scholarly journals The regulatory B cell–mediated peripheral tolerance maintained by mast cell IL-5 suppresses oxazolone-induced contact hypersensitivity

2019 ◽  
Vol 5 (7) ◽  
pp. eaav8152 ◽  
Author(s):  
Hyuk Soon Kim ◽  
Min Bum Lee ◽  
Dajeong Lee ◽  
Keun Young Min ◽  
Jimo Koo ◽  
...  
Keyword(s):  
Mast Cell ◽  
Inflammatory Diseases ◽  
Interleukin 10 ◽  
Lymphoid Cells ◽  
Peripheral Tolerance ◽  
Contact Hypersensitivity ◽  
Lymphoid Tissues ◽  
Dependent Manner ◽  
Peripheral Tissues ◽  
Regulatory B Cell

The function of regulatory immune cells in peripheral tissues is crucial to the onset and severity of various diseases. Interleukin-10 (IL-10)–producing regulatory B (IL-10+ Breg) cells are known to suppress various inflammatory diseases. However, evidence for the mechanism by which IL-10+ Breg cells are generated and maintained is still very limited. Here, we found that IL-10+ Breg cells suppress the activation of IL-13–producing type 2 innate lymphoid cells (IL-13+ ILC2s) in an IL-10–dependent manner in mice with oxazolone-induced severe contact hypersensitivity (CHS). Mast cell (MC) IL-5 was important for maintaining the population of IL-10+ Breg cells in peripheral lymphoid tissues. Overall, these results uncover a previously unknown mechanism of MCs as a type of immunoregulatory cell and elucidate the cross-talk among MCs, IL-10+ Breg cells, and IL-13+ ILC2s in CHS.

scholarly journals Regulation of contact hypersensitivity by interleukin 10.

1994 ◽  
Vol 179 (5) ◽  
pp. 1597-1604 ◽  
Author(s):  
T A Ferguson ◽  
P Dube ◽  
T S Griffith
Keyword(s):  
T Cells ◽  
Neutralizing Antibody ◽  
Inflammatory Cells ◽  
Interleukin 10 ◽  
Lymphoid Cells ◽  
Contact Hypersensitivity ◽  
Mrna Transcription ◽  
Antigenic Challenge ◽  
A Site

Contact hypersensitivity (CHS) responses require the participation of T cells, along with a variety of cytokines and adhesion molecules. In the classical CHS, antigen-specific T cells are recruited to a site of antigenic challenge, where they react with antigen, release cytokines, and attract other inflammatory cells. In the mouse model of CHS, this reaction is elicited in sensitized mice by application of the immunogen 4-7 d after immunization. The reaction peaks at 24 h, is slightly reduced by 48 h, and can return to normal by 72 h. This is in spite of the fact that some antigen is still present at the site of challenge. Here we examined the hypothesis that locally produced interleukin 10 (IL-10) regulates the duration of the response. Our data show that IL-10 protein peaked 10-14 h after antigenic challenge and returned to background by 24 h. The production of IL-10 protein corresponded with, and followed IL-10 mRNA transcription as detected by reverse transcriptase-polymerase chain reaction. During peak IL-10 production after antigenic challenge, it was not possible to transfer CHS with immune lymphoid cells, unless neutralizing antibody to IL-10 was given first. Additionally, when sensitized mice were given neutralizing anti-IL-10 antibody at the time of antigenic challenge, the duration of CHS was prolonged well beyond the natural course of the response. Finally, we demonstrate that rIL-10, when injected into the skin before antigenic challenge, prevented the elicitation of CHS in previously sensitized mice. Taken together, our data show an important role for IL-10 in the natural regulation of CHS responses in vivo.

scholarly journals Mast cells promote small bowel cancer in a tumor stage-specific and cytokine-dependent manner

2018 ◽  
Vol 115 (7) ◽  
pp. 1588-1592 ◽  
Author(s):  
Abdulrahman M. Saadalla ◽  
Abu Osman ◽  
Michael F. Gurish ◽  
Kristen L. Dennis ◽  
Nichole R. Blatner ◽  
...  
Keyword(s):  
T Cells ◽  
Mast Cell ◽  
Mast Cells ◽  
Small Bowel ◽  
Tumor Stroma ◽  
Tumor Stage ◽  
Lymphoid Cells ◽  
Dependent Manner ◽  
Multistep Process ◽  
Murine Mast Cell

