bluuebunny/crossref_metadata_2025_split huggingface dataset:
The tumor necrosis factor superfamily member RANKL suppresses effector cytokine production in group 3 innate lymphoid cells
Authors: Bando Jennifer , Gilfillan Susan , Song Christina , McDonald Keely G , Huang Stanley C-C , Newberry Rodney D , Kobayashi Yasuhiro , Allan David , Carlyle James R , Cella Marina , Colonna Marco 
Published: January 2023

Abstract
While signals that activate group 3 innate lymphoid cells (ILC3s) have been described, the factors that negatively regulate these cells are less well understood. Here we found that the tumor necrosis factor (TNF) superfamily member receptor activator of nuclear factor kB ligand (RANKL) suppressed ILC3 activity in the intestine. Deletion of RANKL in ILC3s and T cells increased C-C motif chemokine receptor 6 (CCR6)+ ILC3 abundance and enhanced production of interleukin-17A (IL-17A) and IL-22 in response to IL-23 and during infection with the enteric murine pathogen Citrobacter rodentium. Additionally, CCR6+ ILC3s produced higher amounts of the master transcriptional regulator RORγt at steady state in the absence of RANKL. RANKL-mediated suppression was independent of T cells, and instead occurred via interactions between CCR6+ ILC3s that expressed both RANKL and its receptor, RANK. Thus, RANK-RANKL interactions between ILC3s regulate ILC3 abundance and activation, suggesting that cell clustering may control ILC3 activity.
IL-6 overexpression triggers inflammation through its only relevant receptor IL-6R
Authors: Mufazalov Ilgiz , Brandfald Michaela , Schelmbauer Carsten , Andruszewski David , Tang Yilang , Masri Joumana , Karbach Susanne , Eich Christina , Wunderlich Thomas , Korn Thomas , Bluestone Jeffrey , Waisman Ari 
Published: January 2023

Abstract
IL-6 is a pleiotropic cytokine that regulates development and function of variety immune cells. Here we used a novel mouse strain in which IL-6 can be overexpressed in a Cre-dependent manner and show that mice with CD11c-Cre mediated IL-6 overexpression succumb from systemic inflammation. High levels of IL-6 perturbed B and T cell development in primary lymphoid organs, bone marrow and thymus. Interestingly, IL-6-triggered inflammation promoted expansion of both Th17 and Treg cells, two cell types known for their reciprocal developmental requirements. However, the most dramatic increase was noted for myeloid cells, mostly neutrophils, which invaded spleen, thymus and blood of mice with IL-6 overexpression. Observed systemic inflammation ultimately led to mice mortality within 11 weeks of age. Mechanistically, IL-6 mediates its biological functions strictly through binding to IL-6R alpha chain followed by recruitment of the signal transducer gp130. Previously, an alternative pathway was suggested in which IL-6 can utilize CD5 to signal via gp130. However, when IL-6R was deleted in mice with IL-6 overexpression these mice were completely protected from IL-6- triggered pathology and fully phenocopied IL-6R deficient mice. In fact, IL-6R deficiency prevented downstream activation of STAT3 in response to IL-6. Together, our data suggest that IL-6R is the only biological relevant receptor for IL-6 in mice.
Expression and function of IL-1 receptor type 2 (IL-1RII) regulating human Th17 responses
Authors: Lee Won-Woo , Kim Dong Hyun , Cho Sunjung 
Published: January 2023

