bluuebunny/crossref_metadata_2025_split huggingface dataset:
N-acetylcysteine reduces reactive oxygen species and pro-inflammatory cytokine production in HLA-B27 positive macrophages and shapes them towards a quiescent metabolic state
Authors: Navid Fatemeh , Nguyen Breanna , Cougnoux Antony , Violet Pierre-Christian , Levine Mark , Colbert Robert A 
Published: January 2023

Abstract
HLA-B27, which predisposes to spondyloarthritis (SpA), has a tendency to misfold, generate endoplasmic reticulum (ER) stress, and activate the unfolded protein response (UPR). The UPR may contribute to SpA pathogenesis by promoting the production of pro-inflammatory cytokines like IL-23 and TNF. During ER stress, cells produce more reactive oxygen species (ROS), which can further worsen the UPR and promote inflammation. Here, we examined whether reducing oxidative stress in HLA-B27+ macrophages affects pro-inflammatory cytokine production and UPR gene expression. Bone marrow-derived macrophages from HLA-B27-transgenic (Tg) treated with IFNg and LPS (stimulated) showed increased ROS production compared to HLA-B7-Tg and wild type (WT) control rats. This was accompanied by robust activation of the UPR only in HLA-B27-expressing cells. Treatment with N-acetylcysteine (NAC), a ROS scavenger, significantly reduced ROS levels in HLA-B27+ macrophages and strongly decreased the transcription of many pro-inflammatory cytokines including Il-23, Il-12, Tnf, Il-6 and Il-1b. The effect of NAC was further verified by ELISA assays available for rat IL-1b, IL-6, and TNFa. NAC treatment also partially reduced UPR markers including spliced Xbp1, and BiP, Chop, Manf and Derlin-3 in HLA-B27+ macrophages. Interestingly, NAC reduced metabolic activity in stimulated macrophages to levels similar to untreated control cells as measured by the Seahorse Assay. Our data demonstrate that reducing ROS levels with NAC ameliorates ER stress-related pro-inflammatory effects of HLA-B27 misfolding. Alteration of the oxidative stress pathway should be further explored for therapeutic intervention in SpA.
Interleukin-17 Drives Interstitial Entrapment of Tissue Lipoproteins in Experimental Psoriasis
Authors: Huang Paul , Zinselmeyer Bernd , Saunders Brian T , Swartz Melody A , Kim Brian S , Randolph Gwendalyn J 
Published: January 2023

Abstract
Lipoproteins trapped in arteries drive atherosclerosis. Extravascular low-density lipoprotein undergoes receptor uptake, whereas high-density lipoprotein (HDL) interacts with cells to acquire cholesterol and then recirculates to plasma. We developed photoactivatable apoA-I to understand how HDL passage through tissue is regulated. We focused on skin and arteries of healthy mice versus those with psoriasis, which carries cardiovascular risk in man. Our findings suggest that psoriasis-affected skin lesions program interleukin-17-producing T cells in draining lymph nodes to home to distal skin and later to arteries. There, these cells mediate thickening of the collagenous matrix, such that larger molecules including lipoproteins become entrapped. HDL transit was rescued by depleting CD4 + T cells, neutralizing interleukin-17, or inhibiting lysyl oxidase that crosslinks collagen. Experimental psoriasis also increased vascular stiffness and atherosclerosis via this common pathway. Thus, interleukin-17 can reduce lipoprotein trafficking and increase vascular stiffness by, at least in part, remodeling collagen.
The cross-talk between infiltrating macrophages and inflamed or malignant colonic epithelium promotes overexpression of ST6GALNAC1 and epithelial MUC1 tumor form MUC1-sTn
Authors: Cascio Sandra , Kvorjak Michael , Ahmed Yamine , Miller Michelle , Al Hashash Jana , Hartman Douglas , Miskov-Zivanov Natasa , Telmer Cheryl , Finn Olivera J 
Published: January 2023

