bluuebunny/crossref_metadata_2025_split huggingface dataset:
Conditioned medium from tonsil-derived mesenchymal stem cells promotes adiponectin production
Authors: Kim Yu-Hee , Cho Kyung-Ah , Park Minhwa , Woo So-Youn , Ryu Kyung-Ha 
Published: January 2023

Abstract
Mesenchymal stem cells (MSCs) and conditioned medium (MSC CM) are now considered to be a good source for the development of regenerative medicine. Previously, we reported that tonsil-derived MSC (T-MSC) CM produces visceral fat reducing effects. As reduction in visceral adiposity is closely related to the increase of adiponectin in circulation, we sought to extend our previous findings and explore the effects of T-MSC CM on adiponectin production. T-MSC CM was collected from previously isolated and characterized T-MSCs and injected into a senescence-accelerated mouse prone 6 (SAMP6), which exhibits characteristics of aging and obesity. We observed reduction of mouse weight and epididymal adipose tissue (eAT) mass following injection of T-MSC CM. Significant increase in adiponectin expression in eAT and total and high molecular weight (HMW) adiponectin in circulation were determined in the T-MSC CM-injected mice compared to the control. In 3T3-L1 adipocytes, T-MSC CM treatment increased adiponectin secretion and multimerization. Furthermore, glucose oxidase was used to induce oxidative stress in 3T3-L1 adipocytes and effects of T-MSC CM on the reduction of reactive oxygen species (ROS) production and oxidative stress markers expression were observed. Restoration in the HMW adiponectin production was also shown which suggests that T-MSC CM may enhance adiponectin multimerization via amelioration in the oxidative stress. Further studies are guaranteed in a purpose of elucidation of anti-oxidants secreted from T-MSCs and these findings highlight the potential therapeutic relevance of T-MSC CM for treatment of obesity or obesity-related diseases. (NRF-2016R1A6A3A11933360)
Platelet TGFBIp induces foam cell formation after platelet phagocytosis
Authors: Kim Ha-Jeong , Rhe Suyeon , Jung Haeuk 
Published: January 2023

Abstract
Foam cells play a critical role in the atherosclerosis development. It is reported that platelets phagocytosis induces foam cell formation by producing more inflammatory cytokines. However, platelet induced foam cell formation mechanism is not clear. TGFBIp is a secreted extracellular matrix protein that is consisted by 4 fasciclin-1 domains. TGFBIp is produced by several cells include macrophages and works as chemoattractant to monocytes. TGFBIp is also in the platelet granule and it is secreted and bound on platelets when platelets are activated. Platelets are removed by macrophages when they are activated. However, the role of TGFBIp on activated platelets is not clear. In this report, we used TGFBIp lacking platelets to investigate the role of TGFBIp in platelets. When macrophages uptake TGFBIp lacking platelets, foam cell formation is less than WT platelets are uptaken.
TLR4 Activation of Small GTPase RhoA Signaling Mediates Endotoxin-Induced Endothelial Barrier Dysfunction
Authors: Tauseef Mohammad , Newaz Mohammad , Al-Ghoul Walid , Aqil Madeeha , Fazal Nadeem 
Published: January 2023

Abstract
Sepsis is an uncontrolled activation of immune response, leads to multi-organ failure and high rate of mortality. Studies show the role of increase in endothelial activation and barrier dysfunction significantly contribute to the pathophysiology in sepsis. Endothelial cells form a tight barrier between blood and underlying tissue, and thus maintain an anti-inflammatory milieu. Here, we investigated the role of small GTPase, RhoA activation in regulating the increase in human coronary artery endothelial (HCAE) permeability in response to TLR4-receptor agonist, endotoxin lipopolysaccharide (LPS). Endothelial permeability was determined by determining the influx of Evans blue-labeled albumin across endothelial monolayer on 0.4μ Transwell filters. Our data show that LPS induced RhoA activation and resulted in increase in HCAE cell monolayer permeability. Thus, we tested the hypothesis that LPS mediated induction of RhoA activates pro-inflammatory signaling and eliciting endothelial barrier dysfunction. Knockdown of RhoA using siRNA approach abrogated LPS induced increase in endothelial permeability. Rho-associated kinase (ROCK) is an effector of the RhoA. To further determine the molecular mechanism involved downstream of RhoA activation, we pretreated the cell with ROCK inhibitor (Y-27632) and we found that LPS failed to induce endothelial permeability in cells treated with Y-27642. In conclusion, our study shows that LPS induces activation of the RhoA - ROCK signaling pathway, which leads to increase in endothelial permeability and barrier dysfunction. Therefore, ROCK emerges as a potential drug target to treat sepsis induced endothelial permeability and inflammation.
The role of innate lymphoid cells in the cardiac inflammation
Authors: Choi Hee Sun , Bracamonte-Baran William , Hou Xuezhou , Diny Nicola , Talor Monica , Cihakova Daniela 
Published: January 2023