Abstract
Th17 cells are a unique subset of proinflammatory cells conferring protection against extracellular bacteria and fungi, but have been also implicated in the pathogenesis of many autoimmune diseases. IL-1β is critical for the differentiation, expansion, in vivo survival, and effector function of Th17 cells. Among components of IL-1 receptor (IL-1R), decoy IL-1RII is a negative regulator of functional IL-1RI-mediated IL-1β signaling. Given its preferential expression on Treg cells, IL-1RII has been suggested to play a role for controlling the Th17 and Treg balance. However, little is known about a molecular mechanism underlying IL-1RII expression and its contribution to modulation of Th17 responses. Here, we found that IL-1RI and IL-1RII expression were rapidly induced by memory CD4+ T cells after stimulation with TCR alone. Cyclosporin A reduced IL-1RII expression, whereas an augmented FOXP3 was associated with enhanced IL-1RII expression. This finding was corroborated by in vitro assays using NFAT inhibitor, dNP2-VIVIT and an inhibitor of FOXP3/NFAT1 interaction, peptide FOXP3 393–403. Moreover, reporter assay suggests that NFAT/FOXP3 binding sites in IL-1RII promoter are critical for its transcription. At day 2 post-stimulation, there were three distinct subsets; IL-1RI+IL-1RII−, IL-1RI+IL-1RII+, and IL- 1RI−IL-1RII− CD4+ T cells, having unique features including cytokine production profile, the expression of Tregassociated genes, and responsiveness to IL-1β, suggesting a pivotal regulatory role of IL-1RII for human Th17 responses. Our findings will be beneficial to understanding a modulatory mechanism on Th17 response and IL- 1β-mediated IL-1R signaling contributing to pathogenesis of autoimmune diseases.
Endogenous antisense RNA and dysregulation of CD39 expression in inflammatory bowel disease
Authors: Longhi Maria Serena , Harshe Rasika , Xie Anyan , Zhang Haohai , Robles Rene' J. , Mukherjee Samiran , Vuerich Marta , Moss Alan C. , Robson Simon C. 
Published: January 2023

Abstract
CD39 is an ectonucleotidase that hydrolyzes extracellular ATP/ADP to generate immunosuppressive adenosine. CD39 is expressed by Tregs, where it contributes to immunosuppression; and by a subset of effector Th17 cells where it limits pathogenicity.
CD39 is regulated at the genetic level via single nucleotide polymorphisms in non-coding regions of the gene. These are associated with decreased CD39 expression and with predisposition to Crohn’s disease. CD39 is also regulated at transcriptional level through the activation of pathways involving the aryl-hydrocarbon-receptor and O2. We have noted the presence of antisense RNA at the 3’ end of the human CD39/ENTPD1 gene. Hence, another form of regulation might be operational at post-transcriptional level and could relate to the presence of endogenous antisense RNAs.
CD39-specific antisense levels were increased in Treg and Th17 cells obtained from the peripheral blood of Crohn’s patients over controls. CD39 antisense is largely localized in the cell nucleus. CD39 expression was at low levels in both cell types in Crohn’s. When testing lamina propria-derived cells, we noted higher CD39 expression and lower antisense levels in Th17 cells isolated from non-inflamed bioptic areas over inflamed areas. Functional analysis revealed that antisense silencing by FANA oligos (AumBiotec) resulted in consequent CD39 upregulation.
In conclusion, our data indicate that regulation of CD39 antisense RNA impacts Treg suppression and Th17 cell modulation of pathogenic potential in Crohn’s disease. Inhibition/blockade of antisense should be considered as a novel therapeutic strategy to restore CD39 along with immune homeostasis in Crohn’s disease and other inflammatory conditions.
Effect of an anti-inflammation treatment on ligature-induced experimental periodontitis
Authors: Hu Anka , Pan keqing , Han Xiaozhe 
Published: January 2023

Abstract

Objective
Inflammation-related immune responses and bone metabolism lead to extensive tooth loss in periodontitis. This study is to investigate the effect of anti-inflammation treatment in vitro and on ligature-induced experimental periodontitis in vivo.

Methods
Splenocytes were isolated from C57BL/6J mice and cultured for 48 hours under the following conditions: control, lipopolysaccharide (LPS) (1 μg/ml), LPS(1 μg/ml)+fenofibrate (1, 10, 50, 100 μM). The mRNA level and secreted protein level of TNF-α expression were detected by RT-qPCR and ELISA respectively. Silk ligatues (7–0) were tied around both maxillary second molars of C57BL/6J mice for two weeks. Optimized dose of fenofibrate (100 μM) and vehicle control were injected into contralateral side of palatal gingiva on days 3, 6 and 9. The palatal gingival tissues and maxillary bone were collected on day 14 to determine expressions of TNF-α, IL1, RANKL/OPG and periodontal bone resorption respectively.

Results
TNF-α expressions of cultured spleen B cells were significantly increased in the presence of LPS when compared with control group, and significantly reduced by fenofibrate treatment in a dose-dependent manner from (1–100 μM). Gingival mRNA levels of TNF-α, IL1 and the ratio of RANKL/OPG were significantly decreased after injection of fenofibrate, when compared to the control side (p&lt;0.05). The periodontal bone loss were significantly decreased on the side with injection of fenofibrate, as compared to the control side (p&lt;0.05).

