bluuebunny/crossref_metadata_2025_split huggingface dataset:
Commensal metabolite indol-3-propionic acid promotes gut barrier function by regulating IL-22 production during intestinal inflammatory conditions
Authors: Romagnoli Pablo A , Shenk Gregory K , Pham Quynh-Mai , Maher Leigh , Khanna Kamal Mohan 
Published: January 2023

Abstract
Microbiota-derived metabolites provide signals to maintain homeostasis of the epithelial cell layer in the intestinal mucosa that in turn shape immune responses to bacterial pathogens. In contrast, disruption of these signals can result in dysregulated responses to microbiota that cause inflammatory bowel diseases (IBD). Here we tested the hypothesis that a metabolite produced via tryptophan metabolism by commensal bacteria, Indol-3-propionic acid (IPA), promotes immune homeostasis and gut barrier function in the intestinal mucosa during inflammatory conditions and prevents IBD. We investigated the effect of IPA on the intestinal mucosa using a model of colitis caused by oral infection with Citrobacter rodentium (Crod). Remarkably, we observed that IPA treatment results in protection of mice from colitis. Our studies show that IPA treatment results in increased expression of IL-22 by intraepithelial lymphocytes (IELs) of the small intestine (S). In fact, most of the IL-22 observed at 4 days following oral Crod infection is produced by IELs from small intestines. Since we have previously shown that IPA is a potential ligand of the nuclear receptor pregnane X receptor (PXR), which contributes to the maintenance of the intestinal barrier function, we further investigated if IPA protects by activating PXR or other pathways in the gut mucosa. Indeed we discovered an increase in the absolute numbers of IL-17A and IFNγ producing lymphocytes from the IEL compartment of the colon by the IPA treatment and this effect was dependent on PXR expression. In conclusion, we believe the discovery of metabolites like IPA that promotes the repair of the intestinal epithelial cell layer can provide new strategies to prevent and treat IBD.
Microbiome-dependent modulation of mucosal immunity at the ocular surface.
Authors: Caspi Rachel R , Drummond Rebecca , Desai Jigarkumar , Silver Phyllis B , Lionakis Michail S , St. Leger Anthony J 
Published: January 2023

Abstract
Mucosal sites that interface with the environment and provide barrier function include the intestine, nasopharynx, lung, female reproductive tract and the ocular surface. Disruption of immune homeostasis at the ocular surface is associated with discomfort, inflammation and potential loss of vision. Immune cells are present within the mucosa of the ocular surface (conjunctiva) and are affected by environmental factors, potentially including microorganisms. However, proof that a resident ocular microbiome exists and influences local immunity has been elusive. We used a mouse model of ocular surface disease to address the question whether commensal microbes are present in ocular mucosa and modulate immunity. Our data indicate that IL-17 is constitutively produced within the conjunctiva-associated lymphoid tissue (CALT) and is necessary to recruit neutrophils to the ocular surface in the steady state and after a bacterial challenge. IL-17 sources in CALT include γδ T cells, αβ T cells and innate lymphoid cells (ILCs), in that order. Notably, conjunctival γδ T cells respond to a strain of Corynebacterium that colonizes the ocular surface by secreting IL-17, which modifies the inflammatory signature within the ocular mucosa. Furthermore, this interaction appears necessary to regulate local immunity at the ocular surface, since elimination of these bacteria by antibiotic treatment, or their introduction into non-colonized mice, correlated inversely with severity of an experimental Candida albicans infection. Our results indicate that a relationship exists between commensals and immune cells at the ocular surface, which is critical for maintenance of homeostasis and host defense within the ocular mucosa.
Group 3 innate lymphoid cells mediate intestinal selection of commensal bacteria-specific CD4+ T cells.
Authors: Sonnenberg Gregory F , Fung Thomas C , Goc Jeremy , Wang Xinxin , Hepworth Matthew R 
Published: January 2023