Abstract
Patients with inflammatory bowel disease (IBD) have an increased risk of developing colitis-associated colon cancer (CACC). Despite the strong relationship between inflammation and cancer, the mechanistic events that contribute to the transition from IBD to CACC remain undefined. Changes in the glycosylation profile of the known oncoprotein MUC1 commonly occur in chronic inflammation and may facilitate progression to cancer. We used a transwell coculture model system to examine the effect of polarized macrophages, such as those contributing to inflammation, on the expression of glycosylation-related enzymes in colon cancer cells. We found that M2-like macrophages induce the expression of ST6GALNAC1 glycosyltransferase which, by adding sialic acid to O-linked GalNAc residues, promotes the formation of the tumor-associated MUC1-sTn glycoform. Cytokine antibody arrays and blocking antibody experiments revealed that high levels of IL-13 and CCL17, present in the conditioned medium of colon cells cocultured with M2 macrophages, activate ST6GALNAC1 expression in colon cancer cells. In silico and in vivo murine and human models of colitis and CACC showed that IL-13 induces the phosphorylation of STAT-6 that directly binds ST6GALNAC1 promoter resulting in its transcription activation and protein over-expression. On the other hand, CCL17 activates ST6GALNAC1 expression via NF-kB pathway signaling. Our findings revealed a novel cross-talk between M2-like macrophages and inflamed and malignant colon cells that contributes to the pathogenesis of colitis and progression to CACC.
Antigen processing and autophagy function in adjuvant treated dendritic cell
Authors: Hashimoto Kahoko , Ootomo Takuya , Hasegawa Akihiro , Kotera Ryoma , Kobayashi Daichi , Nakayama Toshinori 
Published: January 2023

Abstract
Dendritic cell (DC) and macrophage are the powerful antigen presenting cells. These show remarkable antigen processing function. It has been reported that antigen processing is enhanced by adjuvant. In DC and macrophage, LPS or IFNγ induces cell proliferation, cytokine production, antigen presentation to naive T cell. Among DC subset, CD8 positive DC enhances autophagy function especially in cross presentation. It is still nuclear how DC processes antigen by ubiquitin proteasome pathway or by autophagy pathway. To induce more effective immune response on vaccination or immune therapy, we study the effect of adjuvant treatment for autophagy function in DC and macrophage. Three types of different culture condition were used to establish DC subsets and compared to those function of macrophage. Then analyzed the antigen processing capacity as well as the autophagy function.
We induced DC in vitro culture with GM-CSF, GM-CSF with IL-4, GM-CSF with IL-15, then stimulated DCs or macrophage by using LPS or IFNγ for up to 24 hours before antigen uptake. On antigen uptake and processing, GM-CSF induced or GM-CSF with IL-15 induced DC showed antigen processing, however GM-CSF with IL-4 induced DC showed active antigen processing within 60 min. Contrary to active antigen processing, GM-CSF with IL-14 –DC did not show any inducible effect after adjuvant treatment, but GM-CSF or GM-CSF with IL-15-DC increased the autophagy function. On the other hand, macrophage could not obtain autophagy effect thorough adjuvant treatment. DCs were studied the gene expression of cytokines, cell surface molecules such as co-stimulation molecules, mannose receptor, to evaluate antigen uptake capacity, processing pattern and autophagy.
Batf3-dependent Dendritic Cells are Required to Present Cell-associated Antigen to CD4 T Cells
Authors: Ferris Stephen T , Durai Vivek , Wu Renee , Murphy Theresa L , Murphy Kenneth M 
Published: January 2023

Abstract
Dendritic cells (DCs) are required to prime T cells during an immune response. The dogma in the field is that Batf3-dependent DCs (DC1s) prime CD8 T cells and IRF4-dependent DCs (DC2s) prime CD4 T cells. However, recent studies have shown that DC1s are required for induction of Th1 immune responses and to prime autroreactive CD4 T cells in the NOD mouse model of diabetes. Therefore, this segregation of priming theory is flawed. To further study the contribution of DC1s to CD4 T cell priming, we generated an XCR1-cre mouse and crossed it to the MHC class II floxed mouse to generate MHC class II deficient DC1s. We found that the form of antigen directs the priming of T cells. DC2s are superior at presenting soluble antigen as evidenced by normal CD4 and CD8 OVA specific T cell responses in mice lacking DC1s. However, DC1s are superior at presenting cell-associated antigen as evidenced by a lack of OVA specific CD4 and CD8 T cell priming in mice lacking DC1s. Furthermore, CD4 priming during tumor immune responses is absent when DC1s lack MHC class II. Our findings show that the DC subsets differ in the form of antigen that they present. DC1s present cell-associated material; whereas DC2s present soluble antigen.
Loss of gut barrier integrity triggers autoimmune diabetes through microbiota-induced activation of islet-reactive T cells
Authors: Falcone Marika , Sorini Chiara , Cosorich Ilaria , Conte Marta Lo , Facciotti Federica , Sanvito Francesca , Ferrarese Roberto , Canducci Filippo 
Published: January 2023

