bluuebunny/crossref_metadata_2025_split huggingface dataset:
An orexigenic hormone ghrelin enhances LPS-induced IL-10 production in human peripheral blood-derived macrophages. (138.12)
Authors: Baatar Dolgor , Lee Jun Ho , Brill Margaret , Lustig Ana , Carter Arnell , Taub Dennis 
Published: January 2023

Abstract
Ghrelin, a circulating orexigenic hormone, exerts potent therapeutic effect in several models of inflammatory diseases, such as endotoxemic shock, ulcerative colitis and autoimmune encephalomyelitis. Suppression of production of pro-inflammatory cytokines from immune cells has been proposed as a mechanism of this effect of ghrelin. Here we report that ghrelin enhances lipopolysaccharide (LPS)-induced production of the anti-inflammatory cytokine IL-10 from human peripheral blood monocyte-derived macrophages. Interestingly, IL-10 production from LPS-activated monocytes was not affected by ghrelin. Further studies revealed that the ghrelin receptor, namely, growth hormone secretagogue receptor (GHS-R), is significantly upregulated during macrophage differentiation. Moreover, ghrelin enhanced expression of the transcription factor c-Maf essential for IL-10 gene expression in macrophages. Whether induction of c-Maf by ghrelin is responsible for the enhanced IL-10 production and the significance of IL-10 in overall anti-inflammatory action of ghrelin in vivo is currently under investigation.
Simultaneous correlation of cytokine production with Treg and Th17 cell proliferation (138.21)
Authors: Elia Jeanne , Rabenstein Jacob , O'Donnell Erika , Rohrer Jurg 
Published: January 2023

Abstract
Functionally-polarized CD4+ T cell subsets have been identified based on their distinctive patterns of cytokine secretion, transcription factor expression and function. As a signature cytokine, Th17 express high levels of interleukin 17A (IL-17) whereas Treg are characterized by the expression of the Foxp3 transcription factor. In the mouse system TGFb is required for the production of IL-17A, although additional cytokines are produced including Th1 (IL-2, IFNg) and Th2 (IL-4, IL-10 ) cytokines. The goal of the experiment was to evaluate the correlation of cell cycle (VFSE), cytokine production via both CBA and intracellular staining, Foxp3 expression (Treg), and cytokine-induced phosphorylation events. Multiple fixation and permeabilization conditions were used to allow resolution of intracellular cytokines, Foxp3, and phospho-proteins. FoxP3+ CD4 T cells were present at initiation of culture and were shown to divide by appearing on subsequent VFSE peaks. IL-17A began to appear after day 2 and was restricted to newer generations of cells, unlike FoxP3 which was expressed at time 0 and restricted to the older generations. Further analysis showed the IL-17A population coexpressed IL-2 at day 2, but the populations diverged upon maturation, becoming mutually exclusive by day 4. Analysis of Stat5 phosphorylation revealed heterogeneous responses to secreted cytokines, with newer generations of cells showing the most robust phosphorylation responses.
Vagus Nerve Stimulation Produces an Anti-Inflammatory Monocyte Phenotype in Blood. (138.25)
Authors: Valdes-Ferrer Sergio , Rosas-Ballina Mauricio , Olofsson Peder , Chavan Sangeeta , Tracey Kevin 
Published: January 2023

