactic protein 1 (MCP-1), chemokine (C-C motif) ligand 5 (CCL5) and interleukin 6 (IL-6). In this report, we found that murine endothelial cells transfected with Fli-1 specific siRNA produced significantly lower IP-10 after stimulation with Toll-like receptor 4 ligand LPS compared to the cells transfected with control siRNA. The production of IP-10 in endothelial cells with LPS stimulation is dose-dependent. We demonstrated that Fli-1 binds to the IP-10 promoter by Chromatin immunoprecipitation (ChIP) assay. Mechanisms by which Fli-1 regulates expression of IP-10 are currently being investigated. Together, the results indicate that Fli-1 is a novel, critical transcription factor in regulating the expression of the pro-inflammatory chemokine IP-10
Soluble Transforming Growth Factor Beta-1 enhances murine mast cell cytokine release
Authors: Lyons David O. , Plewes Michelle R. , Pullen Nicholas A. 
Published: January 2023

Abstract
TGF-β1 is traditionally known as an immunosuppressive cytokine. Previous studies have investigated its effects on FcɛRI-dependent mast cell activation, yet there is an incomplete understanding of TGF-β1 on mast cell function, for example, without sensitization to IgE. We investigated the effects of soluble TGF-β1 on IL-6 and IL-13 cytokine production in C57BL/6 bone marrow-derived mast cells in the presence and absence of FcɛRI-mediated activation. Our experiments found IL-6 production to be significantly enhanced independent of IgE sensitization or FcɛRI crosslinking; this was similar to treatment with stem cell factor (SCF), which also enhanced IL-6 production in this resting state. Additionally, IL-13 production was significantly enhanced following IgE-mediated stimulation of TGF-β1 treated mast cells; an effect independent of IgE was not observed, and treatment with SCF had no significant impact. Lastly, via confocal microscopy, we interrogated the cell-surface expression of FcɛRI, CD117 (c-Kit; SCF receptor), and TGFβRII with and without soluble TGF-β1 and/or FcɛRI crosslinking. This experiment revealed no apparent effect of TGF-β1 on FcɛRI and CD117 receptor co-localization – in both treatments we observed an equivalent decline in co-localization following IgE-mediated activation. TGFβRII was also found to weakly co-localize with those receptors, however this co-localization was unchanged across all treatments. Together, our findings provide novel insight into the stimulatory role of TGF-β1 on mast cell function both in the presence and absence of an allergic-like stimulus, suggesting alternative pathways play a pivotal role in regulating mast cell function beyond that of a canonical IgE-mediated pathway.
Proposed 3-D Structure of a Critical Protein-Protein Interaction Required for Transcription of the IL1B Gene Coding for Human Interleukin 1β
Authors: Pulugulla Sree H. , Workman Riley , Rutter Nathan , Esposito Emilio X. , Yang Zhiyong , Madura Jeffry D. , Auron Philip E. 
Published: January 2023

Abstract
We previously reported that expression of the human IL1B gene coding for Interleukin 1β in LPS-activated macrophages requires long-range chromatin looping mediated by a mutual DNA binding domain (DBD) interaction between two transcription factors, Spi-1/PU.1 (Spi1) at the promoter and C/EBPβ at a far-upstream enhancer. We have now combined preexisting X-ray structures and advanced computational techniques with additional biochemical and cell-based studies in order to further investigate the structure of this critical interaction. In vitro binding was used to generate a surface interaction map for the two proteins that suggested an association similar to that of a C/EBPβ·Myb X-ray structure reported by others. The distinction is that, in addition to a C/EBPβ leucine zipper interaction similar to that with the Myb DBD, there is an interaction between a carboxyl-tail extension of one of the C/EBPβ leucine zipper monomers with Spi1. This is consistent with our previous report that the carboxyl-tail of C/EBPβ is critical for association with arginine 232 within a pocket at one end of the Spi1 DNA recognition helix. L-arginine, a known anti-inflammatory, was computationally identified to bind in this interaction pocket. In vivo studies of LPS-activated THP-1 macrophages treated with L-arginine decreased IL1B transcription in parallel with a reduction in C/EBPβ association with Spi1 on the IL1B promoter. No significant change in direct binding of Spi1 and C/EBPβ to DNA was observed. These results suggest that L-arginine inhibits IL1B gene expression by competitive inhibition of C/EBPβ binding to Spi1 in the absence of any effect on direct DNA binding for either factor, and support the predicted structure of the C/EBPβ·Spi1 interaction.
The Notch signaling pathway controls basophil responses during helminth-induced type 2 inflammation
Authors: Webb Lauren M. , Peng Seth Alexander , Oyesola Oyebola , Cubitt Rebecca L. , Danko Charles , Wojno Elia Dion Tait 
Published: January 2023

