bluuebunny/crossref_metadata_2025_split huggingface dataset:
NET formation induced by gout-associated monosodium urate crystals requires IL-8-mediated neutrophil migration and is inhibited by the P2Y6 receptor antagonist MRS2578.
Authors: Sil Payel , Hayes Craig , Reaves Barbara , Sokolove Jeremy , Rada Balazs 
Published: January 2023

Abstract
Human neutrophils generate inflammatory responses within the joints of gout patients upon encountering Monosodium Urate (MSU) crystals. Studies (including ours) show that neutrophil extracellular traps (NETs) are found abundantly in the synovial fluid (SF) of gout patients and are crucial for the onset of the autoinflammatory cascade. Our goal is to shed light on possible roles of purinergic signaling and neutrophil migration in mediating in vitro NET formation induced by MSU crystals.
Our data show that gout SF supernatants have significantly higher levels of the neutrophil granule markers, myeloperoxidase (MPO) and human neutrophil elastase (HNE), and NETs than SF specimens from MSU-negative osteoarthritis patients. MSU crystal-triggered NETs in human neutrophils contain active DNA-bound MPO and HNE. MRS2578, a purinergic P2Y6 receptor antagonist, reduces the release of extracellular DNA, MPO and HNE in MSU crystal-stimulated neutrophils. Releases of MPO, HNE and NETs were measured by commercial ELISA and our proprietary NET-DNA ELISA assays. We found that MRS2578 reduces MSU crystal-induced IL-8 release, neutrophil chemotaxis and characteristic formation of DNA aggregates. The store operated calcium entry (SOCE) channel inhibitor (SK96365) blocked MSU crystal-induced NET release. Our results indicating that the P2Y6-SOCE-IL-8 axis is involved in MSU crystal-induced NET formation provide a novel mechanism potentially relevant in gout inflammation. Our work on the role of the P2Y6-SOCE-IL-8 axis in MSU crystal-triggered NET formation could potentially lead to a better understanding of the mechanism of gout joint inflammation and, thereby, help in improving the care of gout patients.
The transcription factor HIF1α controls expression of the cytokine IL-22 in CD4 T cells
Authors: Zenewicz Lauren A , Budda Scott A , Girton Alanson 
Published: January 2023

Abstract
IL-22 is expressed by activated lymphocytes and is important in modulation of tissue responses during inflammation. The cytokine induces proliferative and anti-apoptotic pathways in epithelial cells allowing enhanced cell survival. This can have positive effects, such as in the maintenance of epithelial barriers in the gastrointestinal tract, but also negative effects, such as contributing to colorectal tumorigenesis. As IL-22 can be dual-natured, we hypothesized that its biological activity should be tightly regulated in order to limit IL-22 expression to the sites of inflammation. One such environmental cue could be low oxygen, which often accompanies inflammation. We show that in CD4 T cells IL-22 expression is upregulated in hypoxia, and this upregulation is dependent on the transcription factor hypoxia-inducible factor 1α (HIF1α). This finding has implications on the regulation of Il22 gene expression and the cytokine’s presence in different inflammatory environments.
Wnt/β-catenin signaling regulates IL-15-mediated terminal maturation and interferon-gamma production of invariant NKT cells.
Authors: Pyaram Kalyani , Chang Cheong-Hee 
Published: January 2023

Abstract
The Wnt/β-catenin signaling pathway is important for various cellular functions including survival and proliferation. The indispensable role of this pathway in conventional T cell development is well established but little is known about its role in innate T cell development. In this study, we investigated the role of the Wnt/β-catenin signaling in the development of invariant natural killer T (NKT) cells using mice that express a constitutively active form of b-catenin (CAT-Tg) or deficient in β-catenin (CAT-KO). Thymic NKT cells were increased in CAT-Tg and decreased in CAT-KO mice compared to their wild type littermates. Thymic NKT cells progress from Stage 0 to Stage 3 as they mature. In the absence of Wnt signaling (CAT-KO), we observed accumulation of Stage 0 NKT cells. In contrast, in CAT-Tg mice, the final maturation was compromised - more Stage 2 but less Stage 3 NKT cells. Thus, stage-specific regulation of Wnt signaling may be critical for the thymic NKT development. Indeed, endogenous β-catenin expression was high in early stages but low in late stages, suggesting that its reduction mounts the stage-2 to -3 NKT transition. The CAT-Tg mice also had lower number of IFN-gamma expressing NKT cells, which, in these cells, correlated with reduced expression of transcription factor Tbet and CD122 (IL-2R & IL-15R subunit), requisites for final maturation and IFN-gamma expression of NKT cells. Further, although PLZF, a master transcription factor for NKT cell development is expressed at high levels in CAT-Tg NKT cells, Wnt signaling-mediated NKT cell maturation was found to be independent of PLZF. Together, our data shows that regulation of Wnt/β-catenin signaling is necessary for terminal maturation and IFN-gamma production of NKT cells.
Bone marrow fat induces inflammation that inhibits B lymphopoiesis
Authors: Kennedy Domenick Edward , Knight Katherine L 
Published: January 2023