Abstract
Cytokine production and immune cell migration are under the control of the nervous system. Electrical stimulation of the vagus nerve attenuates cytokine production in endotoxemia, and down-modulates neutrophil migration in animal models of inflammation. The effect of vagus nerve stimulation (VNS) on PBMC phenotypes has not been characterized. We performed VNS or sham surgery in mice (n=5 group) and 24 hours later collected blood for analysis by flow cytometry. The total number of CD11b+ expressing cells was not affected, but CD11b+/Ly-6C+ monocytes significantly decreased in frequency (0.5% vs. 3.2%; p=0.005). VNS decreased dendritic cell numbers defined as CD11b+, CD11c+ (0.4% vs. 1.8%; p=0.042), or CD11c+, F4/80+ (1.6% vs. 2.7%; p=0.025). VNS did not affect the total number of circulating T cells (CD3+). VNS did not affect CD11b+ or Ly-6Clow, which are known to be VEGF-producing and anti-inflammatory. The present results indicate that VNS reduced the proportion of circulating pro-inflammatory monocytes and dendritic cells, and decreased the expression of monocytic lineage cells, in particular those expressed by M1 monocytes which are known to secrete TNF, Il-6, IL-12 (and reduced amounts of IL-10). Together, this indicates that direct activation of a neural circuit can down-modulate inflammatory cell phenotypes in blood, producing an anti-inflammatory cellular milieu.
Physiological control of NKT cell activation by extracellular adenosine via A2B adenosine receptor (138.27)
Authors: Kini Radhika , Subramanian Meenakshi , Ohta Akiko , Sitkovsky Michail , Ohta Akio 
Published: January 2023

Abstract
Negative regulatory mechanism of immune responses is essential to prevent excessive inflammatory tissue injury. Adenosine involves in physiological down-regulation of inflammation via A2A adenosine receptor (A2AR). In this study, we provide evidence that A2B adenosine receptor (A2BR) is also important in the physiological control of hepatic inflammation. Acute hepatitis induced by intravenous concanavalin A (Con A) injection was significantly more severe in A2BR-/- mice than in wild-type mice. The exaggerated inflammation in A2BR-/- mice accompanied higher levels of IL-4 from NKT cells suggesting A2BR-mediated suppression of NKT cell activation. In vitro activation of NKT cells by α-galactosylceramide (α-GalCer) showed that stimulation of A2BR is inhibitory to NKT cell activation. Furthermore, injection of α-GalCer induced higher serum cytokine levels and stronger liver damage in A2BR-/- mice. These results show that the lack of A2BR diminished negative regulatory mechanism of NKT cells by endogenously produced adenosine and, therefore, caused more severe acute hepatitis. Indeed, transfer of A2BR-/- NKT cells into RAG2-/- mice resulted in stronger Con A-induced liver injury than wild-type NKT cells. There have been controversial reports regarding the role of A2BR in inflammation. Our results demonstrate that NKT cell-mediated immune responses are under the physiological control of extracellular adenosine through A2BR signaling.
A novel means of immunoregulation: CD46 attenuates effector responses of human conventional and unconventional T cells by distinct mechanisms (138.8)
Authors: Le Friec Gaelle , Cardone John , Vantourout Pierre , Roberts Andrew , Cope Andrew , Hayday Adrian , Kemper Claudia 
Published: January 2023

Abstract
Many studies including human genetics have implicated IL10-producing cells as key in limiting immune pathology during infection and in preventing autoimmunity. Here we show that the complement regulator CD46 regulates IL10 production in an IL2-dependent fashion. More specifically, CD3/CD46-activation of human CD4+ T cells in low IL2 induces strong IFNγ secretion, whereas increasing IL2 induces a ‘switch’ to immunosuppressive Tr1-like cells that are initially IFN-γ+/IL10+, and then IL-10+. We propose that CD46 activation initially promotes antimicrobial Th1 effector responses, while expansion of this response increases local IL2, promoting a CD46-dependent switch to IL10-mediated immunoregulation. The significance of this in vivo is supported by the failure of CD3/CD46-activated CD4+ T cells from rheumatoid arthritis patients to switch to the IL10+ state, producing ≥20-fold more IFNγ than IL10. IL10-switching of CD4+ T cells is mediated by the CYT-1 isoform of the alternatively spliced cytoplasmic tail of CD46. Interestingly, human γδ T cells, whose importance to the early effector phase of immune responses is increasingly apparent, express predominantly the CYT-2 isoform of CD46. Thus, they do not produce IL10 in response to TCR/CD46 co-engagement, but rather significantly decrease their IFNγ and TNFα production. Thus, we propose that CD46 uses distinct molecular mechanisms to regulate unconventional and conventional T cells across the span of the immune response.
IL-12 induces human CD4+CD45RA-CD25hiCD127low/neg regulatory T cells to secrete IFNγ and IL-10 and acquire a non-regulatory effector phenotype (138.9)
Authors: Dominguez-Villar Margarita , Hafler David , Baecher-Allan Clare 
Published: January 2023

