Loss of Bladder Epithelium Induced by Cytolytic Mast Cell Granules

Choi, Hae Woong; Bowen, Samantha; Miao, Yanying; Chan, Cheryl; Miao, Edward A.; Åbrink, Magnus; Moeser, Adam J.; Abraham, Soman N.

doi:10.1016/j.immuni.2016.11.003

Cited by 72 publications

(75 citation statements)

References 35 publications

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“…However, during infections with helminth parasites, connective tissue mast cells migrate closer to the mucosal surfaces and may change their protease expression [57,59]. In addition, a recent study showed that activated urine bladder mast cells released granules containing chymase/mMCP-4, inducing apoptosis and shedding of the epithelial umbrella cells, to remove the infection with uropathogenic E. coli [60]. Furthermore, in the intestine mMCP-4 contributes to homeostatic epithelial cell migration and barrier function [34].…”

Section: Discussionmentioning

confidence: 99%

The Chymase Mouse Mast Cell Protease-4 Regulates Intestinal Cytokine Expression in Mature Adult Mice Infected with Giardia intestinalis

Peirasmaki

Svärd

et al. 2020

Cells

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Mast cells have been shown to affect the control of infections with the protozoan parasite Giardia intestinalis. Recently, we demonstrated that Giardia excretory-secretory proteins inhibited the activity of the connective tissue mast cell-specific protease chymase. To study the potential role of the chymase mouse mast cell protease (mMCP)-4 during infections with Giardia, mMCP-4 +/+ and mMCP-4 −/− littermate mice were gavage-infected with G. intestinalis trophozoites of the human assemblage B isolate GS. No significant changes in weight gain was observed in infected young (≈10 weeks old) mMCP-4 −/− and mMCP-4 +/+ littermate mice. In contrast, infections of mature adult mice (>18 weeks old) caused significant weight loss as compared to uninfected control mice. We detected a more rapid weight loss in mMCP-4 −/− mice as compared to littermate mMCP-4 +/+ mice. Submucosal mast cell and granulocyte counts in jejunum increased in the infected adult mMCP-4 −/− and mMCP-4 +/+ mice. This increase was correlated with an augmented intestinal trypsin-like and chymotrypsin-like activity, but the myeloperoxidase activity was constant. Infected mice showed a significantly lower intestinal neutrophil elastase (NE) activity, and in vitro, soluble Giardia proteins inhibited human recombinant NE. Serum levels of IL-6 were significantly increased eight and 13 days post infection (dpi), while intestinal IL-6 levels showed a trend to significant increase 8 dpi. Strikingly, the lack of mMCP-4 resulted in significantly less intestinal transcriptional upregulation of IL-6, TNF-α, IL-25, CXCL2, IL-2, IL-4, IL-5, and IL-10 in the Giardia-infected mature adult mice, suggesting that chymase may play a regulatory role in intestinal cytokine responses.Cells 2020, 9, 925 2 of 19 infections, including infections with G. intestinalis [9][10][11]. However, there is little insight into how Giardia spp. cause disease; they are not invasive and secrete no known toxins [12]. Recent research suggests that G. intestinalis can secrete a large number of immunomodulatory proteins, possibly regulating host immune responses [13][14][15][16]. However, the mechanisms on how interactions between the host and Giardia either lead to parasite clearance or to disease remain to be understood.Recent studies have shown the importance of different immune cells in giardiasis, where both innate and adaptive immunity seem to play significant roles [17][18][19]. Accumulated data suggest that there is a mixed Th1/Th2/Th17 response during giardiasis [19,20]. When G. intestinalis attach to the microvillus brush border of intestinal epithelial cells (IECs) there is a production of chemokines and cytokines that will attract immune cells to the intestinal submucosa [20][21][22]. However, the effects differ depending on model systems used. In cultured human IECs challenged by G. intestinalis trophozoites (assemblage B, isolate GS), several chemokines were highly up-regulated early-at 1.5 h after challenge [21]. In experimental infections of gerbils with the WB isolate (ATCC 50803)...