Abstract
Recent evidence suggests that the intestinal environment and, specifically, modifications of the microbiome profile, regulate the pathogenesis of extra-intestinal autoimmune diseases such as Type 1 Diabetes (T1D) by inducing intestinal inflammation and increasing gut permeability. Although low-grade intestinal inflammation and alterations of gut barrier integrity are found in humans and animal models of T1D, a direct causal link between enteropathy and triggering of beta cell autoimmunity is yet to be established. Here we show that breakage of the gut barrier integrity (by low-dose DSS administration) in BDC2.5XNOD mice carrying a transgenic TCR specific for a beta cell-autoantigen leads to activation of the islet-reactive T cell clone (BDC2.5) within the gut mucosa and onset of T1D. The intestinal activation of islet-reactive T cells requires the presence of gut microbiota and is abolished when mice are depleted of endogenous commensal microbiota. Importantly, we found that gut microbial antigens are directly capable to activate the diabetogenic BDC2.5 T cells with a TCR-mediated mechanism. Our results indicate that loss of the intestinal barrier continuity is directly responsible for activation of islet-specific T cells by commensal gut microbiota and provide a strong rationale to design innovative therapeutic interventions in “at risk” individuals aimed at restoring gut barrier integrity to prevent T1D.
Impact of genetic polymorphisms on human immune cell gene expression
Authors: Schmiedel Benjamin J , Singh Divya , Madrigal Ariel , Valdovino-Gonzalez Alan G , White Brandie M , Zapardiel-Gonzalo Jose , Ha Brendan , Altay Gokmen , Greenbaum Jason A , McVicker Graham , Seumois Grégory , Rao Anjana , Kronenberg Mitchell , Peters Bjoern , Vijayanand Pandurangan 
Published: January 2023

Abstract
While many genetic variants have been associated with risk for human diseases, how these variants affect gene expression in various cell types remains largely unknown. To address this gap, the DICE (database of immune cell expression, expression quantitative trait loci (eQTLs), and epigenomics) project was established. Considering all human immune cell types and conditions studied, we identified cis-eQTLs for a total of 12,254 unique genes, which represent 61% of all protein-coding genes expressed in these cell types. Strikingly, a large fraction (41%) of these genes showed a strong cis-association with genotype only in a single cell type. We also found that biological sex is associated with major differences in immune cell gene expression in a highly cell-specific manner. These datasets will help reveal the effects of disease risk-associated genetic polymorphisms on specific immune cell types, providing mechanistic insights into how they might influence pathogenesis (https://dice-database.org).
Idiopathic inflammatory myopathy patients with different autoantibody exhibit unique peripheral blood T cell subsets
Authors: Li Ju-Pi , Chang Shih-Hsin , Tsay Gregory J , Chen Der-Yuan , Lan Joung-Liang 
Published: January 2023

Abstract
Idiopathic inflammatory myopathy (IIM), a heterogeneous group of systemic autoimmune diseases, is characterized clinically by weakness of skeletal muscle. Patients with IIM often show a myositis-specific autoantibody (MSA) such as anti-melanoma differentiation-associated gene-5 (MDA5 group) or anti-aminoacyl-tRNA synthetase (ARS group, including Jo-1, EJ, PL-12, PL-7, OJ, and KS), indicating that the adaptive immune system may alter in IIM patients. T cells (CD3+) play important roles in regulation of the adaptive immune system and usually subdivide into naïve cells (TN) and memory T cells (TM). Based on the surface expression of different cell markers, TM cells can be divided into central memory T (TCM, CD45RA−CD62L+) and effector memory T (TEM, CD45RA−CD62L−) cells. After antigenic stimulation, a subset of TEM cells re-expresses CD45RA, called TTEMRA. Here we examined peripheral blood T cell subsets in MDA5 group (n=22), ARS group (n=34) and healthy control individuals (HC group, n=30) using flow cytometry analysis. We found that TTEMRA population was increased in MDA5 group. TN population was reduced and TTEMRA population was enhanced in ARS group. Th17 and Th1 cells were more abundant in MDA5 and in ARS group, respectively. Treg cells was increased in both of MDA5 and ARS group. In addition, in MDA5 group, death patients (n=5) had fewer Treg cells compared with alive patients (n=17), suggesting reduced Treg cells may be associated with mortality. Therefore, peripheral blood T cell subsets may be correlated with specific clinical manifestations for IIM patients with distinct MSA.
Novel roles of lipid mediators in psoriatic skin inflammation
Authors: Sumida Hayakazu , Kita Yoshihiro , Shimizu Takao , Sato Shinichi 
Published: January 2023