Conclusion
An anti-inflammation treatment, fenofibrate, inhibited the inflammation and periodontal bone loss in ligature-induced experimental periodontitis.
Gαq deficiency accelerates the onset of experimental lupus
Authors: He Yan , Qian Hongyan , Shi Guixiu 
Published: January 2023

Abstract
Systemic lupus erythematosus is related to abnormal expression of type I interferon signature genes and characterized by a variety of clinical manifestations and autoantibody production. Tetramethylpentadecane (TMPD), also called as pristine, induced a murine model of systemic lupus erythematosus. Taking pristine to genetically normal mice results in the production of lupus-like autoantibodies and glomerulonephritis, similar to human lupus nephritis. Our previous studies have shown a crucial role of Gαq in immune system. In this study, we treated Gnaq+/− mice with pristane using C57BL/6 mice as controls. Gnaq+/− mice developed antinuclear antibodies earlier than the control mice; also, their titers were higher than the controls. pDCs were increased in the peritoneal lavage fluid of Gnaq+/− mice injected for 7 days compared to controls. Th1 and Th17 cells both were increased significantly in injected Gnaq+/− mice after a month. Gnaq+/− mice took place into more severe kidney damage than controls. Together all, our findings demonstrate that Gαq deficiency accelerated lupus occurrence.
Inflammation in PTSD is a consequence of dysregulated WNT signaling orchestrated by long non-coding RNA LINC00926 and lysine methyltransferase MLL1
Authors: Bam Marpe , YANG XIAOMING , Nagarkatti Prakash S , Nagarkatti Mitzi 
Published: January 2023

Abstract
Posttraumatic Stress Disorder patients experience chronic inflammation. It is not known whether immune dysregulation causes PTSD or the psychiatric imbalance occurs first. Moreover, little is known about the molecular mechanisms involved in the immune dysregulation. Our past work indicates the involvement of epigenetic mechanisms such as histone methylation in the regulation of inflammation in PTSD. By employing RNA-Seq, we identified upregulated expression of WNT10B and LINC00926 in the PBMCs of PTSD. Thus, we hypothesized that LINC00926 overexpression in PTSD results in increased H3K4me3 (gene activating histone methylation) around the promoter of WNT10B leading to its upregulation which in turn, regulated the elevated expression of inflammatory cytokines like IFNg and IL17. Thus, we first confirmed the interaction between LINC00926 and the histone H3K4 methyltransferase, MLL1. Then, by in vitro knockdown of LINC00926 we confirmed lowered expression of WNT10B implying that the interaction between LINC00926 and MLL1 possibly leads to increased H3K4me3 on WNT10B promoter and thereby its upregulation. Following this, we confirmed increased H3K4me3 around WNT10B promotor of PTSD patients by ChIP-Seq. Finally, we confirmed that upregulated WNT10B indeed contributed to the elevated expression of IFNg and IL17. In conclusion, our data implies that upregulation of LINC00926 in PTSD leads to inflammatory state by a mechanism that involves interaction with MLL1 resulting in increased H3K4me3 around WNT10B promotor and, eventually leads to elevated expression of proinflammatory cytokines. Our report is the first to show that inflammation in PTSD is a result of altered epigenetic mechanism involving LINC00926 and WNT10B.
Alternative Macrophage Programming After Clot Phagocytosis
Authors: Schenkel Alan , Aragon Jordon , Mills Cole , Glennon Moriah , Garcia Niko , LaFleur Caitie , Horn Kadi 
Published: January 2023

Abstract
Repair program(s) in "alternatively activated" macrophages can help with short-term wound responses after sterile damage events. Clot resolution by fibrinolysis and phagocytosis by tissue macrophages can activate anti-inflammatory and pro-fibrotic signals like Transforming Growth Factor- β. It has been hypothesized by the late Andrew Tager and Rachel Chambers that some forms of human pulmonary fibrosis may involve chronic alveolar damage, leakage of blood components, clots, and subsequent pro-fibrotic events that then fail to remodel back to normal alveolar structure. We found evidence of chronic bleeds and hemosiderin-positive macrophages in the lungs of Platelet Endothelial Cell Adhesion Molecule-1 deficient mice that developed a progressive and fatal pulmonary fibrosis. We are testing this hypothesis in vitro using murine broncho-alveolar macrophages exposed to aged clots. Interestingly, fresh blood and clots were not efficiently phagocytosed by the murine myeloid leukemia cell line RAW264 nor by broncho-alveolar macrophages. Clots needed to be aged for two days first. Ingestion also causes the macrophages to become fluorescent, which is a useful way to assess phagocytosis. We are now developing mRNA sequencing protocols to assess the gene programs of macrophages over time.
Alpha2B-adrenergic receptor regulates neutrophil recruitment in MSU-induced peritoneal inflammation
Authors: WEI YINGYING , Duan Lihua , Chen Jie , Rao Xiaoquan , Tao Ying , Zhong Jixin 
Published: January 2023