Abstract
Regulatory T cells (Treg) play a pivotal role in maintaining a balance between the immune response and peripheral tolerance. Recent evidence indicates that regulatory T cells are more functionally plastic than originally thought. Not only does the cytokine milieu modulate their capacity to suppress, but it can also induce Tregs to secrete cytokines (IL-17). The IL-12 family of cytokines (IL-12, IL-23, IL-27, IL-35) are key players in the regulation of T cell responses. We have studied the distinct effects that these cytokines (IL-12, IL-23 and IL-27) exert on human Treg function and phenotype. RESULTS: Surprisingly, we have found that IL-12 induces memory CD127lo Tregs to express T-bet and produce IFN-gamma and IL-10. Furthermore, in this state, these Tregs not only exhibit a non-regulatory effector phenotype, but they are also markedly less able to suppress the activation of co-cultured CD4 T cells. Importantly, although these IL-12-treated Tregs are less suppressive, their Foxp3 expression is not significantly altered. Additional data indicates that this is a transient state of reduced Treg suppression.. Thus this represents a way for the immune system to inactivate Treg function to allow an immune response to proceed.
Immuno-signature of CD4+ Treg and T inducer cells (139.14)
Authors: Perna Avi , Nosworthy Lara , Yang Xifeng 
Published: January 2023

Abstract
T regulatory cells (Tregs), a subset of well-known suppressive T effector cells, are phenotypically characterized as CD4+CD25high Foxp3+CD39+. A recent report has identified CD4+CD25-CD39+ cells as T “inducer” (Tind) and demonstrated their ability to potentiate proliferation and cytokine production in vitro. In this study, we examined the expression of surface molecules on Tregs and Tind in normal healthy individuals by multicolor flow cytometric analysis utilizing a panel of fluorochrome conjugated mAbs to integrins, ICAMs, chemokine receptors, co-stimulatory molecules, and activation markers. In comparison with conventional CD4+ T cells, both Tregs and Tind cells showed higher expression of integrins (integrin aL, a4, a5, b1) and some chemokine receptors (CCR2, CCR4, CCR6 and CXCR3), but lower of PECAM-1, CCR7 and CXCR4. Additionally, an enhanced expression of activation markers ICOS, CD95(Fas), PD-1 and CD45RO was observed on both cell types. In contrast, the expression of CD7, CD127 and CD38 was at lower levels on Tregs and Tind than conventional CD4+ T cells. Comparison of Tregs and Tind showed the expression levels of most markers were non-differential. However, Tregs expressed less CD127 and CD38 than Tind, whereas Tind expressed more PD-1 than Tregs. These findings suggest Tind and Tregs may possess a functional relationship.
T-bet-independent effects of IL-12 family cytokines on regulation of Th17 responses to infection (139.5)
Authors: Smeltz Ronald , Cobb Dustin , Hambright Derek 
Published: January 2023