Mast cells (MCs) are tissue resident sentinels that mature and orchestrate inflammation in response to infection and allergy. While they are also frequently observed in tumors, the contribution of MCs to carcinogenesis remains unclear. Here, we show that sequential oncogenic events in gut epithelia expand different types of MCs in a temporal-, spatial-, and cytokine-dependent manner. The first wave of MCs expands focally in benign adenomatous polyps, which have elevated levels of IL-10, IL-13, and IL-33, and are rich in type-2 innate lymphoid cells (ILC2s). These vanguard MCs adhere to the transformed epithelial cells and express murine mast cell protease 2 (mMCP2; a typical mucosal MC protease) and, to a lesser extent, the connective tissue mast cell (CTMC) protease mMCP6. Persistence of MCs is strictly dependent on T cell-derived IL-10, and their loss in the absence of IL-10–expressing T cells markedly delays small bowel (SB) polyposis. MCs expand profusely in polyposis-prone mice when T cells overexpress IL-10. The frequency of polyp-associated MCs is unaltered in response to broad-spectrum antibiotics, arguing against a microbial component driving their recruitment. Intriguingly, when polyps become invasive, a second wave of mMCP5+/mMCP6+ CTMCs expands in the tumor stroma and at invasive tumor borders. Ablation of mMCP6 expression attenuates polyposis, but invasive properties of the remaining lesions remain intact. Our findings argue for a multistep process in SB carcinogenesis in which distinct MC subsets, and their elaborated proteases, guide disease progression.

Antagonism of mmu-mir-106a attenuates asthma features in allergic murine model

2012 ◽  
Vol 113 (3) ◽  
pp. 459-464 ◽  
Author(s):  
Amit Sharma ◽  
Manish Kumar ◽  
Tanveer Ahmad ◽  
Ulaganathan Mabalirajan ◽  
Jyotirmoi Aich ◽  
...  
Keyword(s):  
Airway Inflammation ◽  
Inflammatory Diseases ◽  
Allergic Airway Inflammation ◽  
Interleukin 10 ◽  
Dependent Manner ◽  
Th2 Response ◽  
Lung Histology ◽  
Health And Disease

MicroRNAs (miRs) regulate immunological pathways in health and disease, and a number of miRs have been shown to be altered in mouse models of asthma. The secretion of interleukin-10 (IL-10), an anti-inflammatory cytokine, has been shown to be defective in many inflammatory diseases including asthma. We recently demonstrated that miR-106a inhibits IL-10 in a post-transcriptional manner. In this study, we investigated the effect of inhibition of mmu-miR106a in asthmatic condition to find its possible role as a therapeutic target. Our in vitro experiments with mouse macrophage, RAW264.7, revealed that mmu-miR-106a potentially decreased IL-10 along with increase in proinflammatory cytokine. Furthermore, administration of mmu-miR-106a to naive mice reduced IL-10 levels in lungs in a dose-dependent manner without altering lung histology. Most interestingly, knockdown of mmu-miR-106a in an established allergic airway inflammation has significantly alleviated most of the features of asthma such as airway hyperresponsiveness, airway inflammation, increased Th2 response, goblet cell metaplasia, and subepithelial fibrosis along with increase in IL-10 levels in lung. This represents the first in vivo proof of a miRNA-mediated regulation of IL-10 with a potential to reverse an established asthmatic condition.

scholarly journals Resveratrol Is a Natural Inhibitor of Human Intestinal Mast Cell Activation and Phosphorylation of Mitochondrial ERK1/2 and STAT3

2021 ◽  
Vol 22 (14) ◽  
pp. 7640
Author(s):  
Sabrina Bilotta ◽  
Lakshmi Bhargavi Paruchuru ◽  
Katharina Feilhauer ◽  
Jörg Köninger ◽  
Axel Lorentz
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Cell Activation ◽  
Inflammatory Diseases ◽  
Critical Role ◽  
Mast Cell Activation ◽  
Dependent Manner ◽  
Cytokines And Chemokines ◽  
Mitochondrial Fractions ◽  
Anti Inflammatory

