C3a-derived peptide binds to the type I Fc R and inhibits proximal-coupling signal processes and cytokine secretion by mast cells

It is well known that mast cells (MCs) initiate type I allergic reactions and inflammation in a quick response to the various stimulants, including—but not limited to—allergens, pathogen-associated molecular patterns (PAMPs), and damage-associated molecular patterns (DAMPs). MCs highly express receptors of these ligands and proteases (e.g., tryptase, chymase) and cytokines (TNF), and other granular components (e.g., histamine and serotonin) and aggravate the allergic reaction and inflammation. On the other hand, accumulated evidence has revealed that MCs also possess immune-regulatory functions, suppressing chronic inflammation and allergic reactions on some occasions. IL-2 and IL-10 released from MCs inhibit excessive immune responses. Recently, it has been revealed that allergen immunotherapy modulates the function of MCs from their allergic function to their regulatory function to suppress allergic reactions. This evidence suggests the possibility that manipulation of MCs functions will result in a novel approach to the treatment of various MCs-mediated diseases.

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Antigen-Induced Release of Esterase (Protease) Activity from Rat Mast Cells as a Modulator of Type I Allergic Reaction?

International Archives of Allergy and Immunology ◽

10.1159/000232893 ◽

1981 ◽

Vol 66 (1) ◽

pp. 159-164 ◽

Cited By ~ 2

Author(s):

O.-H. Wilhelms ◽

E. Roesch

Keyword(s):

Mast Cells ◽

Allergic Reaction ◽

Protease Activity ◽

Type I ◽

Rat Mast Cells

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Beyond IgE: Alternative Mast Cell Activation Across Different Disease States

International Journal of Molecular Sciences ◽

10.3390/ijms21041498 ◽

2020 ◽

Vol 21 (4) ◽

pp. 1498 ◽

Cited By ~ 7

Author(s):

David O. Lyons ◽

Nicholas A. Pullen

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Cell Activation ◽

Autoimmune Disorders ◽

Receptor Expression ◽

Mast Cell Activation ◽

Food Allergies ◽

Type I ◽

Disease States ◽

Ige Mediated

Mast cells are often regarded through the lens of IgE-dependent reactions as a cell specialized only for anti-parasitic and type I hypersensitive responses. However, recently many researchers have begun to appreciate the expansive repertoire of stimuli that mast cells can respond to. After the characterization of the interleukin (IL)-33/suppression of tumorigenicity 2 (ST2) axis of mast cell activation—a pathway that is independent of the adaptive immune system—researchers are revisiting other stimuli to induce mast cell activation and/or subsequent degranulation independent of IgE. This discovery also underscores that mast cells act as important mediators in maintaining body wide homeostasis, especially through barrier defense, and can thus be the source of disease as well. Particularly in the gut, inflammatory bowel diseases (Crohn’s disease, ulcerative colitis, etc.) are characterized with enhanced mast cell activity in the context of autoimmune disease. Mast cells show phenotypic differences based on tissue residency, which could manifest as different receptor expression profiles, allowing for unique mast cell responses (both IgE and non-IgE mediated) across varying tissues as well. This variety in receptor expression suggests mast cells respond differently, such as in the gut where immunosuppressive IL-10 stimulates the development of food allergy or in the lungs where transforming growth factor-β1 (TGF-β1) can enhance mast cell IL-6 production. Such differences in receptor expression illustrate the truly diverse effector capabilities of mast cells, and careful consideration must be given toward the phenotype of mast cells observed in vitro. Given mast cells’ ubiquitous tissue presence and their capability to respond to a broad spectrum of non-IgE stimuli, it is expected that mast cells may also contribute to the progression of autoimmune disorders and other disease states such as metastatic cancer through promoting chronic inflammation in the local tissue microenvironment and ultimately polarizing toward a unique Th17 immune response. Furthermore, these interconnected, atypical activation pathways may crosstalk with IgE-mediated signaling differently across disorders such as parasitism, food allergies, and autoimmune disorders of the gut. In this review, we summarize recent research into familiar and novel pathways of mast cells activation and draw connections to clinical human disease.

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Mast Cell Responses to Viruses and Pathogen Products

International Journal of Molecular Sciences ◽

10.3390/ijms20174241 ◽

2019 ◽

Vol 20 (17) ◽

pp. 4241 ◽

Cited By ~ 21

Author(s):

Jean S. Marshall ◽

Liliana Portales-Cervantes ◽

Edwin Leong

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Immune Responses ◽

Viral Infection ◽

Viral Infections ◽

Inflammatory Responses ◽

Local Source ◽

Type I ◽

Viral Challenge ◽

Cell Responses

Mast cells are well accepted as important sentinel cells for host defence against selected pathogens. Their location at mucosal surfaces and ability to mobilize multiple aspects of early immune responses makes them critical contributors to effective immunity in several experimental settings. However, the interactions of mast cells with viruses and pathogen products are complex and can have both detrimental and positive impacts. There is substantial evidence for mast cell mobilization and activation of effector cells and mobilization of dendritic cells following viral challenge. These cells are a major and under-appreciated local source of type I and III interferons following viral challenge. However, mast cells have also been implicated in inappropriate inflammatory responses, long term fibrosis, and vascular leakage associated with viral infections. Progress in combating infection and boosting effective immunity requires a better understanding of mast cell responses to viral infection and the pathogen products and receptors we can employ to modify such responses. In this review, we outline some of the key known responses of mast cells to viral infection and their major responses to pathogen products. We have placed an emphasis on data obtained from human mast cells and aim to provide a framework for considering the complex interactions between mast cells and pathogens with a view to exploiting this knowledge therapeutically. Long-lived resident mast cells and their responses to viruses and pathogen products provide excellent opportunities to modify local immune responses that remain to be fully exploited in cancer immunotherapy, vaccination, and treatment of infectious diseases.