Abstract
Gout is one of the most common metabolic disorders in human and its disease activity has been associated with sympathetic nervous system. α2B-adrenergic receptor (α2BAR), a subtype of α2 adrenergic receptor, have a critical role in many diseases. However, the role of α2BAR in the pathogenesis of gout remains unclear. Here, we assessed the effects and mechanisms of α2BAR on the MSU-induced peritonitis that mimics human gout by using the α2BAR-overexpressing mice (α2BAR-Tg). We found that the number of recruited neutrophils was significantly increased in the α2BAR-Tg mice after MSU treatment, when compared with wild type mice. In contrast, the number of macrophages was not changed. Importantly, there is no difference in the IL-1β levels and caspase-1 activity between wild type and α2BAR-Tg mice in the gout animal model. Notably, the enhanced neutrophil migration in α2BAR-Tg mice was dependent on the expression of α2BAR on neutrophils, but not the expression in other tissues or cells. In vitro experiments confirmed the promotive effect of α2BAR on neutrophil migration. In conclusion, our data provide direct evidence that α2BAR plays a critical role in neutrophil migration and MSU-induced inflammation. Thus, α2BAR might serve as a promising therapeutic target for gout.
22q11.2 Deletion Syndrome (DiGeorge) and Mutations in Forkhead Box N1 (FOXN1) cause a Thymic Hypoplasia through distinct Developmental Processes
Authors: van Oers Nicolai S , Du Qiumei , Huynh Larry , Coskun Fatma , Dozmorov Igor , Raj Prithvi , Khan Shaheen , Wysocki Christian , Markert Mary Louise , de la Morena Maria Teresa 
Published: January 2023

Abstract
Patients with 22q11.2 deletion syndrome and those with mutations in the Forkhead Box N1(FOXN1) transcription factor (Nude/SCID) can both present with a thymic hypoplasia that results in a severe T cell lymphopenia. In both clinical conditions, the thymic anlage fails to develop properly within the 3rdpharyngeal pouch during embryogenesis. We characterized the development of the thymus in mouse models of 22q11.2 deletion syndrome (22q11.2del) and a new set of mice with mutations in Foxn1that genocopied a SCID patient with novel compound heterozygous mutations in FOXN1. Both sets of mice develop hypoplastic thymic lobes. An analysis of thymopoiesis in embryos revealed distinct development problems. The hypoplastic thymii from the 22q11.2del mice were primarily sized restricted, with normal percentages of all thymocyte subsets apparent. This contrasted a severe deficiency of thymocytes due to the Foxn1mutations, which primarily affected the development and expansion of thymic epithelial cells. Comparative gene expression analyses of e13.5 fetal thymii revealed differentially regulated transcripts that define the basis of the hypoplasia. A dysregulated mesenchymal cell signature was apparent in the 22q11.2del model, which contrasted the epithelial transcript disruption due to the Foxn1mutations. These results suggest different strategies are necessary to correct the thymic tissue abnormalities in patients who present with thymic hypoplasias due to their congenital disorders.
Small intestinal lamina propria immune cells dyshomeostasis is associated with alcoholic steatohepatitis in the mouse
Authors: Hao Liuyi , Zhong Wei , Sun Xinguo , Zhou Zhanxiang 
Published: January 2023