Abstract
To investigate the role of innate lymphoid cells (ILCs) in the heart, we have established a pericarditis model in which mice develop pericarditis upon IL-33 injections. Studies have shown the role of group 2 innate lymphoid cells (ILC2s) mostly in mucosal organs such as lung and gut, however, the role of ILC2s in the heart has been overlooked. We found that the number of ILC2s increases in the heart after IL-33 treatment. The aim of this work is to examine the role of ILC2s in inflammatory heart disease using the IL-33-induced pericarditis model. We hypothesize that IL-33 induces cardiac resident ILCs to become activated ILC2s to produce large amounts of IL-5 and IL-13, driving the development of pericarditis. To determine whether ILCs are required for pericarditis development, we compared WT mice to Rag2−/− mice and to Rag2−/−γc−/− mice which lack all of lymphoid cells including ILCs. Whereas Rag2−/− mice developed pericarditis, Rag2−/−γc−/− mice were completely protected. This indicates that the adaptive immune response is not required for the development of IL-33-induced pericarditis, but ILCs may play a pathogenic role. We assessed cytokine production by ILC2s in pericarditis to determine the function of ILC2s in the heart. Cardiac ILC2s were a major source of IL-5 and IL-13. The number of eosinophils in the heart was significantly reduced by anti-IL-5 treatment, which prevented the development of pericarditis. In addition, IL-13−/− mice developed less severe pericarditis compared to WT mice. These data suggest that ILCs play a critical role in inflammatory heart diseases. The pathogenic mechanism of ILC2s in the heart could provide insight into novel therapeutic strategies for treating cardiac inflammation including pericarditis.
CD300f-expressing dendritic cells are critical for controlling chronic gut inflammation
Authors: LEE HA-NA , Linjie Tian , Krzewski Konrad , Coligan John E. 
Published: January 2023

Abstract
Pro-inflammatory cytokine overproduction and excessive cell death, coupled with the impaired apoptotic cell clearance, have been implicated as causes for failure to resolve gut inflammation in inflammatory bowel diseases. CD300f (CLM-1), a cell surface receptor that recognizes phosphatidylserine exposed on apoptotic cells, is important for immune homeostasis. In this study, we show that CD300f -expressing dendritic cells play a crucial role in regulating gut inflammatory responses. CD300f-deficient mice fail to resolve colonic inflammation, due to defects in dendritic cell function associated with abnormal apoptotic cell build-up in the gut. CD300f-deficient dendritic cells display hyperactive phagocytosis of apoptotic cells, which stimulates them to excessive TNF-α secretion. This, in turn, induces secondary IFN-γ overproduction by colonic T cells, leading toprolonged gut inflammation. Our data highlight a previously unappreciated role of dendritic cells in controlling gut homeostasis, and show that CD300f regulation of apoptotic cell uptake is essential for suppressing overactive dendritic cell-mediated inflammatory responses, thereby controlling the development of chronic gut inflammation.
Sex and the Nba2 lupus susceptibility interval are differentially associated with specific costimulatory molecule expression profiles on dendritic cells in mice.
Authors: Bupp Melanie R Gubbels , Jorgensen Trine N , Thoner Timothy 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE), an autoimmune disorder that primarily affects women, is characterized by the production of autoreactive antinuclear autoantibodies and elevated levels of serum interferon-alpha (IFN-α). Female B6 mice congenic for the Nba2 lupus susceptibility interval develop a lupus-like disease with elevated serum IFN-α secreted by plasmacytoid dendritic cells (pDC). We hypothesized that genetic and/or sex-specific differences in DC activation states may contribute to differential susceptibility to lupus. Therefore, we compared the expression levels of CD80, CD86, CD40, CD40L, ICOSL, and MHC Class II with flow cytometry on DCs in male and female control (B6) and lupus-prone (B6.Nba2) mice. pDCs from pre-disease, 8-week old, B6.Nba2 lupus-prone mice expressed greater levels of CD80 than did those from B6 controls, while levels did not vary by sex. Additionally, CD19+ Siglec H-pDCs were found to express greater levels of costimulatory molecules as a whole than other pDC subsets. Interestingly, a greater proportion of male conventional dendritic cells (cDCs) expressed ICOSL as compared to female cells, regardless of genetics. These data indicate that Nba2 pDCs exist in a more activated state as compared to control cells, while male cDCs (regardless of lupus-susceptibility) may maintain a larger regulatory T cell population, via increased expression of ICOSL, as compared to female cells. It will be important to test these and other possible functional consequences of sex- and Nba2-specific costimulatory profiles and to determine if they are reflective of developmental events unique to each sex and strain.
‘The role of leukocyte NADPH oxidase in the regulation of IL-1 family cytokines and innate lymphoid cells in serum-induced arthritis.’
Authors: CHAN TZU-YI , Shieh Chi-Chang K 
Published: January 2023