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Hispidulin Inhibits Mast Cell-Mediated Allergic Inflammation through Down-Regulation of Histamine Release and Inflammatory Cytokines

Molecules ◽

10.3390/molecules24112131 ◽

2019 ◽

Vol 24 (11) ◽

pp. 2131 ◽

Cited By ~ 6

Author(s):

Dong Eun Kim ◽

Kyoung-jin Min ◽

Min-Jong Kim ◽

Sang-Hyun Kim ◽

Taeg Kyu Kwon

Keyword(s):

Mast Cells ◽

Inflammatory Cytokines ◽

Immunoglobulin E ◽

Inflammatory Diseases ◽

Allergic Inflammation ◽

Interleukin 4 ◽

Type I ◽

Ige Mediated ◽

Factor Α ◽

Jnk Activation

Hispidulin (4′,5,7-trihydroxy-6-methoxyflavone) is a natural compound derived from traditional Chinese medicinal herbs, and it is known to have an anti-inflammatory effect. Here, we investigated the effect of hispidulin on the immunoglobulin E (IgE)-mediated allergic responses in rat basophilic leukemia (RBL)-2H3 mast cells. When RBL-2H3 cells were sensitized with anti-dinitrophenyl (anti-DNP) IgE and subsequently stimulated with DNP-human serum albumin (HSA), histamine and β-hexosaminidase were released from the cells by degranulation of activated mast cells. However, pretreatment with hispidulin before the stimulation of DNP-HSA markedly attenuated release of both in anti-DNP IgE-sensitized cells. Furthermore, we investigated whether hispidulin inhibits anti-DNP IgE and DNP-HSA-induced passive cutaneous anaphylaxis (PCA), as an animal model for Type I allergies. Hispidulin markedly decreased the PCA reaction and allergic edema of ears in mice. In addition, activated RBL-2H3 cells induced the expression of inflammatory cytokines (tumor necrosis factor-α and interleukin-4), which are critical for the pathogenesis of allergic disease, through the activation of c-Jun N-terminal kinase (JNK). Inhibition of JNK activation by hispidulin treatment reduced the induction of cytokine expression in the activated mast cells. Our results indicate that hispidulin might be a possible therapeutic candidate for allergic inflammatory diseases through the suppression of degranulation and inflammatory cytokines expression.

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Role of common cytokine receptor γ chain (γc)– and Jak3-dependent signaling in the proliferation and survival of murine mast cells

Blood ◽

10.1182/blood.v96.6.2172 ◽

2000 ◽

Vol 96 (6) ◽

pp. 2172-2180 ◽

Cited By ~ 92

Author(s):

Kotaro Suzuki ◽

Hiroshi Nakajima ◽

Norihiko Watanabe ◽

Shin-ichiro Kagami ◽

Akira Suto ◽

...

Keyword(s):

Bone Marrow ◽

Mast Cells ◽

Cytokine Receptor ◽

Type I ◽

Dependent Manner ◽

Type Ii ◽

Wild Type ◽

Peritoneal Mast Cells ◽

The Common

Abstract The regulatory roles of the common cytokine receptor γ chain (γc)– and Jak3-dependent signaling in the proliferation and survival of mast cells were determined using γc-deficient (γc−) and Jak3-deficient (Jak3−) mice. Although the mast cells in γc− and Jak3− mice were morphologically indistinguishable from those in wild-type mice, the number of peritoneal mast cells was decreased in γc− and Jak3− mice as compared with that in wild-type mice. Among γc-related cytokines, interleukin (IL)-4 and IL-9, but not IL-2, IL-7, or IL-15, enhanced the proliferation and survival of bone marrow–derived mast cells (BMMCs) from wild-type mice. However, the effects of IL-4 and IL-9 were absent in BMMCs from γc− and Jak3−mice. In addition, IL-4Rα, γc, and Jak3, but not IL-2Rβ or IL-7Rα, were expressed in BMMCs. In contrast, IL-13 did not significantly induce the proliferation and survival of BMMCs even from wild-type mice, and IL-13Rα1 was not expressed in BMMCs. Furthermore, IL-4 phosphorylated the 65-kd isoform of Stat6 in BMMCs from wild-type mice but not from γc− and Jak3− mice. These results indicate that γc- and Jak3-dependent signaling is essential for IL-4– and IL-9–induced proliferation and survival of murine mast cells, that the effects of IL-4 are mediated by type I IL-4R and that type II IL-4R is absent on mast cells, and that IL-4 phosphorylates the 65-kd isoform of Stat6 in mast cells in a γc- and Jak3-dependent manner.

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