Mast cells play a critical role as main effector cells in allergic and other inflammatory diseases. Usage of anti-inflammatory nutraceuticals could be of interest for affected patients. Resveratrol, a natural polyphenol found in red grapes, is known for its positive properties. Here, we analyzed the effects of resveratrol on FcεRI-mediated activation of mature human mast cells isolated from intestinal tissue (hiMC). Resveratrol inhibited degranulation and expression of cytokines and chemokines such as CXCL8, CCL2, CCL3, CCL4, and TNF-α in a dose-dependent manner. Further, resveratrol inhibited the phosphorylation of extracellular signal-regulated kinase (ERK) 1/2 and signal transducer and activator of transcription (STAT) 3. ERK1/2 is known to be involved in cytokine expression of hiMC and to directly interact with STAT3. Mitochondrial STAT3 is phosphorylated by ERK1/2 and contributes to mast cell degranulation. We were able to isolate mitochondrial fractions from small hiMC numbers and could show that activation of mitochondrial STAT3 and ERK1/2 in hiMC was also inhibited by resveratrol. Our results indicate that resveratrol inhibits hiMC activation by inhibiting the phosphorylation of mitochondrial and nuclear ERK1/2 and STAT3, and it could be considered as an anti-inflammatory nutraceutical in the treatment of mast cell-associated diseases.

scholarly journals IL-10-Producing ILCs: Molecular Mechanisms and Disease Relevance

2021 ◽  
Vol 12 ◽  
Author(s):  
Hui Sun ◽  
Yuzhang Wu ◽  
Yi Zhang ◽  
Bing Ni
Keyword(s):  
Nk Cells ◽  
Molecular Mechanisms ◽  
Inflammatory Diseases ◽  
Cell Types ◽  
Interleukin 10 ◽  
Vital Role ◽  
Lymphoid Cells ◽  
Stable Production ◽  
Disease Relevance ◽  
And Function

Innate lymphoid cells (ILCs) are mainly composed of natural killer (NK) cells and helper-like lymphoid cells, which play a vital role in maintaining tissue homeostasis, enhancing adaptive immunity and regulating tissue inflammation. Alteration of the distribution and function of ILCs subgroups are closely related to the pathogenesis of inflammatory diseases and cancers. Interleukin-10 (IL-10) is a highly pleiotropic cytokine, and can be secreted by several cell types, among of which ILCs are recently verified to be a key source of IL-10. So far, the stable production of IL-10 can only be observed in certain NK subsets and ILC2s. Though the regulatory mechanisms for ILCs to produce IL-10 are pivotal for understanding ILCs and potential intervenes of diseases, which however is largely unknown yet. The published studies show that ILCs do not share exactly the same mechanisms for IL-10 production with helper T cells. In this review, the molecular mechanisms regulating IL-10 production in NK cells and ILC2s are discussed in details for the first time, and the role of IL-10-producing ILCs in diseases such as infections, allergies, and cancers are summarized.

scholarly journals The role of lymphatics in intestinal inflammation

2021 ◽  
Vol 41 (1) ◽  
Author(s):  
Ryota Hokari ◽  
Akira Tomioka
Keyword(s):  
Immune Cell ◽  
Intestinal Inflammation ◽  
Inflammatory Diseases ◽  
Dietary Lipid ◽  
Peripheral Tolerance ◽  
Lipid Absorption ◽  
Lymphoid Tissues ◽  
Cell Trafficking ◽  
Lymphocyte Migration ◽  
And Function

AbstractThe lymphatic vasculature returns filtered interstitial arterial fluid and tissue metabolites to the blood circulation. It also plays a major role in lipid absorption and immune cell trafficking. Lymphatic vascular defects have been revealed in inflammatory diseases, Crohn’s disease, obesity, cardiovascular disease, hypertension, atherosclerosis, and Alzheimer’s disease. In this review, we discuss lymphatic structure and function within the gut, such as dietary lipid absorption, the transport of antigens and immune cells to lymph nodes, peripheral tolerance, and lymphocyte migration from secondary lymphoid tissues to the lymphatics and the immune systems. We also discuss the potential roles of these lymphatics on the pathophysiology of inflammatory bowel disease and as new targets for therapeutic management.

scholarly journals Evaluation of Anti-Inflammatory Activities of a Triterpene β-Elemonic Acid in Frankincense In Vivo and In Vitro