Abstract
Adipocytes accumulate in the bone marrow (BM) during aging and obesity, correlating with decreased B lymphopoiesis. We previously found that adipocyte factors induce MDSCs, which in turn inhibit B lymphopoiesis via IL-1 production. In this study, we asked what adipocyte factor(s) promotes MDSC accumulation. By cytokine array, we found that adipocyte conditioned medium (ACM) contains inflammatory cytokines known to induce MDSCs (ex. IL-6, G-CSF, C3a). These and other adipocyte factors can activate the NLRP3 inflammasome, leading us to test if blocking NLRP3 activation would prevent MDSC accumulation. Cultures of mouse BM progenitors with OP9 cells in the presence of ACM yielded many MDSCs and few B lineage cells. However, glybenclamide (NLRP3 inhibitor) treatment reduced MDSC accumulation and increased B lymphopoiesis, suggesting that adipocyte factors induce MDSCs through inflammasome activation. Adipocytes fill the BM of rabbits by 2 months of age, a time when B lymphopoiesis is arrested. To determine if the arrest of B lymphopoiesis could be due to adipocyte-initiated BM microenvironmental changes, we co-cultured BM progenitors and OP9 cells with or without conditioned medium generated from BM fat explants (BM fat-CM) taken from &gt;2 month old rabbits. These cultures resulted in decreased numbers of B lineage cells and increased numbers of myeloid cells, similar to the myeloid skew seen in BM of &gt;2 month rabbits. We conclude that rabbit BM fat can initiate the loss of B cell development. Strategies to modulate BM fat volume and inflammatory state could be useful for boosting B lymphopoiesis in the aging and obese populations.
Effects of treatment guidelines for the management of anaphylaxis on patient and caregiver adherence
Authors: Brown Duncan , Locklear Julie , Karjalainen Martin , Lehnigk Ulrike , Saathoff Friederike 
Published: January 2023

Abstract

OBJECTIVE
Treatment guidelines recommend a prescription for two doses of an epinephrine auto-injector (EAI) be given at discharge following an anaphylactic event and patients carry these at all times to ensure timely access to epinephrine. However, previous research suggests approximately 30% of patients will not carry any EAI, and of those that do, approximately 10% have expired. This web-based US survey aims to understand patients’ and caregivers’ adherence to these proposed treatment guidelines.

METHODS
159 patients aged 18–65 years (M= 29.7; 32.1% male) and 215 caregivers of individuals under aged 18 years (M = 23.3; 39.5% male) participated in the survey. All participants had been prescribed an EAI for self-administration or for administration as a caregiver. The survey took place between November 15 and November 30, 2015.

RESULTS
18.2% of patients and 15.4% of caregivers did not store a single EAI at home; 61.0% of patients and 62.8% of caregivers indicated only one EAI was available at home. 83.0% of patients did not have access to an EAI at work and 35.8% of caregivers reported their child did not have access to an EAI at school. Only 8.0% of caregivers indicated two EAIs were available for their children at school. Caregivers were more likely to identify lack of training as the cause of an error compared to patients (p=0.02). No difference was identified for EAI compliance between those treating anaphylaxis with an EAI and those who have not used an EAI.

CONCLUSION
This survey revealed a suboptimal adherence to proposed treatment guidelines on the part of patients and caregivers. The findings bring into question the reliability of current education systems and safety information delivered by healthcare providers and retained by EAI users.
Transcriptional profiling of mast cell and basophil responses to differential stimuli identifies unique gene signatures.
Authors: Chhiba Krishan D , Hsu Chia-Lin , Berdnikovs Sergejs , Bryce Paul J 
Published: January 2023