Abstract
Psoriasis is a common chronic inflammatory cutaneous disease thought to arise as a result of infiltration of inflammatory cells and activation of keratinocytes. Psoriasis has been considered as a classical Th1 disease; however, Th17 cells are attracting much interest. Previous knowledge on the pathology of psoriasis has been obtained mostly through the study of human data and samples. In addition, recently developed animal models for psoriatic skin inflammation recapitulates the hallmarks of human psoriasis and provide us new insights on psoriasis. Lipid mediators and their receptors regulate a variety of physiological processes and involved in multiple pathologies including immune-related diseases. Here, we explored novel lipid mediators involved in psoriatic skin inflammation using clinical samples and imiquimod-induced psoriasis model. In particular, mass spectrometry analysis for multiplex quantitation of eicosanoids using imiquimod-treated murine skin samples revealed unique kinetics of various lipid mediators in the time-series from early induction phase to chronic resolution phase. These data motivated us to focus on some lipid mediators such as leukotriene B4 (LTB4) and prostaglandin E2 (PGE2). As an example, BLT1 (known as LTB4 receptor) and CXCR2 have been revealed to coordinately promote neutrophil infiltration into the skin during the early phase of imiquimod-induced inflammation. Further analysis on PGE2 is in progress and some data indicates the novel functions of PGE2 and mPGES-1, an upstream enzyme for PGE2 production, in the pathogenesis in psoriasis. These insights may aid in the rational design of novel treatments for broad spectrum of inflammatory and immune disorders beyond psoriasis.
Role of CD137L in lumbar spinal cord microglial cytokine responses following sciatic nerve crush
Authors: Cao Ling 
Published: January 2023

Abstract
Previously, we showed that CD137 ligand (CD137L; AKA 4-1BBL) contributes to the development of behavioral hypersensitivity and functional recovery in mice following peripheral nerve injury-induced neuropathic pain. Mice that lack CD137L showed reduced sensory sensitivity and faster functional recovery. Here, we sought to further investigate the potential involvement of lumbar spinal cord microglial responses in CD137L-mediated behavioral changes following sciatic nerve crush. Lumbar spinal cord microglia were isolated from both wild type B6 and CD137L knockout (KO)_B6 mice via positive selection based on CD11b expression using magnetic beads at days 0 (naïve), 3, 7, 14, 28 and 56 following sciatic nerve crush or sham surgery. Following RNA extraction, qRT-PCR were performed to examine cytokine/chemokine expression in isolated microglia. Our preliminary results suggest that male mice had more measurable cytokine/chemokine responses than female mice. Despite that many cytokines are below the detection levels, we were able to observe increased expression of several chemokines, CCL2, CCL3, CCL4 and CCL5 in microglia from CD137L KO mice, which appeared to peak early following injury (Days 3–14) than that in microglia isolated from WT mice. Future study will determine the involvement of microglial chemokine responses in CD137L mediated sensory hypersensitivity and delayed functional recovery following peripheral nerve injury.
The effects of altered TGFβ signaling on human T follicular helper cell development and function
Authors: Schmiechen Zoe C , Weissler Katherine , Laky Karen , Guerrerio Pamela 
Published: January 2023

Abstract
T follicular helper (Tfh) cells are a subset of CD4+ T cells that play a crucial role in the development of memory B cells and plasma cells. T follicular regulatory (Tfr) cells oppose Tfh cells and suppress humoral immune responses. Patients with Loeys-Dietz Syndrome (LDS) type 1 and 2 have an autosomal dominant mutation in the genes encoding TGFβ Receptor 1 or 2, respectively, and have a strong predisposition to develop allergic diseases. We hypothesized that altered development and function of Tfh cells could contribute to increased IgE-mediated allergic phenotypes in LDS. Comparing a cohort of pediatric LDS patients with age-matched healthy volunteers, we found that LDS patients have significantly higher levels of serum IgE and IgG and lower levels of IgM. Congruently, LDS patients have an increased frequency of memory T cells, Th2 cells, and Tfh cells and a significantly lower frequency of Tfr cells. The increase in Tfh cells in LDS was restricted to the CCR4+ CCR6− subset, which has been associated with Th2 immune responses. In vitro, Tfh cells from LDS patients co-cultured with autologous naïve B cells demonstrated a greater ability to induce plasma cell differentiation compared to age-matched healthy volunteers. Additionally, naïve CD4+ T cells from LDS patients cultured in the presence of recombinant TGFβ1 and IL-12 or IL-4 were more likely to differentiate into Tfh cells compared to healthy age-matched controls, suggesting a cell-intrinsic propensity for naïve CD4+ T cells in LDS patients to acquire a Tfh fate. Collectively, our data suggest that LDS mutations alter the development and function of Tfh cells in a manner that promotes IgE-mediated disease.
FcγRIIB on CD11c+ cells alters liver and adipose tissue inflammation affecting glucose tolerance and atherosclerosis in female mice
Authors: Marvin Jennifer , Balsamo Joseph A , Rhoads Jillian P , Major Amy S 
Published: January 2023