Abstract
Innate lymphoid cells (ILCs) have been recently identified in different tissues as an important class of innate immune cells involved in the inflammatory response during health and disease. Our previous studies showed that reactive oxygen species (ROS) act as negative feedback to regulate IL-1β-mediated inflammation, accounting for the more severe arthritis in the absence of leukocyte NADPH oxidase (NOX2), which is responsible for producing most of the ROS in inflammatory tissues. In this study, we set out to identify and characterize innate lymphoid cells in the arthritic joints based on the hypothesis that leukocyte-produced ROS are critical for modulating innate lymphoid cells activation and IL-1 family cytokines production in serum induced arthritis. We found that serum-induced joint inflammation may be more severe and induce higher IL-1β, IL-18 but less IL-33 cytokines expression and a population of lineage-negative CD45 positive cells was identified in the synovial fluid and tissue of diseased joints. Comparison of ILC populations between WT and Ncf1−/− arthritic mice showed that ILC2 and NCR posetive ILC3 were more abundant in the joint of NOX2 deficient mice. Moreover, the phagocytic NADPH oxidase was an essential regulator of ILC3 populations switching in the inflammatory tissues of arthritis. Given the fact that these cells are capable of rapid cytokine production and leukocyte-produced ROS appear to affect these ILC populations, our ongoing investigations promise to reveal novel redox-sensitive immunoregulatory mechanisms mediated by ILC through IL-1 family cytokines.
Assessment of endocrine molecular entities targeted by inflammation that are involved in the onset of autoimmune diabetes.
Authors: Mora Conchi , Saavedra-Ávila Noemí Alejandra , Sala Ester , Sengupta Upasana , Verdaguer Joan , Stratmann Thomas , Sicinski Peter , Lahti Jill 
Published: January 2023

Abstract
Type 1 diabetes (T1D) is an autoimmune disease caused by pancreatic beta cells demise due to the attack of self-lymphocyte repertoire. We aim to identify molecular entities targeted by the autoimmune assault to pancreatic beta cells that are causally related to T1D progression. The proinflammatory biological niche in which beta cells are immersed during the autoimmune insult promotes deep phenotypical changes crucial for the pathogenic process. These changes lead mainly to beta cell fitness impairment, cell cycle intervention and apoptosis triggering.
By using the Microarray technology we identified a series of genes the expression of which is altered in the islet endocrine cells prior to diabetes onset in the NOD (Non Obese Diabetic) mice. One of those genes encodes for cyclin D3 that triggers cell cycle progression through G1 phase towards the S phase. Cyclin D3 can also bind certain transcription factors and activate inflammation process and development of the T cells (NFκB, GATA). The cyclin D3 promoter has binding sequences to NFκB a transcription factor linked to the action of T1D-related proinflammatory cytokines such as IL-1beta and TNFalpha. We found that cyclin D3 is the only D-type cyclin the expression of which is regulated by inflammation in NOD endocrine islet cells. Moreover we found that cyclin D3 protects beta cells against cytokine-induced apoptosis and is required for proper beta cell function. Moreoever, we observed that CDK11, another cell-cycle related gene that interacts with cyclin D3, is also regulated by inflammation in endocrine islet cells. We have assessed whether there is a causal relationship between the coordinated differential expression of both genes during the insulitic assault and diabetes onset
Taking a ‘Toll’ on Skin: A novel TLR9-deficient Model of Cutaneous Lupus
Authors: Mande Purvi , Taravati Keyon , Rosenblum Michael , Rothstein Ann Marshak 
Published: January 2023