Abstract
Inflammatory CD4+ T cell responses to self or commensal bacteria underlie the pathogenesis of autoimmunity and inflammatory bowel disease (IBD), respectively. While selection of self-specific T cells in the thymus limits responses to mammalian tissue antigens, the mechanisms that control selection of commensal bacteria-specific T cells remain poorly understood. Here we demonstrate that group 3 innate lymphoid cell (ILC3)-intrinsic expression of major histocompatibility complex class II (MHCII) is regulated similarly to thymic epithelial cells, and that MHCII+ ILC3s directly induce cell death of activated commensal bacteria-specific T cells. Further, MHCII on colonic ILC3s was reduced in pediatric IBD patients. Collectively, these results define a selection pathway for commensal bacteria-specific CD4+ T cells in the intestine and suggest that this process is dysregulated in human IBD. On going studies are interrogating the role and regulation of MHCII+ ILC3s in the context of allergy, autoimmunity and tumorigenesis.
An enzyme from a human commensal bacterium triggers enhanced intestinal barrier function
Authors: Pedicord Virginia Anh , Rangan Kavita J. , Craig Jeffrey W. , Loschko Jakob , Rogoz Aneta , Hang Howard C. , Mucida Daniel 
Published: January 2023

Abstract
Intestinal infections affect billions of people worldwide. Commensal intestinal bacteria can prevent pathogenic infection, as demonstrated by drastically increased susceptibility to infection upon antibiotic use; however, the molecular mechanisms by which individual bacterial species contribute to pathogen resistance have yet to be fully elucidated. Using a human commensal Enterococcus faecium strain, we show that colonization of mice with E. faecium elicits improved intestinal epithelial barrier function and decreased antibiotic-induced susceptibility to Salmonella infection. This protection requires host antimicrobial peptide (AMP) expression and MyD88 and Nod2 signaling and corresponds to E. faecium secretion of a unique enzyme, secreted antigen A (SagA). Ectopic expression of SagA by non-protective bacterial species is sufficient to confer similar probiotic efficacy against Salmonella pathogenesis and induce AMP expression in the intestinal epithelium. These studies reveal a mechanism for E. faecium-mediated pathogen resistance and identify a specific factor produced by commensal bacteria that triggers a protective program in the mammalian intestine.
Periostin regulates fibrocyte function to promote myofibroblast differentiation and lung fibrosis
Authors: Ashley Shanna L , Wilke Carol A , Moore Bethany B 
Published: January 2023

Abstract
Fibrocytes are bone-marrow-derived circulating mesenchymal precursors (CD45+, col 1+) that are recruited to fibrotic areas. Fibrocytes secrete a number of profibrotic mediators including periostin; a matricellular protein that regulates cellular interactions with extracellular matrix (ECM) components. In bleomycin-induced fibrosis, loss of periostin by either structural or hematopoietic cells can limit the development of pulmonary fibrosis. To test the hypothesis that hematopoietic-derived fibrocytes might secrete soluble factors to signal structural myofibroblasts differentiation, wild-type (WT) fibroblasts were treated with conditioned medium from fibrocytes isolated from bleomycin-treated WT or periostin−/− mice. After 24 hours we saw marked decrease in α-smooth muscle actin protein expression in cells treated with the conditioned medium from periostin−/− fibrocytes. Adoptive transfer of WT fibrocytes augmented lung fibrosis to a greater extent than did transfer of fibrocytes from periostin−/− mice. We performed in vitro analyses of lung mesenchymal cells isolated from WT and periostin−/− mice by sorting fibroblasts and fibrocytes then treating with TGFβ1 or periostin. Additionally, connective tissue growth factor (CTGF), endothelin-1 (ET-1) and lysl oxidase (LOX) mRNA expression was downregulated in periostin−/− bleomycin-treated fibrocytes. Taken together these data suggest that fibrocytes may augment bleomycin-induced fibrosis via secretion of periostin and other soluble factors that promote myofibroblasts differentiation.
Innate Lymphoid Cell and Helper T Cell Subpopulations in Chronic Rhinosinusitis
Authors: Dietz Caroline Padro , Reed Robyn C , Luong Amber U. 
Published: January 2023