Abstract
Mast cells (MC) and basophils (BΦ) are key effector cells in allergy that are developmentally related. Functionally, they both release mediators like histamine and granule proteases. However, studies also suggest that MC and BΦ have non-redundant roles in allergic diseases. Their ability to respond to IL-33—an epithelium-derived cytokine that helps initiate allergic inflammation—is not well understood. To fully characterize the transcriptional responses and heterogeneity of MC and BΦ, we performed large-scale comparative microarrays of bone marrow-derived mast cells (BMMCs) and basophils (BMBs) either at rest, upon IgE activation, or upon IL-33 activation. Hierarchical clustering demonstrated that BMMCs had activation-specific transcriptional signatures. IgE-crosslinking upregulated 1803 unique genes including Ccl7, Fxyd6, and Cd33; while IL-33 stimulation induced 1918 genes including Il1b, Cd72, and Tnfaip2. Focused bioinformatics pathway analysis demonstrated IgE-activation aligned with pathways relating to complement activation and CD137 signaling, while IL-33 initiated responses in the NF-κB and IL-10 signaling pathways. Furthermore, BMBs activated via IgE-crosslinking induced type 2 immune response genes like Il2, Il4, Ccl17 and Il13 which were surprisingly absent in IL-33 stimulated BMBs. Further analysis revealed cell-specific transcriptional signatures with 4360 genes that were significant in BMBs but not in BMMCs after IgE activation, and 1645 after IL-33 stimulation. Here we show that MC and BΦ have cell-specific and activation-specific transcriptional responses, and our data suggest novel gene networks and pathways that may shape how the immune system responds to allergens and innate cytokines.
Biological markers of infection may assist in the identification of early stage viral infection and serve as a surrogate biomarker to identify asymptomatic Ross River or Barmah Forest virus infection
Authors: Dean Melinda M , Dunford Melanie , Flower Robert L , Faddy Helen M 
Published: January 2023

Abstract

Background and Aims
Although Ross River virus (RRV) and Barmah Forest virus (BFV) pose a risk to transfusion safety, in Australia, blood donations are not screened for either. RRV and BFV pathogenesis is poorly understood; however, mannose binding lectin (MBL) levels have been associated with RRV disease severity. We investigated biological markers to identify early stages of infection in asymptomatic RRV or BFV infection.

Methods
Samples from 7001 blood donations from donors at risk for RRV and/or BFV were tested for anti-RRV (IgM) and/or anti-BFV (IgM). MBL level was assessed in 139 anti-RRV (IgM) positive samples, 143 anti-BFV (IgM) positive samples and clinical samples (10 RRV, 10 BFV). MCP-1, MIG, TNF-α, IFN-α, IFN-γ, IL-8, IL-10 and IP-10 were quantified in these samples and 50 seronegative samples.

Results
Anti-RRV (IgM) was detected in 2.3%, and anti-BFV (IgM) in 2.4%, of donations, consistent with asymptomatic infection. MBL deficiency was not associated with seropositivity, but higher MBL levels were evident in RRV patients. IP-10, MIG, MCP-1 and IL-8 were elevated in RRV patients and IFN-γ, MCP-1 and IL-8 higher in BFV patients. For both anti-RRV (IgM) and anti-BFV (IgM) positive donations, IL-8 was elevated compared to IgM negative donors. All statistical analysis unpaired T-test, 95% CI.

Conclusions
Asymptomatic RRV or BFV infection occurs in blood donors. The frequency of MBL deficiency was similar between samples from clinical and presumed asymptomatic RRV or BFV infection. Measurement of IL-8 may assist in the identification of early stage viral infection and function as a surrogate biomarker for early stage RRV or BFV infection.
Chronic STING-dependent activation of TBK1 suppresses mTORC1 activity and dysregulates cellular metabolism in mice
Authors: Gonugunta Vijaya Kumar , Hasan Maroof , Dobbs Nicole , Ali Aktar , Palchik Guillermo , Calvaruso Maria , DeBerardinis Ralph J , Yan Nan 
Published: January 2023

Abstract
Trex1−/− mice suffer from systemic inflammation caused largely by chronic activation of the cGAS-STING-TBK1-IRF3 signaling pathway. We showed previously that Trex1-deficient cells have reduced mTORC1 activity, although the underlying mechanism is unclear. Here, we performed detailed metabolic analysis in Trex1−/− mice and cells that revealed defects in mitochondrial respiration, reduced adiposity, increased energy expenditure and glycolysis. We also found that Trex1−/− mice and cells exhibit chronically suppressed mTORC1 activity. Furthermore, we provide genetic evidence corroborated with cellular and biochemical validation to show that metabolic dysregulation in Trex1−/− mice is caused by STING-dependent activation of TBK1, but not the downstream IRF3-mediated signaling and inflammation, and that TBK1 binds to the mTORC1 complex and inhibits its activity in Trex1−/− cells. Our data thus establish chronic STING-dependent activation of TBK1 as a novel regulatory axis of mTORC1 and cellular metabolism.
Macrophage-mediated lysine methyltransferase, Setdb2, regulates inflammation in wound healing
Authors: Kimball Andrew S , Joshi Amrita , Allen Ron , Bermick Jennifer , Schaller Matthew , Carson Beau , Kunkel Steven L , Gallagher Katherine 
Published: January 2023