Abstract
T-bet is an IFN-γ-inducible transcription factor that promotes Th1 differentiation. Previously we reported that T-bet (Tbx21)-deficient mice develop a robust Th17 response to parasitic infection, despite a normal Th1/IFN-γ response. The purpose of this study was to determine if IFN-γ exerted any influence on antigen-specific Th17 responses to T. cruzi, a parasite and causative agent of Chagas disease. Neutralization of endogenous IFN-γ or addition of recombinant IFN-γ to purified CD4+ T cell cultures from T. cruzi-infected mice had minimal effect on IL-17 production. CD4+ T cells expressed IFN-γRα, thus were capable of responding to IFN-γ. To determine if IFN-γ could act in an APC-dependent manner, we neutralized IFN-γ and IL-12 in splenocyte cultures, since one effect of IFN-γ on APC is induction of IL-12. While anti-IFN-γ modestly increased IL-17 production, addition of anti-IL-12 led to a significant enhancement of antigen-specific IL-17. In contrast, addition of IL-23 to T-bet-deficient cultures led to a striking increase in IL-17 production. These data show that IL-12 and IL-23 can influence Th17 responses in a T-bet-independent manner; and that the effects of IFN-γ are not necessarily related to its ability to induce T-bet expression in T cells. These data further illustrate the synergy between T cell and APC-intrinsic factors in regulation of Th17 responses to infection.
Estrogen related receptor-α is a global metabolic and fate determinant for T lymphocytes (139.8)
Authors: Michalek Ryan , Jacobs Sarah , Chang Ching-yi , Ilkayeva Olga , Maciver Nancie , Jones Russell , Giguere Vincent , McDonnell Donald , Rathmell Jeffrey 
Published: January 2023

Abstract
T lymphocyte activation initiates rapid cell growth and proliferation that is fueled by increased glucose metabolism. Molecular factors contributing to this transition and how metabolism impacts immunity, however, have remained uncertain. We have uncovered a critical role for the orphan nuclear receptor Estrogen Related Receptor-alpha (ERRα) in this metabolic program and T cell differentiation. In the absence of ERRα activated T cells failed to elevate glucose metabolism, resulting in diminished growth, proliferation, and effector function. The generation of inducible regulatory T cells was also selectively inhibited in the absence of ERRα. Metabolomic analysis demonstrated that the loss of ERRα promoted a shift from glycolytic metabolism to lipid oxidation. Importantly, defects in growth and differentiation in the absence of ERRα were overcome by addition of excess lipids as an alternate mitochondrial fuel. Furthermore, induction of lipid metabolism in T cells selectively promoted the generation of regulatory T cells in vitro and in vivo and suppressed the differentiation of effector Th17 cells in vitro. Together, these results demonstrate that ERRα is essential to drive glucose metabolism of activated T cells and that metabolic phenotype can strongly influence T cell differentiation.
Effect of green tea extract and epigallocatechin gallate on bovine neutrophil function (140.10)
Authors: Kimura Kayoko , Palic Dusan , Roth James 
Published: January 2023

Abstract
Neutrophils play an important role as the first line of defense in protecting hosts from microbial invasion, but the delayed migration and prolonged presence of neutrophils can result in sustained inflammation. The aim of this study was to determine effect of green tea extract (GT) and its major anti-inflammatory component, epigallocatechin gallate (EG), on bovine neutrophils in order to decipher possible clinical use of GT and EG to alleviate inflammation. Effects of GT and EG on degranulation, oxidative burst, CD11b expression, and neutrophil apoptosis were investigated at concentrations from 1 to 100 μg/mL (GT) or μM (EG) in different assay conditions. Concurrent, pre, and post treatment of GT and EG with saline or standard stimulant (calcium ionophore or phorbol myristate acetate) significantly reduced degranulation and superoxide production compared to control (no GT/EG). Significant reduction in CD11b expression was observed in EG treated samples, but not all GT samples had similar effect. GT and EG at concentrations of 50 and 100 μg/mL (GT) or μM (EG) triggered neutrophil apoptosis determined by Annex-V cell surface binding and 7 amino-actinoycin intracellular staining. The in vitro reduction of cattle neutrophil function suggests potential of GT and EG to be used in clinical applications as support to anti-inflammatory therapy.
Azole derivative drugs inhibit neutrophil chemotaxis by blocking the Calcium permeant channel TRPM2 (140.12)
Authors: Partida-Sanchez Santiago , Sumoza-Toledo Adriana , Bhagat Harivadan , Lange Ingo , Cortado Hanna , Fleig Andrea 
Published: January 2023