Abstract
Circulating levels of oxidized lipoprotein (oxLDL) correlate with myocardial infarction (MI) risk. Previous work demonstrates that oxLDL immune complexes can signal through FcγRs on bone marrow-derived dendritic cells (BMDCs), enhancing their activation and inflammatory cytokine secretion. While global FcγR−/− studies show that activating FcγRs are proatherogenic, the role of inhibitory FcγRIIb is unclear. We sought to determine the role of DC-specific FcγRIIb on atherosclerosis and glucose tolerance, as both are important MI risk factors. Bone marrow chimeras were generated by rescuing lethally irradiated female Ldlr−/− mice with hematopoietic cells from littermate CD11c-Cre+or CD11c-Cre− Fcgr2bfl/fl donors. Four weeks after transplant, recipients were placed on a Western diet for eight weeks. Quantitation of atherosclerosis in the proximal aorta demonstrated a 58% increase CD11c− Cre+ Fcgr2bfl/fl recipients. We discovered that hepatic cholesterol, scavenger receptor CD36, and MHC Class II were increased on CD11c+CD11b+ cells in CD11c-Cre+ Fcgr2bfl/fl recipients. Furthermore, study of aortic draining lymph nodes revealed a 50% reduction in TREGS. To study glucose tolerance, six-week-old CD11c-Cre+ and CD11c-Cre− Fcgr2bfl/fl mice were placed on a 60 kcal% fat diet. Despite similar weight gain, CD11c-Cre+ Fcgr2bfl/fl mice were significantly more glucose intolerant after six weeks. Analysis of white adipose tissue (WAT) demonstrated a two-fold increase in pro-inflammatory AT DCs with increased MHC Class II and CD86. Collectively, these results demonstrate that the absence of FcγRIIb on CD11c+ cells results in increased liver and AT inflammation, influencing atherogenesis and development of glucose intolerance.
BeO-exposure induces B cell-mediated Noninfectious Granuloma Formation in the Lung
Authors: Atif Shaikh M , Mack Douglas , McKee Amy S , Rangel-Moreno Javier , Martin Allison K , Getahun Andrew , Maier Lisa A , Cambier John C , Tuder Rubin M , Fontenot Andrew P 
Published: January 2023

Abstract
Susceptibility to chronic beryllium disease (CBD)is linked to HLA-DP molecules possessing a glutamic acid at the 69thposition of the β-chain (βGlu69), with the most prevalent βGlu69-containing molecule being HLA-DP2. We have previously shown that exposure of HLA-DP2 transgenic mice to beryllium oxide (BeO) results in the development of mononuclear infiltrates in a peribronchovascular distribution and a beryllium-specific, HLA-DP2-restricted CD4+T cell response. In addition to T cells, B cells constituted a major portion of infiltrated leukocytes in the lung of BeO-exposed HLA-DP2 Tg mice and were localized within ectopic lymphoid aggregates and granulomas. B cell depletion had no effect on the development of Be-specific CD4+T cells. However, B cell depletion was associated with a loss of lymphoid aggregates and granulomas as well as a significant increase in lung injury in BeO-exposed mice compared to the isotype-treated group. Furthermore, B cell recruitment to the lung was independent of antigen and dependent on MyD88 signaling through the secretion of CXCL13. Adoptively-transferred WT B cells into BeO-exposed μMT mice significantly reduced lung injury. B cells also surrounded granulomas in transbronchial biopsies from CBD patients, confirming a role for B cells in CBD. Overall, our data suggest a novel modulatory role for B cells in the formation of granulomas and lymphoid aggregates, resulting in the protection of the lung against sterile particulate exposure.