Abstract
Epigenetic regulation of macrophages can alter their function and impact tissue inflammation and wound repair. Unregulated inflammation at the wound level in inflammatory diseases like type 2 diabetes (T2D) leads to significant morbidity and mortality. Recent work by our group and others has shown that chromatin-modifying enzymes influence inflammatory gene expression in macrophages and other immune cells. Here we show that Setdb2, a histone methyltransferase, is induced in macrophages during the inflammatory phase of wound healing. Specifically, Setdb2 repressed expression of NF-κB-induced inflammatory genes, including IL-1B. This coincided with occupancy by Setdb2 at the IL-1B promoter, which in the absence of Setdb2 displayed diminished trimethylation of histone 3 lysine 9 (H3K9me3) in bone marrow derived macrophages (BMDM). Mice with the inability to upregulate setdb2 in their macrophages (Setdb2f/fLyz2cre+) demonstrated impaired healing during the inflammatory phase of wound healing. This corresponded with decreased H3K9me3 at the promoter of IL-1B and other inflammatory genes in macrophages isolated from the wounds of these animals. Further, LPS was able to upregulate setdb2 expression in BMDM and hence TLR4 signaling may play a role in regulation of inflammation in wound tissue. This suggests that a Setdb2-mediated alteration of NF-κB pathways represents an important mechanism for successful wound healing.
Thiostrepton inhibits psoriasis-like inflammation induced by TLR7, TLR8, and TLR9
Authors: Lai Chao-Yang , Yeh Da-Wei , Lu Chih-Hao , Liu Yi-Ling , Huang Li-Rung , Kao Cheng-Yuan , Chen Huan-Yuan , Huang Chi-Ying F. , Chang Chung-Hsing , Luo Yunping , Xiang Rong , Chuang Tsung-Hsien 
Published: January 2023

Abstract
Toll-like receptors 7, 8 and 9 (TLR7-9) comprise a subfamily of TLR. Activation of these TLRs has been linked to the pathogenesis of autoimmune diseases such as rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), and psoriasis. Thus antagonists of these TLRs are being investigated for their therapeutic applications on these diseases. Bortezomib is a proteasome inhibitor known to suppress activation of these TLRs. This drug is approved for the treatment of multiple myeloma, and its inhibitory effects on autoimmune disorders such as psoriasis, RA, and SLE have also been investigated in animal models. In an attempt to develop novel TLR7-9 inhibitors, we searched the Gene Expression Omnibus database for gene expression profiles in cells treated with bortezomib. These profiles were then used as an input to screen the Connectivity Map database for chemical compounds with similar functions as bortezomib. Here we report that the antibiotic thiostrepton is a novel TLR7–9 inhibitor. Like bortezomib, thiostrepton effectively inhibits TLR7–9 activation in cell-based assays and dendritic cells. In contrast to bortezomib, thiostrepton is less cytotoxic to dendritic cells, and its inhibitory activity is more specific to TLR7–9. Thiostrepton inhibits TLR9 localization in endosomes for activation via two mechanisms. One mechanism is similar to the proteasome inhibitory function of bortezomib, and the other is through inhibition of endosomal acidification. In different animal models, thiostrepton attenuated LL37- and imiquimod-induced psoriasis-like inflammation. These results indicated that thiostrepton is a novel and specific inhibitor to TLR7–9.
IL-10 Producing Regulatory B cells are Decreased and Functional Impaired in Myasthenia Gravis
Authors: Sheng JianRong , Soliven Betty 
Published: January 2023