Abstract
Type 2 inflammation is characterized by production of the cytokines IL-4, IL-5 and IL-13 and is required for clearance of gastrointestinal helminth parasites, which infect over 2 billion people worldwide. Basophils are innate immune cells that promote expulsion of the helminth Trichuris muris in mice. However, the molecular mechanisms that control basophil function and gene expression during helminth-induced Type 2 inflammation remain unclear. We show that during T. muris infection, basophils localized to the intestine and upregulated components of the Notch signaling pathway, which regulates inflammatory gene expression programs. In vitro, Notch inhibition abrogated IL-33-elicited IL-4 and IL-6 production from basophils by directly targeting Il4 and Il6. Transcriptional profiling of Notch-deficient basophils revealed that Notch directs basophil responsiveness to inflammatory cues and effector gene expression. Mice lacking basophil-intrinsic Notch signaling had impaired worm clearance and decreased intestinal Type 2 effector mechanisms following infection. These findings demonstrate that Notch regulates basophil gene expression and effector function during helminth-induced Type 2 inflammation. We are now actively investigating how basophils interact with other cells in the intestine to orchestrate optimal Type 2 immune activation, and the role Notch plays in this process. These findings increase our understanding of the molecular signals that control innate immunity during Type 2 inflammation and may have far-reaching impact on the development of therapeutics aimed at modulating Type 2 immune responses.
Langerhans cells are required for the priming and induction of an optimal immune response against an acute DNA virus infection
Authors: Wong Eric , Xu Ren-Huan , Tang Lingjuan , Meng Jennie , Sigal Luis J. 
Published: January 2023

Abstract
Resistance to ectromelia (ECTV) virus infection is dependent on the induction of a strong type I interferon (T1-IFN) response, which our lab has recently determined is primarily mediated by inflammatory monocytes (iMo) that are recruited to the draining lymph node (dLN). However, the mechanism behind how iMo are recruited is unclear. Accumulation of iMo is dependent on the production of CCL2 and CCL7 by CD11c+MHC-IIhi migratory dendritic cells (skin-mDCs) that originate from the skin of the footpad (initial site of infection), specifically CD103+CD207+ double-positive dermal DCs (DP dermal DCs), CD103−CD207− double-negative DCs (DN dermal DCs) and Langerhans cells. The transport of skin-mDCs to the dLN is dependent on the intrinsic utilization of the TLR9-MyD88-IRF7 axis, highlighting a key role for DNA sensing mechanisms in the skin. Analysis of infected and uninfected skin-mDC subsets reveal differential effector roles between the groups, with DP dermal DCs and Langerhans cells exhibiting high expression of pro-inflammatory cytokines and chemokines. Ablation of skin-mDC recruitment to the dLN with pertussis toxin (Ptx) resulted in a reduction in iMo accumulation and subsequent T1-IFN/pro-inflammatory expression with significantly higher mortality in infected B6 mice (which are normally 100% resistant to ECTV-related mortality). Finally, depletion of Langerhans cells, but not DP dermal DCs, resulted in a significant reduction in iMo accumulation in the dLN and consequently high mortality rates, therefore indicating that Langerhans cells may play an integral role in the priming and breadth of the host immune response against acute viral infections.
Oxidative stress enhances mitochondrial DNA-dependent type I interferon responses.
Authors: Lei Yuanjiu , Martinez Camila Guerra , West Phillip 
Published: January 2023