Molecules ◽  
2019 ◽  
Vol 24 (6) ◽  
pp. 1187 ◽  
Author(s):  
Yue Zhang ◽  
Ying-li Yu ◽  
Hua Tian ◽  
Ru-yu Bai ◽  
Ya-nan Bi ◽  
...  
Keyword(s):  
Inflammatory Diseases ◽  
Interleukin 10 ◽  
The Body ◽  
Raw264.7 Cells ◽  
Control Group ◽  
Intragastric Administration ◽  
Dependent Manner ◽  
Anti Inflammatory

The purpose of this research was to extract and separate the compounds from frankincense, and then evaluate their anti-inflammatory effects. The isolated compound was a representative tetracyclic triterpenes of glycine structure according to 1H-NMR and 13C-NMR spectra, which is β-elemonic acid (β-EA). We determined the content of six different localities of frankincense; the average content of β-EA was 41.96 mg/g. The toxic effects of β-EA administration (400, 200, 100 mg/kg) for four weeks in Kunming (KM) mice were observed. Compared with the control group, the body weight of mice, the visceral coefficients and serum indicators in the β-EA groups showed no systematic variations. The anti-inflammatory effects of β-EA were evaluated in LPS-induced RAW264.7 cells, xylene-induced induced ear inflammation in mice, carrageenin-induced paw edema in mice, and cotton pellet induced granuloma formation in rats. β-EA inhibited overproduction of tumor necrosis factor-α(TNF-α), interleukin-6 (IL-6), monocyte chemotactic protein 1 (MCP-1), soluble TNF receptor 1 (sTNF R1), Eotaxin-2, Interleukin 10 (IL-10) and granulocyte colony-stimulating factor (GCSF) in the RAW264.7 cells. Intragastric administration with β-EA (300, 200, and 100 mg/kg in mice, and 210, 140, and 70 mg/kg in rats) all produced distinct anti-inflammatory effects in vivo in a dose-dependent manner. Following treatment with β-EA (300 mg/kg, i.g.), the NO level in mice ears and PGE2 in mice paws both decreased (p < 0.01). In conclusion, our study indicates that β-EA could be a potential anti-inflammatory agent for the treatment of inflammatory diseases.

The neuropeptide neuromedin U activates eosinophils and is involved in allergen-induced eosinophilia

2006 ◽  
Vol 290 (5) ◽  
pp. L971-L977 ◽  
Author(s):  
Maiko Moriyama ◽  
Satoru Fukuyama ◽  
Hiromasa Inoue ◽  
Takafumi Matsumoto ◽  
Takahiro Sato ◽  
...  
Keyword(s):  
Cell Adhesion ◽  
Inflammatory Diseases ◽  
Human Peripheral Blood ◽  
Collagen Type I ◽  
Eosinophil Infiltration ◽  
Type I ◽  
Dependent Manner ◽  
Peripheral Tissues ◽  
Eosinophil Cell

Neuromedin U (NMU) is a neuropeptide expressed not only in the central nervous system but also in various organs, including the gastrointestinal tract and lungs. NMU interacts with two G protein-coupled receptors, NMU-R1 and NMU-R2. Although NMU-R2 is expressed in a specific region of the brain, NMU-R1 is expressed in various peripheral tissues, including immune and hematopoietic cells. Our recent study demonstrated an important role of NMU in mast cell-mediated inflammation. In this study, we showed that airway eosinophilia was reduced in NMU-deficient mice in an allergen-induced asthma model. There were no differences in the antigen-induced Th2 responses between wild-type and NMU knockout mice. NMU-R1 was highly expressed in the eosinophil cell line, and NMU directly induced Ca2+mobilization and extracellular/signal-regulated kinase phosphorylation. NMU also induced cell adhesion to components of the extracellular matrix (fibronectin and collagen type I), and chemotaxis in vitro. Furthermore, NMU-R1 was also expressed in human peripheral blood eosinophils, and NMU induced cell adhesion in a dose-dependent manner. These data indicate that NMU promotes eosinophil infiltration into inflammatory sites by directly activating eosinophils. Our study suggests that NMU receptor antagonists could be novel targets for pharmacological inhibition of allergic inflammatory diseases, including asthma.