Abstract
Myasthenia gravis (MG) is a prototype of antibody-mediated neuromuscular disease causing fluctuating weakness and disability. Experimental autoimmune MG (EAMG) is an animal model of human MG. In our previous study, adoptive transfer of CD1dhiCD5+B cells expanded in vivo by GM-CSF prevented and suppressed EAMG; and IL-10 production within CD1dhi CD5+ B cells played an important role in immune regulation of EAMG. In this study, we aimed to analyze the frequency and function of these regulatory B (Bregs) subsets (CD38hi CD24hi and CD5+ CD1dhi) in MG patients and healthy controls. We found that MG patients had lower frequencies of Breg subsets (CD38hi CD24hi and CD5+ CD1dhi), and lower percentages of B10 cells within each subset compared to controls. Depletion of CD38hi CD24hiB cell subset from the PBMCs of MG patients did not lead to any significant increase in the percentage of CD4+ IFNγ and CD4+ TNFα, in contrast to healthy controls. We concluded that IL-10 producing regulatory B cells were decreased and functional impaired in MG patients, which might suggest a crucial role of Bregs in the development of MG.
Mouse Fcgamma Receptor IV dependent inflammatory cytokine and chemokine response contributes to progression of atherosclerosis in apoE hyperlipidemic mice
Authors: Nagarajan Shanmugam , Zhu Xinmei , Feck Doug , Popovic Bane , Velayutham Murugesan 
Published: January 2023

Abstract
Fcgamma receptors (FcγRs) are classified as activating (FcγRI, III, and IV) and inhibitory (FcγRII) receptors. Others and we have demonstrated that combined deficiency of all the three activating FcγRs (I, III and IV) in apolipoprotein E (apoE)-Fcγ chain double knockout (dKO) mice decreased atherosclerosis. In this report, we investigated the independent role of FcγRI and FcγRIV in the progression of atherosclerosis. We tested the hypothesis that FcγRI and FcγRIV exacerbate atherosclerosis using apoE-FcγRI dKO and apoE-FcγRIV dKO mice. Our results show that arterial lesions were not different between apoE-FcγRI dKO and apoE knockout (apoE KO) mice. Interestingly, arterial lesions were significantly decreased in a regular chow or a high-fat diet fed apoE-FcγRIV dKO male and female mice, relative to apoE KO mice. Bone marrow chimeras were used to address the relative contribution of FcγRIV expressed on hematopoietic cells including macrophages and dendritic cell. ApoE KO mice transplanted with apoE-FcγRIV dKO marrow showed significantly reduced arterial lesions relative to recipient mice transplanted with apoE KO marrow. Next, we investigated whether pro-inflammatory response contributed to the pro-atherogenic effect of FcγRIV. Activated CD4+ T cells of apoE-FcγRIV dKO mice showed increased secretion of IL-10, whereas IFN-γ and IL-17 by T cells were decreased. Interestingly, dendritic cells at the lesion-prone vascular site from apoE-FcγRIV dKO mice induced increased IL-10 secretion by LDL-specific T cells. Collectively, our findings suggest that the pro-inflammatory responses initiated by FcγRIV, one of the activating FcγRs, contribute to the progression of atherosclerosis. Supported by NIH grant HL086674.
Single-walled carbon nanotubes disturbed the immune and metabolic regulation function on 13-weeks after a single intratracheal instillation
Authors: Park Eun-Jung , Hong Young-Shick , Lee Byoung-Seok , Yoon Cheolho , Jeong Uiseok , Kim Younghun 
Published: January 2023

Abstract
Due to their unique physicochemical properties, the potential health effects of single-walled carbon nanotubes (SWCNTs) have attracted continuous attention together with their extensive application. In this study, we aimed to identify local and systemic health effects following long pulmonary persistence of SWCNTs. As expected, SWCNTs remained in the lung on 13-weeks after a single intratracheal instillation (50, 100, and 200 μg/kg). In the lung, the number of total cells and the percentages of lymphocytes and neutrophils were significantly raised at 200 μg/kg dose compared to the control, and Th1-polarized immune response was induced accompanying an enhanced expression of tissue damage-related genes and an increased release of chemokines. Additionally, SWCNTs enhanced the expression of antigen presentation-related proteins on the surface of antigen-presenting cells, but maturation of dendritic cells was inhibited by their long persistence. As compared to the control, the significant increase in the percentage of neutrophils in WBC and the remarkable decrease of BUN and potassium level were observed in the blood of mice treated with the highest dose accompanied by the down-regulation in the expression of antigen presentation-related proteins on splenocytes. Moreover, protein and glucose metabolism was disturbed with an up-regulation of fatty acid β-oxidation. Taken together, we conclude that SWCNTs may induce adverse health effects by disturbing the immune and metabolic regulation function in the body. Therefore, careful application of SWCNTs is necessary for the enforcement of safety in nano-industries.