Abstract
It is increasingly well-appreciated that mitochondrial DNA (mtDNA) can engage the cGAS-STING cytosolic DNA sensing machinery to trigger type I interferon (IFN-I) responses. However, the exact immunostimulatory features of mtDNA and whether other nucleic acid sensors participate in triggering IFN-I remain poorly defined. We have discovered that mitochondrial reactive oxygen species potentiate mtDNA-driven IFN-I responses by enhancing the immunostimulatory properties of this DNA toward the cGAS-STING pathway. Moreover, we report that elevated oxidative stress results in the accumulation of mtDNA species with unique secondary structures that enhance IFN-I production. Finally, we report that Zbp1/DAI cooperates with cGAS to sustain IFN-I responses triggered by mtDNA. These results provide new insight into the molecular mechanisms of mtDNA recognition by the cytosolic DNA sensing machinery, with broad implications for understanding human diseases with mtDNA as a pathogenic inflammatory driver.
Type I and II IFNs differentially regulate IFNGR1 to tune IFNγ responsiveness in myeloid cells
Authors: Crisler William J. , Eshleman Emily M. , Lenz Laurel L. 
Published: January 2023

Abstract
Interferons (IFNs) act on macrophages to shape immune responses against microbial infections and tumors. Type I and II IFNs signal to induce transcription of IFN-stimulated genes (ISGs). Binding of the type II IFN (IFNγ) to its receptor, IFNGR, induces ISGs that enhance macrophage inflammatory and anti-microbial activity critical for bacterial infection. Conversely, when type I IFNs bind their receptor (IFNAR), they reduce expression of myeloid cell surface IFNGR and dampen macrophage responsiveness to IFNγ. Macrophages stimulated with IFNγ also reduce cell surface IFNGR, but this was previously attributed to ligand-induced receptor internalization. Here, we confirm the ability of IFNγ stimulation to rapidly reduce cell surface IFNGR in cultured mouse and human macrophages. However, we find this ligand-induced reduction in IFNGR is associated with reduced ifngr1 transcript abundance. Unlike IFNβ, IFNγ did not impede de novo transcription from an ifngr1 promoter-driven reporter construct, suggesting IFNγ reduces ifngr1 transcript abundance via a distinct mechanism. BMDMs pulsed with IFNγ transiently became refractory to a secondary IFNγ treatment as measured by impaired STAT1 phosphorylation. As shown previously, type I IFNs cause a reduction in myeloid cell surface IFNGR1 seen 72 hpi with systemic L. monocytogenes (Lm), and this reduction was abrogated by myeloid cell expression of a transgenic IFNGR1 in fGR1 mice. In contrast, IFNγ was responsible for a reduction in IFNGR on myeloid cells early after systemic Lm infection (24 hip), and this was not abrogated in fGR1 mice. Together, our results demonstrate that type I and II IFNs act via distinct mechanisms to prevent hyper-activation of myeloid cells following exposure to IFNγ.
Cholinergic signaling in the dorsal motor nucleus regulates systemic inflammatory responses via the vagus nerve
Authors: Kressel Adam M. , Tsaava Téa , Pavlov Valentin A. , Chavan Sangeeta S. , Tracey Kevin J. 
Published: January 2023