Abstract
Endosomal Toll-like receptors (TLRs), TLR7 and TLR9 have been implicated in the pathogenesis of systemic lupus erythematosus (SLE). However, their role in cutaneous lupus (CL) is not well established, in part due to lack of appropriate mouse models for CL. We developed a novel murine model of CL that depends on T cell recognition of an ovalbumin (OVA) peptide on MHC class II+ cells and closely mimics human CL. These mice develop epidermal hyperplasia associated with mononuclear interface dermatitis and IgG deposition at the dermal-epidermal border within 4 weeks of administration of “pseudo-alloantigen” (OVA)-specific DO11 T cells. Importantly, cutaneous disease is entirely dependent on expression of TLR7 and the loss of TLR9. TLR9KO recipients have fewer DO11 Tregs, more germinal center B cells and more plasma cells than TLR9-sufficient recipients. They make autoantibodies specific for Ro52, a common self-reactivity in human CL. Additional clinical manifestations include extensive accumulation of IFNγ-producing DO11 T cells, elevated class II expression by keratinocytes (KC) and epidermal dendritic cells and extensive KC death. Preliminary data point to a mechanistic role of FasL in KC death that presumably drives skin lesions in this model. Intriguingly, radiation chimeras identify a critical role for radio-resistant TLR9KO cells in the development of cutaneous lesions in this model, suggesting a role for KC or Langerhans cell expression of TLR9 in constraining the development of CL. Our model thus provides a novel, rapid and reproducible system for investigating the opposing roles of TLR9 in CL and SLE. Findings from this study will have important applications in designing TLR-targeting molecules as therapeutic agents for CL.
Identification of perturbations in macrophage polarization in active systemic lupus erythematosus.
Authors: Labonte Adam C , Bachali Prathyusha , Catalina Michelle , Robl Robert , Geraci Nicholas , Lipsky Peter , Grammer Amrie 
Published: January 2023

Abstract
SLE is characterized by abnormalities in B cell and T cell function, but the role of disturbances in the polarization of macrophages (Mφ) into functional subpopulations has not been delineated. Gene expression profiles were analyzed to identify differentially expressed (DE) genes between healthy controls and patients with either inactive (SLEDAI &lt; 6) or active (SLEDAI ≥ 6) SLE. While hundreds of DE genes were identified in B and T cells of active SLE patients (760 and 164 genes respectively), there were no DE genes found in B or T cells from patients with inactive SLE compared to healthy controls. In contrast, large numbers of DE genes were found in myeloid cells from both active (2,135) and inactive (1,260) SLE patients. Many of these DE genes were known to play roles in Mφ polarization, including the M1 genes STAT1 and SOCS3 and the M2 genes STAT3, STAT6, and CD163. M1-associated genes were far more frequent in data sets from active versus inactive SLE patients. To further characterize the relationship between M1 phenotype and disease activity, Weighted Gene Cluster Network Analysis (WGCNA) was used to identify modules of genes associated with clinical activity in SLE patients. Among these were disease activity-correlated modules containing polarization signatures of predominantly M1-associated genes. No disease activity-correlated modules were enriched in M2-associated genes. In summary, altered Mφ gene expression is characteristic of both active and inactive SLE. However, disease activity is associated with an alteration in the functional differentiation of Mφ to the M1 proinflammatory phenotype. This switch in Mφ phenotype is related to the altered expression of genes by T cells and B cells characteristic of active SLE.
The absence of estrogen receptor alpha (ERα) protects females during nephrotoxic serum-induced nephritis by preventing up-regulation of lipid metabolism.
Authors: Corradetti Chelsea , Madaio Michael , Caricchio Roberto 
Published: January 2023