Abstract
Azole derivatives exert direct anti-inflammatory activity in fungal infections and other cutaneous inflammatory conditions. Inhibition of PMN chemotaxis and leukotriene biosynthesis has been suggested to explain this phenomenon, yet the molecular mechanism of action for these drugs remains unknown. Recently we showed that NAD+ derived metabolites, cADPR and ADPR; regulate PMN chemotaxis by inducing extracellular Ca2+ influx via the ion channel TRPM2. Here we investigated whether azole derivatives inhibit PMN chemotaxis in vitro by altering the production of NAD+-derived metabolites or by blocking plasma membrane channel-conducted Ca2+ influx. First, we demonstrated that econazole and clotrimazole significantly inhibited PMN directionality and speed in an EZ-Taxiscan chemotaxis assay. Interestingly, econazole and clotrimazole, as well as FA, another compound proposed to block the TRPM2 channel, blocked fMLP-induced Ca2+ influx, rendering defective Ca2+ responses comparable to those responses observed in fMLP-stimulated TRPM2 KO PMN. Moreover, we found that pre-treatment of neutrophils with econazole or clotrimazole did not alter NAD+ metabolism, but its effect was by blocking a membrane channel with physiological properties similar to TRPM2. Collectively, these data suggest that compounds, which antagonize TRPM2-mediated Ca2+ signaling pathway, may function as effective inhibitors of PMN recruitment, and will likely prove useful in the treatment of inflammatory diseases.
Evaluation of the effects of disease-causing mutations in type I TNF receptor (TNFR1) on neutrophil responses (140.8)
Authors: Pelletier Martin , Bulua Ariel , Kastner Daniel , Siegel Richard 
Published: January 2023

Abstract
Mutations in the type 1 TNF receptor (TNFR1) cause an autosomal-dominantly inherited autoinflammatory disorder called TNF receptor-associated periodic syndrome (TRAPS). The disease is characterized by recurrent fevers with abdominal pain, migratory rash and inflammation. Patients also develop serositis, including peritonitis, as a manifestation of disease flares. TRAPS-associated mutant receptors do not traffic to the cell surface and accumulate in the endoplasmic reticulum, which may lead to abnormal TNF-independent receptor signaling and sustained inflammation. We examined the contents of peritoneal lavage fluid after intraperitoneal injection of LPS in TNFR1 mutant mice. Interestingly, heterozygous TNFR1 mutant mice had increased neutrophil infiltrates into the peritoneal cavity after LPS injection. We have investigated whether the exaggerated infiltration of neutrophils in mice with TNFR1 mutations is due to an intrinsic neutrophil abnormality or the release of more neutrophil-attracting chemokines by macrophages. We have performed chemotaxis experiments using neutrophils isolated from TRAPS patients as well as TNFR1 mutant mice, and measured the migratory responses of neutrophils toward chemoattractants and macrophage-derived supernatants. These results will provide insights into whether the intracellularly retained mutant TNFR1 may function to enhance local neutrophil accumulation in response to inflammatory stimuli in a cell autonomous manner.
Innate imprinting of resident alveolar macrophages by a preceding allergic bronchial inflammation increases the inflammatory reactivity through autocrine IFN-β. (141.18)
Authors: Naessens Thomas , Vander Beken Seppe , De Koker Stefaan , Lienenklaus Stefan , Vakaet Luc , Grooten Johan 
Published: January 2023