Abstract
Chronic rhinosinusitis (CRS) is an inflammatory disease of the upper airways subtyped by the absence (CRSsNP) or presence (CRSwNP) of nasal polyps. Allergic fungal rhinosinusitis (AFRS) is a clinical subtype of CRSwNP characterized by fungal growth within the sinuses. CRSwNP and AFRS are characterized as type 2 inflammatory diseases based on elevated IL-5 and IL-13 within sinus mucosa. In contrast, CRSsNP is classified as a type 1 disease with elevated type 1 cytokines such as IFN-γ. Although Th1 and Th2 cells have been traditionally described as type 1 and 2 cytokine producers, innate lymphoid cells (ILCs) have emerged as another significant source.
To determine the cell sources responsible for these cytokine elevations, the presence of type 1–3 ILCs (ILC1–3) and Th1 and Th2 cells in surgically-derived inflamed mucosa from CRSsNP (n=8), CRSwNP (n=14), and AFRS (n=8) patients were analyzed by flow cytometry. Overall, we found elevated total ILCs in CRSwNP (3.15 ± 0.66%) in comparison to CRSsNP (0.77 ± 0.22%, p=0.01). When further examined, all three types of ILCs were significantly elevated in CRSwNP (ILC1: 0.30 ± 0.09%, ILC2: 0.91 ± 0.31%, ILC3: 0.10 ± 0.02%) in comparison to CRSsNP (ILC1: 0.13 ± 0.05%, p=0.03, ILC2: 0.37 ± 0.18%, p=0.04, ILC3: 0.05 ± 0.01%, p=0.05), supporting a greater innate immune system focus in CRSwNP. In contrast, Th1 cells were significantly elevated in CRSsNP (72.23 ± 5.13%) in comparison to CRSwNP (52.72 ± 5.0%, p=0.009) and AFRS (45.19 ± 5.18%, p=0.003), indicating that the majority of IFNγ-secreting cells were of the adaptive immune system. The characterization of CRSwNP as an innate immune disease and CRSsNP as an adaptive immune system disease indicate potential therapeutic targets in the treatment of CRS.
Inducible bronchus-associated lymphoid tissue plays an important role in the induction of antigen-specific immune response by Ag85B-hPIV2-based anti-tuberculosis vaccine in mice
Authors: Nagatake Takahiro , Wada Yasuko , Matsumoto Naomi , Shimojou Michiko , Hirata Soichiro , Nasu Ayaka , Suzuki Hidehiko , Hosomi Koji , Ogami Kentaro , Tsujimura Yusuke , Kawano Mitsuo , Nosaka Tetsuya , Yasutomi Yasuhiro , Kunisawa Jun 
Published: January 2023

Abstract
Mycobacterium bovis bacilli Calmette-Guerin is the only licensed tuberculosis vaccine, which has been considered to be insufficient against adult pulmonary tuberculosis. As most of pathogens, including Mycobacterium tuberculosis, naturally enter the host through respiratory surface, nasal vaccine is an ideal method to prevent the diseases by inducing antigen-specific immune responses at respiratory sites as well as systemic compartments. Our group recently developed Ag85B-expressing human parainfluenza type 2 virus (Ag85B-hPIV2) as a nasal vaccine against tuberculosis. In this study, we aimed to elucidate the mechanisms underlying the induction of antigen-specific immune responses by Ag85B-hPIV2. We found that inducible bronchus-associated lymphoid tissue (iBALT) played an important role in the induction of antigen-specific immune responses. Intranasal administration of hPIV2 vector induced iBALT formation with induction of Th17 cells and CD11b+CD11c+ cells both of which are known to require for the formation and maintenance of iBALT structure, respectively. When iBALT structure was disrupted by depletion of CD11b+ cells in CD11b-diphtheria toxin receptor transgenic mice, Ag85B-specific immune response was diminished in the lung. These findings indicate that iBALT genesis is an essential process required in Ag85B-hPIV2 anti-tuberculosis mucosal vaccine.
Development and validation of a novel flow cytometric macrophage phenotyping method.
Authors: Welder Daniel A , Slief Sarah , Morton Rebecca , Baatar Dolgor 
Published: January 2023

Abstract
Macrophages differentiate into pro-inflammatory M1 or anti-inflammatory M2 phenotypes. M2 macrophages suppress anti-tumor responses, and phenotyping tumor-associated macrophages can be of prognostic value. Expression of mRNA of inducible nitric oxide synthase (iNOS) or arginase 1 is a well-accepted marker of murine M1 or M2 macrophages, respectively. However, macrophages need to be isolated and purified in order to evaluate the mRNA expression. There are no reliable and simple methods for detection of macrophage markers which would not require cell purification. Here we report the development and validation of a novel flow cytometric macrophage phenotyping method.
Murine macrophage RAW 264.7 cells were treated with endotoxin and IFN-γ to stimulate iNOS expression. Alternatively, RAW 264.7 cells were stimulated with 8-bromo-cAMP to induce arginase 1 expression. Our new technique allowed successful detection of iNOS expression in RAW 264.7 cells by flow cytometry, which correlated well with NO production measured by Griess assay. We also developed a method which allowed us to successfully detect the Arginase I expression by flow cytometry. Arginase I expression also correlated well with arginase activity as measured by an Abnova arginase assay kit.
Our results suggest that murine macrophage phenotype can be successfully determined by flowcytometric measurement of iNOS and arginase 1 expression.
Establishment of a humanized lupus model
Authors: Ren Jingjing , Liao Xiaofeng , Luo Xin M 
Published: January 2023