Abstract
The intestine represents the largest compartment of the immune system. Small intestinal lamina propria (SILP) immune processes are increasingly implicated in controlling disease development in the body. We have shown that reduction of tight junction proteins, system dysbiosis, and endotoxins translocation to the liver accounts for alcohol-induced steatohepatitis. However, the underlying mechanisms are still unclear. The present study investigated the effects of SILP antigen presenting cells dyshomeostasis on the pathogenesis of alcoholic steatohepatitis. Alcohol-induced liver inflammation was analyzed by inflammatory immune cells infiltration and proinflammatory cytokine gene expression. Chronic alcohol exposure (8 weeks) not only cause enteric dysbiosis but also increased plasma endotoxins (LPS) levels. The frequency of CD64-CD45+MHCII+CD11chi dendritic cells and CD64+F4/80+CD11b+ macrophage were both increased in SILP after chronic alcohol exposure. Further analysis demonstrated that alcohol exposure differently regulates CD103+ and CD103- dendritic cells subsets ratio. Intestinal IL-12p70 was significantly decreased after alcohol exposure. alcohol feeding also increased th2 cells but decreased th1 cells in SILP. The present study demonstrated that small intestinal immune cells activation may account for alcohol-induced dysbiosis, and thereby being a pathophysiological factor in the development of alcoholic steatohepatitis.
Identification of Peripheral Immune Mechanisms playing a protective role in Alzheimer's Disease progression
Authors: Agrawal Anshu , Baulch Janet , Acharya Munjal , Agrawal Sudhanshu 
Published: January 2023

Abstract
Alzheimer’s disease (AD) has become the most common form of dementia in the elderly. Recent studies have highlighted the role of inflammation and the immune system in the etiology of AD. However, there is a key gap in knowledge regarding the immune processes in healthy aged individuals as compared to AD patients. We have recently demonstrated that healthy aged subjects display a weak immune/inflammatory response to Amyloid beta–Aβ peptide (1–42) characterized by high IgM antibody responses. In contrast, MCI or AD patients exhibit high levels of IgG antibody against Aβ indicative of a strong immune response. IL-21, an inflammatory cytokine that enhances the differentiation of B cells and facilitates the class switching of IgM to IgG antibodies, is also upregulated in the plasma of AD patients compared to healthy aged controls. In support of these human data, our pre-clinical in vivo experiments using the 5xFAD mouse model of AD also display increased immune activation as compared to age-matched control mice. Similar to humans, we observed a decreased IgM and increased IgG response against Aβ. Furthermore the increased IgM antibody response correlated negatively with cognitive dysfunction. In addition, we also observed an increase in the proportions of T follicular helper (Tfh) cells which secrete IL-21, and enhance the B cell class switch to IgG antibodies in AD mice. In summary, our data indicate that weak immune/inflammatory response against Aβ is protective and facilitates the clearance of Aβ without inducing damaging levels of inflammation. In contrast, strong immune/inflammatory response against Aβ such as those observed in MCI and AD subjects and mice enhance inflammation and aid AD progression.
IL-35+ regulatory immune cells in diabetic nephropathy
Authors: Singh Kailash , Luo Zhenkan , Carlsson Per-Ola , Hansell Peter , Sandler Stellan 
Published: January 2023

Abstract
Diabetes causes an elevation of the blood glucose level and a long-term hyperglycemia contributes to kidney damage, i.e. diabetic nephropathy (DN). DN exhibits signs of inflammation and infiltration of mononuclear cells in kidney. Regulatory T cells (Tregs), regulatory B cells (Bregs), tolerogenic antigen presenting cells (tolAPCs) maintain the homestasis of the immune system, specifically by producing anti-inflammatory cytokine IL-35. Despite intensive research the role of Tregs, Bregs and tol APCs and IL-35 is not yet clear. Herein, we investigated the role of these immune cells in mice and patients.
The circulating concentration of IL-35 was lower in T1D patients with DN and without DN than healthy controls. Proportions of IL35+Treg, IL-35+Bregs, IL-35+tolAPCs were lower but IL-17+Tregs were higher in patients with DN compared to healthy controls, suggesting a phenotypic shift of Tregs. The proportions of IL35+Treg, IL-35+Bregs, IL-35+tolAPCs were lower in kidneys of diabetic mice. Furthermore, IFN-gamma+ Tregs were higher in kidneys of diabetic mice, indicating a phenotypic shift of Treg cells.
After the administration of IL-35 in diabetic mice the mice became normoglycemic and had a lowered albumin creatinine ratio compared to control mice. The IL-IL35+Treg, IL-35+Bregs, IL-35+tolAPCs were increased in IL-35 treated mice. IFN-gamma+Tregs were decreased and the number of Foxp3+ cells was decreased, and mononuclear cells infiltration was also decreased in kidneys of IL-35 treated mice.
Our data suggest that IL-35+ regulatory immune cells are impaired in DN and systemic administration of IL-35 prevents the development of DN in mouse models of DN.