Abstract
The autonomic nervous system regulates organ homeostasis via neural reflex circuits. The inflammatory reflex is the prototypical neural circuit composed of afferent and efferent fibers that travel via the vagus nerve to regulate TNF production. Previous studies have demonstrated that stimulation of the cervical vagus nerve attenuates serum TNF levels and cytokine production in the spleen, but efferent vagus nerve neurons originate both in the dorsal motor nucleus of the vagus (DMV) and in the nucleus ambiguus (NA) in the brainstem. The origin of the specific fibers that regulate splenic TNF production was previously unknown. Here, we selectively stimulated cholinergic neurons in the DMV and measured TNF in endotoxemic mice. A fiber-optic cannula was inserted under stereotactic guidance into the DMV in transgenic mice expressing channelrhodopsin under the choline acetyltransferase promoter. Animals were subjected to either optogenetic stimulation (n=15) or no light (sham control, n=15) for five minutes (473nm laser, 20Hz, 25% duty cycle). After 24 hours, animals were challenged with intraperitoneal lipopolysaccharide (0.25mg/kg), and serum collected after 90 min. Optogenetic stimulation but not sham stimulation of the cholinergic neurons in the DMV significantly attenuated endotoxin-induced serum TNF levels. Additionally, direct neural recording of splenic nerve activity during optogenetic stimulation of the DMV revealed that signals originating in the brainstem travel via the vagus nerve to the spleen. Together these studies provide new insights into the identity and central origin of the efferent vagus nerve fibers regulating TNF production during endotoxemia.
The histone acetyltransferase MOF promotes macrophage inflammation in diabetic wounds.
Authors: den Dekker Aaron D. , Joshi Amrita , Davis Frank M. , Kimball Andrew , Boniakowski Anna , Schaller Matthew , Kunkel Steven L. , Moore Bethany B. , Gallagher Katherine 
Published: January 2023

Abstract
Macrophage (Mϕ) plasticity is essential for the repair and remodeling of wounds. However, under pathologic conditions such as type 2 diabetes (T2D), Mϕs exist in a chronic inflammatory state that drives continued tissue destruction and results in impaired wound healing. We have previously shown that Mϕs isolated from wounds in a murine model that mimics physiologic development of T2D (diet-induced obese mice; DIO) display increased levels of inflammatory cytokines at both a gene expression and protein level. Although the underlying mechanisms remain unclear, we and others have shown that Mϕ phenotype can be controlled by epigenetic modifications that alter gene expression. Our recent work provides evidence that the diabetic milieu alters gene expression and sets an “epigenetic signature” in myeloid cells that result in an exaggerated inflammatory phenotype and delayed wound healing in a murine model. Further, our recent work has found that the histone acetyl transferase, Males absent on the first (MOF), responsible for acetylation of lysine 16 on histone H4 (H4K16), was critical for expression of genes involved in fatty acid metabolism. In the present study, we find that wound Mϕs from DIO mice have increased expression of MOF at day 5, when Mϕs shift from a pro-inflammatory to an anti-inflammatory state within wound tissue. This change in MOF was accompanied by increased expression of components of MOF regulatory complexes, MSL1/2 and KANSL1. Our findings reveal a previously unreported role for MOF in promoting a pro-inflammatory state in innate immune cells. Moreover, our data suggest that the diabetic milieu promotes increased expression of MOF which, in turn, may contribute to maintaining the persistent inflammatory state in wound Mϕs.
Regulatory circuits governing identity and function of human type 1 ILCs
Authors: Collins Patrick , Cella Marina , Porter Sofia , Mccullen Matthew , Colonna Marco , Oltz Eugene M. 
Published: January 2023

Abstract
Innate lymphocytes develop from common progenitors but diverge functionally into a broad range of subsets that comprise a rapid response system to pathogens. In mice, type 1 innate lymphoid cells (ILCs), characterized by IFN-g expression, segregate into two major groups: cytotoxic natural killer (NK) cells and cytokine-producing, helper like ILC1s. In humans, this functional dichotomy is complicated further by heterogenous populations of circulating or tissue-resident NK cells, which exhibit distinct potentials for cytotoxicity or cytokine expression. Although developmental and functional kinships among NK cells have been studied extensively in mice, little is known about the molecular programs governing NK populations in humans. Here, we present integrated “-omics” analysis of human type 1 ILCs from blood and mucosal tissues, which identifies the key factors and biologic pathways establishing cell-type and functional identifies, as well as their underlying gene regulatory programs.