Abstract
Systemic lupus erythematosus (SLE), a systemic autoimmune disease, involves mild to severe manifestations in multiple organs. Currently, lupus-prone mouse models are used to understand the mechanisms of SLE development and discover new therapies. However, due to differences between rodents and humans, such as physiological development, disease progression, and response to therapies and drugs, many mechanisms and therapies discovered in mice may not be efficiently transferred from murine lupus models to SLE patients. Here we present a humanized mouse model of lupus as a new technology to bridge the gap between rodent models and patients. In our model, which involves vigorous selection of donors, we engraft peripheral blood mononuclear cells (PBMCs) from SLE patients into NOD/SCID/IL2Rgnull (NSG) mice to build a human-specific disease-based immune system in the mice. To avoid graft versus host disease, we stimulate PBMCs before transferring them into either female or male NSG mice. This method enhances the survival and maintenance of the engrafted cells. Human T cells and B cells that are critical to lupus development can be detected in the peripheral blood and spleen of humanized mice with no sex preference two weeks after engraftment. The model responds well to dexamethasone treatment with reduced proteinuria and decrease of spleen weight, indicating that our model could be used for preclinical studies for SLE. The therapeutic window can be as long as 3 weeks. This model allows for mechanistic studies and testing of potential therapies of SLE directly on human immune system in vivo without putting human life at risk.
Effect of methanolic extract of Annona muricta leaves on macrophage effector functions
Authors: Cetina-Dorantes Adan Josue , Arana-Argaez Victor , Torres-Romero Julio , Canul-Canche Jaqueline , Ramirez-Camacho Mario 
Published: January 2023

Abstract

Introduction
Annona muricata (guanabana), is a common plant in various tropical regions of the world. Annona muricata is widely used in traditional Mayan medicine for the treatment of gastrointestinal diseases, skin infections, inflammatory disorders, sedative, to reduce fever and as a treatment for cancer and diabetes. The reports of the traditional medicine about its properties and recent studies suggest that Annona muricata could enhance the effector mechanisms of the immune system.

Aim of the study
The aim of this study was to evaluate the immunomodulatory effect of methanolic extract of Annona muricata (AML-ME) leaves on macrophage function.

Materials and methods
The effect of Annona muricata on the immune system was tested in the monocyte THP-1 cell line. Prior to any test, the monocytes were differentiated to macrophages by the action of 100 ng/mL PMA for 24 hours The effect of AML-ME (75–800 μg/mL) on macrophage proliferation was measured using the MTT assay. The effect of AML-ME on production of nitric oxide, IL-6 and tumor necrosis factor alfa (TNF-α) production was assessed on macrophages treated with the AML-ME (75–800 μg/mL) for 24 hours and later activated with Escherichia coli lipopolysaccharide for another 24 hours.

Results
AML-ME showed to have no effect on THP-1 macrophages proliferation. However, it promotes, in a concentration-dependent manner, the production of nitric oxide, IL-6 and TNF-α.

Conclusion
The methanolic extract of Annona muricata leaves possesses immunomodulatory properties capable of modulate the effector functions of human macrophages. Further studies to elucidate the components of the extract as well as the mechanism of action this molecules are recommended
Stimulating antigen-specific regulatory T cells for an atherosclerosis vaccine
Authors: Benne Naomi , Jiskoot Wim , Kuiper Johan , Slutter Bram 
Published: January 2023