Abstract
Glomerulonephritis (GN) is one of the most serious manifestations of systemic lupus erythematous (SLE). Lupus GN is characterized by severe inflammation and necrosis, and it accounts for most morbidity and mortality. There is sex bias in SLE and estrogens may play an important role in GN susceptibility and progression. Interestingly, estrogen receptor alpha (ERα) in the renal tissue is highly expressed and the renal specific estrogen-induced gene activation is second only to that of reproductive organs. We have found that absence of estrogen receptor alpha protects female mice from developing nephritis, despite the presence of immune complexes in the kidneys and production of pro-inflammatory cytokines. Timecourse microarray analysis of glomeruli isolated from kidneys during nephrotoxic-induced nephritis (NTN) revealed significant up-regulation of genes related to lipid metabolism, such as Acsl1 and Cyp4a14, in WT females compared to ERαko females. Oil red-O staining of the nephritic kidney sections revealed increased lipid presence in the WT females compared to the ERαko females, supporting the microarray data. From these results, we conclude that during NTN, the up-regulation of lipid metabolism occurs downstream of ERα activation and is essential for the progression to end-stage renal failure. Therefore, females lacking ERα have impaired capacity of increasing their lipid metabolism under inflammatory stress, do not exacerbate pro-inflammatory responses, and this results in protection from severe glomerulonephritis. Our results demonstrate that lipid metabolism via the activation of ERα in the renal tissue contributes to local inflammation and disease progression.
Spontaneous secretion of peptidyl-arginine deiminase 2 and cell surface exposure of peptidyl-arginine deiminase 4 by neutrophils
Authors: Zhou Yebin , Chen Bo , Mittereder Nanette , Chaerkady Raghothama , Strain Martin , Rahman Saifur , Ma Wenting , Low Choon Pei , Chan Denice , Neal Frances , Bingham Clifton O , Sampson Kevon , Darrah Erika , Bowen Michael , Andrade Felipe , Vousden Katherine , Sims Gary P , Mustelin Tomas Mikael 
Published: January 2023

Abstract
Autoantibodies directed against citrullinated epitopes of proteins are highly diagnostic of rheumatoid arthritis (RA) and elevated levels of protein citrullination can be found in the joints of RA patients. Although the pathophysiological mechanisms and the cell type(s) responsible for the increase in protein citrullination remain incompletely understood, the neutrophil is emerging as a prime suspect. Here we report that fully viable resting neutrophils from healthy donors have enzymatically active PAD4 exposed on their surface and that they spontaneously secrete enzymatically active PAD2. Activation of the neutrophils by several stimulatory agents, such as immune complexes, tumor necrosis factor a, phorbol myristate acetate, and agonists of Toll-like receptors1, 5, 7, and 9, increased the immunoreactive amount of PAD4 on the cells. However, immune complex, LPS and PMA stimulation reduced PAD2 secretion. The presence of extracellular PAD2 and PAD4 was not caused by NETosis, apoptosis, or lysis of the cells, as verified by gating on live cells and adding NETosis inhibitor in flow cytometry experiments. Neutrophils from the blood of RA patients also exposed PAD4 on their surface at levels similar to those from healthy subjects. Our data add a novel pathway for the extracellular citrullination of proteins by PAD2 and PAD4 in RA and suggest that this pathway is part of normal neutrophil biology also in the absence of disease.
TACI-deficient macrophages alleviate metabolic disease symptoms in obese mice
Authors: Liu Lunhua , Allman Windy R , Coleman Adam S , Siddiqui Shafiuddin , Akkoyunlu Mustafa 
Published: January 2023

Abstract
TACI (transmembrane activator and calcium-modulator and cyclophilin ligand interactor) is one of receptors for the TNF superfamily cytokines BAFF (B cell activating factor) and APRIL (A Proliferation Inducing Ligand). In this study, we investigated the role of TACI in high fat diet induced obesity and metabolic disease. Compared to WT mice, TACI KO mice exhibited less weight gain, decreased body fat, enhanced glucose tolerance and insulin sensitivity. Improved metabolic changes in TACI KO mice were accompanied by significantly less accumulation of CD8+ T cells and F4/80+CD11c+ inflammatory macrophages in visceral fat pad. In addition, TACI KO mouse adipose tissue contained elevated numbers of ILC2, eosinophils and M2 macrophages. Underscoring the protective phenotype of M2-skewed macrophages, the transfer of TACI KO macrophages into obese WT mouse significantly improved insulin sensitivity and glucose tolerance in WT mouse. Interestingly, adoptively transferred TACI KO macrophages into WT mice also increased numbers of the host M2 macrophages and eosinophils in the adipose tissue. We identified IL-10 secreted by TACI KO macrophages was majorly responsible for the improved insulin sensitivity because not only TACI KO macrophage culture media contained high levels of IL-10 but also an IL-10 blocking antibody abolished the enhancement of insulin signaling provided by TACI KO macrophage culture media. These findings indicate that macrophage TACI mediated inflammatory signals promote obesity induced metabolic changes. Consequently, TACI blocking reagents may offer therapeutic benefits to obese patients suffering from metabolic complications.