scholarly journals The neuropeptide neuromedin U promotes inflammation by direct activation of mast cells

2005 ◽  
Vol 202 (2) ◽  
pp. 217-224 ◽  
Author(s):  
Maiko Moriyama ◽  
Takahiro Sato ◽  
Hiromasa Inoue ◽  
Satoru Fukuyama ◽  
Hitoshi Teranishi ◽  
...  
Keyword(s):  
Mast Cell ◽  
Mast Cells ◽  
Inflammatory Responses ◽  
Inflammatory Diseases ◽  
Neutrophil Infiltration ◽  
Mast Cell Degranulation ◽  
Plasma Extravasation ◽  
Intraplantar Injection ◽  
Peripheral Tissues ◽  
Deficient Mice

Neuromedin U (NMU) is a neuropeptide that is expressed in the gastrointestinal tract and central nervous system. NMU interacts with two G protein–coupled receptors, NMU-R1 and NMU-R2. Whereas NMU-R2 localizes predominantly to nerve cells, NMU-R1 is expressed in peripheral tissues including lymphocytes and monocytes, suggesting a role of NMU in immunoregulation. However, the functions of NMU in peripheral tissues have not been clarified. In this study, using NMU-deficient mice, we first demonstrated that NMU plays an important role in mast cell-mediated inflammation. Complete Freund's adjuvant-induced mast cell degranulation as well as edema and neutrophil infiltration, which occurred weakly in mast cell–deficient WBB6F1-W/Wv mice, did not occur in NMU-deficient mice. Moreover, intraplantar injection of NMU into paws induced early inflammatory responses such as mast cell degranulation, vasodilation, and plasma extravasation in WT mice but not in WBB6F1-W/Wv mice. NMU-R1 was highly expressed in primary mast cells, and NMU induced Ca2+ mobilization and degranulation in peritoneal mast cells. These data indicate that NMU promotes mast cell–mediated inflammation; therefore, NMU receptor antagonists could be a novel target for pharmacological inhibition of mast cell–mediated inflammatory diseases.

scholarly journals Group 2 innate lymphoid cells in bone marrow regulate osteoclastogenesis in a reciprocal manner via RANKL, GM-CSF and IL-13

2021 ◽  
Author(s):  
Yoshiki Momiuchi ◽  
Yasutaka Motomura ◽  
Emiko Suga ◽  
Hiroki Mizuno ◽  
Junichi Kikuta ◽  
...  
Keyword(s):  
Bone Marrow ◽  
Innate Lymphoid Cells ◽  
Lymphoid Cells ◽  
M2 Macrophage ◽  
Dependent Manner ◽  
Bone Homeostasis ◽  
Rankl Expression ◽  
Peripheral Tissues ◽  
Gm Csf ◽  
Group 2

Abstract Group 2 innate lymphoid cells (ILC2s) are tissue-resident cells that play different roles in different organs by sensing surrounding environmental factors. Initially, it was thought that ILC2s in bone marrow (BM) are progenitors for systemic ILC2s, which migrate to other organs and acquire effector functions. However, accumulating evidence that ILC2s differentiate in peripheral tissues suggests that BM ILC2s may play a specific role in the BM as a unique effector per se. Here, we demonstrate that BM ILC2s highly express the receptor activator of nuclear factor κB ligand (RANKL), a robust cytokine for osteoclast differentiation and activation, and RANKL expression on ILC2s is up-regulated by interleukin (IL)-2, IL-7 and all-trans retinoic acid (ATRA). BM ILC2s co-cultured with BM-derived monocyte/macrophage lineage cells (BMMs) in the presence of IL-7 induce the differentiation of tartrate-resistant acid phosphatase (TRAP)-positive osteoclasts in a RANKL-dependent manner. In contrast, BM ILC2s stimulated with IL-33 down-regulate RANKL expression and convert BMMs differentiation into M2 macrophage-like cells rather than osteoclasts by granulocyte macrophage colony-stimulating factor (GM-CSF) and IL-13 production. Intravital imaging using two-photon microscopy revealed that a depletion of ILC2s prominently impaired in vivo osteoclast activity in an IL-7 plus ATRA-induced bone loss mouse model. These results suggest that ILC2s regulate osteoclast activation and contribute to bone homeostasis in both steady state and IL-33-induced inflammation.

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