Abstract
Macrophages play an important and dynamic role in the initiation, propagation and resolution of inflammation. We investigated the dynamics of resident alveolar macrophages (rAM) and its pathophysiological consequences in experimental asthma. Using CD45 chimeric mice and intratracheal instilled fluorescent microparticles to distinguish resident from elicited AM, we observed a near complete disappearance of rAM during consecutive allergen challenges. As a consequence, after clearance of inflammation, inflammation-experienced rAM replaced the initial population of rAM. Strikingly, these secondary rAM showed a markedly altered responsiveness to LPS stimulation. Especially genes induced by IFN-β showed strongly increased expression in secondary rAM as opposed to their near absent induction in primary rAM. This switch from an IFN-β deficient to an IFN-β adequate phenotype increased the inflammatory sensitivity of secondary rAM as observed with rAM from IFN-β -/- mice. Also the basal differentiation status of secondary rAM was modified, dependent on the nature of the preceding allergic inflammation. M2-biased differentiation was seen following eosinophilic asthma while M1-biased differentiation was present following neutrophilic hypersensitivity pneumonitis. Taken together, these observations indicate innate imprinting of rAM by preceding allergic inflammation in the lungs.
Absence of the Type I IL-4 receptor increases the severity of airway inflammation in a murine model of asthma (141.6)
Authors: Dasgupta Preeta , Smith Elizabeth , Keegan Achsah 
Published: January 2023

Abstract
The TH2 cytokines, IL-4 and IL-13, play critical roles in inducing allergic lung inflammation, eosinophilia, mucus hypersecretion and also drive alternative activation of macrophages (AAM). Although both cytokines share receptor subunits and signaling machinery, it is becoming apparent that IL-4 and IL-13 have differential roles in asthma pathogenesis. While clearly important in TH2 differentiation, the contribution of IL-4 signaling via the Type I receptor in allergic responses remains unclear. Here, we adoptively transferred wild-type ova primed CD4+ T cells into C57BL/6, Rag2KO, or gamma c (γc) KO mice. We found that γc KO mice developed increased inflammation around the airways and blood vessels in the lungs upon ova challenge when compared to WT and Rag2KO mice. Moreover, significantly higher numbers of eosinophils were present in the bronchoalveolar lavage (BAL) and lung tissue in γc KO mice. Immunohistochemical studies showed that all mouse strains expressed characteristic AAM proteins FIZZ1 and YM1 in lung epithelial cells, while macrophages expressed only YM1. Interestingly, γc KO mice had high levels of FIZZ1 protein in their BAL at baseline, which dropped sharply upon ova treatment. These results suggest that the Type I R acts to suppress allergic lung inflammation and, in the presence of TH2 effectors, the Type II R can mediate allergic responses in its absence. Further experiments are required to fully elucidate the role of the Type I IL-4R and γc in asthma.
Type I IFN facilitates the expansion of CD4+CD25+Foxp3+ regulatory T cells through upregulation of GITRL on dendritic cells (143.13)
Authors: Hong Jian 
Published: January 2023

Abstract
Interferon-beta (IFN-β) is a disease-modifying agent used in the treatment for multiple sclerosis (MS). Its mechanisms are complex and still not fully understood. It was observed clinically that the number of CD4+CD25+FOXP3+ regulatory T cells increase in patients treated with IFN-β for over 6 months. Here we demonstrate that IFN-β-induced up-regulation of glucocorticoid-induced TNF receptor ligand (GITRL) on dendritic cells (DC) promotes the proliferation of anergic Treg cells in mice. In vitro treatment of DC with IFN-β increases the expression of GITRL at both mRNA (by ~5 folds in PCR) and protein level (by ~25% in flow cytometry). Purified Treg cells, when stimulated with anti-CD3 and anti-CD28 Abs, remarkably proliferate in the presence of IFN-β pretreated DC. Blockade of GITRL with antibody diminishes the ability of DC to stimulate Treg cell proliferation. IFN-β shows no effect on the TGF-β induced conversion of CD4+CD25- T cells to Foxp3+ Treg cells in mice. DCs of IFNAR-/- mice are less potent in facilitating the proliferation of Treg cells. Treatment of EAE mice with mIFN-β for 2 months results in the upregulation of peripheral Foxp3+ Treg cells. However, in mice depleted with DC by liposomal clodronate treatment, IFN-β failed to induce the increase of Treg cells in vivo. Our findings are not only essential for the understanding of the effect of IFN-β in the treatment for MS but also provide insight into how Treg cells accordingly respond to inflammation.