Abstract
Atherosclerosis is a chronic inflammatory disease of the large and medium sized arteries affecting millions of people world-wide. It is characterised by sub-endothelial retention of low density lipoprotein (LDL), which, over time, leads to the formation of an atherosclerotic plaque. Regulatory T cells (Treg) have been shown to reduce chronic inflammation in atherosclerosis and provide a protective effect. Whereas repeated immunisations with high doses of plaque-specific antigens can induce Treg and reduce the atherosclerotic plaques, particulate formulations may require fewer immunisations and less antigen by specific targeting of the immune system. Therefore, we optimised liposomal formulations to elicit potent Treg responses. Liposomes (average diameter 150–200 nm) consisting of the lipids DSPC, DSPG and cholesterol in different molar ratios were loaded with an ovalbumin-derived CD4+ T cell-specific peptide (OVA323). Murine BMDCs were pulsed with formulations and subsequently cultured with OT-II transgenic CD4+T cells. Compared to free OVA323 or OVA323 mixed with empty liposomes, encapsulation of OVA323 induced increased numbers of Treg as measured by FoxP3 expression. Interestingly, liposomes with the composition 4:1:2 DSPC:DSPG:cholesterol induced the highest Treg responses and also prevented Th1 differentiation as determined by IFN-γ production. Subsequent studies suggest that the 4:1:2 liposomes achieve the optimal balance of antigen loading, flexibility and surface charge to induce Treg. In conclusion, this indicates that liposome composition influences Treg differentiation and liposomes may be used to elicit antigen-specific Treg responses for atherosclerosis vaccination.
CD48 is upregulated on pathogenic CD4+ T cells and is a therapeutic target in experimental autoimmune encephalomyelitis
Authors: McArdel Shannon , Brown Daniel , Sharpe Arlene H 
Published: January 2023

Abstract
CD48 (SLAMF2) is an adhesion and costimulation molecule constitutively expressed on hematopoietic cells, and a member of the signaling lymphocyte activation molecule family of immune receptors. Polymorphisms in CD48 have been linked to susceptibility to multiple sclerosis (MS), and differential expression of its homolog CD58 (LFA-3), found exclusively in humans, is associated with disease remission in MS. We examined CD48 expression on lymphocytes during experimental autoimmune encephalomyelitis (EAE), a mouse model of MS, and found that a population of CD4+ T cells upregulated CD48 expression during disease. CD48++ CD4+ T cells were predominantly CD44+ and Ki67+, were most prominent in the CNS, and included IL-17+, GM-CSF+ and IFN-γ+ cells. Administration of an anti-CD48 mAb during EAE attenuated both clinical disease and accumulation of lymphocytes in the CNS. Treatment coincided with reduced expansion of effector CD4+ T cells and reduced numbers of pathogenic cytokine-producing CD4+ T cells in the spleen at early time points. These effects were partially dependent on FcγRs, as anti-CD48 could not limit disease in Fcɛr1γ−/− mice or in wild type mice receiving anti-CD16/CD32 mAb, and failed to reduce the number of cytokine-producing effector CD4+ T cells. Our data suggest that anti-CD48 mAb can both limit CD4+ T cell proliferation and preferentially deplete pathogenic CD4+ T cells during EAE, thereby preventing or attenuating disease. This highlights the potential of CD48 to serve as a marker of pathogenic effector T cells and a therapeutic target for autoimmunity.
A critical role of CD200R signaling in limiting the growth and metastasis of CD200 positive melanoma
Authors: Bai Xue-Feng , Liu Jin-Qing , Talebian Fatemeh , Wu Lisha , Markowitz Joseph , Wu Laichu , Carson William E , Basu Sujit 
Published: January 2023

Abstract
CD200 is a cell surface glycoprotein that functions through engaging CD200 receptor on cells of the myeloid lineage and inhibits their functions. Expression of CD200 has been implicated in a variety of human cancer cells including melanoma cells and has been thought to play a protumor role. However, our previous studies using B16 melanoma and J558 plasmacytoma models suggest that tumor expressed CD200 may inhibit tumor growth and metastasis via shaping tumor microenvironment. In this study, we have further evaluated the role of CD200R signaling in tumor growth and metastasis using CD200R-deficient mice. We found that CD200R-deficient mice exhibited accelerated growth of CD200-positive, but not CD200-negative B16 tumors. Strikingly, CD200R-deficient mice receiving CD200-positive B16 cells intravenously exhibited massive tumor growth in multiple organs including liver, lung, kidney and peritoneal cavity, while the growth of the same tumors in wild type mice is limited. CD200-positive tumors grown in CD200R-deficient mice contained higher numbers of CD11b+Ly6C+ myeloid cells, exhibited increased expression of VEGF and HIF-1a genes with increased angiogenesis and showed significantly reduced infiltration of CD4+ and CD8+ T cells. The Liver from CD200R-deficient mice under metastatic growth of CD200-positive tumors contained significantly increased numbers of CD11b+Gr1− myeloid cells, FoxP3+ regulatory T cells; liver T cells also had reduced capacity in the production of IFN-g or TNF-a. Taken together, we have revealed critical roles of CD200R signaling in limiting the growth and metastasis of CD200 positive tumors.