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Section: Discussionmentioning

confidence: 99%

The Chymase Mouse Mast Cell Protease-4 Regulates Intestinal Cytokine Expression in Mature Adult Mice Infected with Giardia intestinalis

Peirasmaki

Svärd

et al. 2020

Cells

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“…These studies were performed using Mcpt4 −/− mice, which do not exhibit any marked defect in the expression of proteases with trypsin‐like or CPA activity, for example, MCPT6 or CPA3, respectively . In the first study, Choi et al investigated how mast cells contribute to protection against urinary tract infections (UTIs) caused by uropathogenic E. coli . Uropathogenic E. coli gain access to the bladder and rapidly invade superficial bladder epithelial cells to avoid being flushed out when urine is voided.…”

Section: Mast Cells and Bacterial Infectionsmentioning

confidence: 99%

“…These studies were performed using Mcpt4 −/− mice, which do not exhibit any marked defect in the expression of proteases with trypsinlike or CPA activity, for example, MCPT6 or CPA3, respectively. 42 In the first study, Choi et al 60 The second study was performed by our own group. By using mice with c-KIT-independent mast cell deficiency, we showed that mast cells are required for an effective immune response during systemic GBS infections.…”

Section: Protective Effects Of Mast Cell-restricted Proteasesmentioning

confidence: 99%

The contribution of mast cells to bacterial and fungal infection immunity

Piliponsky

Romani

2018

Immunological Reviews

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Mast cells are hematopoietic progenitor-derived, granule-containing immune cells that are widely distributed in tissues that interact with the external environment, such as the skin and mucosal tissues. It is well-known that mast cells are significantly involved in IgE-mediated allergic reactions, but because of their location, it has also been long hypothesized that mast cells can act as sentinel cells that sense pathogens and initiate protective immune responses. Using mast cell or mast cell protease-deficient murine models, recent studies by our groups and others indicate that mast cells have pleiotropic regulatory roles in immunological responses against pathogens. In this review, we discuss studies that demonstrate that mast cells can either promote host resistance to infections caused by bacteria and fungi or contribute to dysregulated immune responses that can increase host morbidity and mortality. Overall, these studies indicate that mast cells can influence innate immune responses against bacterial and fungal infections via multiple mechanisms. Importantly, the contribution of mast cells to infection outcomes depends in part on the infection model, including the genetic approach used to assess the influence of mast cells on host immunity, hence highlighting the complexity of mast cell biology in the context of innate immune responses.

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“…will be important to identify potential downstream targets aimed at suppressing MC degranulation and disease. Alternatively, knowledge of how CRF 1 enhances MC function could also be applied to situations in which augmenting MC responses would be beneficial to the host, such as for the clearance of pathogens [70,71] or as vaccine adjuvants [72,73].…”

Section: Discussionmentioning

confidence: 99%

Frontline Science: Corticotropin-releasing factor receptor subtype 1 is a critical modulator of mast cell degranulation and stress-induced pathophysiology

Ayyadurai

Gibson²,

D’Costa

et al. 2017

Journal of Leukocyte Biology

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Life stress is a major risk factor in the onset and exacerbation of mast cell-associated diseases, including allergy/anaphylaxis, asthma, and irritable bowel syndrome. Although it is known that mast cells are highly activated upon stressful events, the mechanisms by which stress modulates mast cell function and disease pathophysiology remains poorly understood. Here, we investigated the role of corticotropin-releasing factor receptor subtype 1 (CRF) in mast cell degranulation and associated disease pathophysiology. In a mast cell-dependent model of IgE-mediated passive systemic anaphylaxis (PSA), prophylactic administration of the CRF-antagonist antalarmin attenuated mast cell degranulation and hypothermia. Mast cell-deficient mice engrafted with CRF bone marrow-derived mast cells (BMMCs) exhibited attenuated PSA-induced serum histamine, hypothermia, and clinical scores compared with wild-type BMMC-engrafted mice. mice engrafted with CRF BMMCs also exhibited suppressed in vivo mast cell degranulation and intestinal permeability in response to acute restraint stress. Genetic and pharmacologic experiments with murine BMMCs, rat RBL-2H3, and human LAD2 mast cells demonstrated that although CRF activation did not directly induce MC degranulation, CRF signaling potentiated the degranulation responses triggered by diverse mast cell stimuli and was associated with enhanced release of Ca from intracellular stores. Taken together, our results revealed a prominent role for CRF signaling in mast cells as a positive modulator of stimuli-induced degranulation and in vivo pathophysiologic responses to immunologic and psychologic stress.

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Loss of Bladder Epithelium Induced by Cytolytic Mast Cell Granules

Cited by 72 publications

References 35 publications

The Chymase Mouse Mast Cell Protease-4 Regulates Intestinal Cytokine Expression in Mature Adult Mice Infected with Giardia intestinalis

The Chymase Mouse Mast Cell Protease-4 Regulates Intestinal Cytokine Expression in Mature Adult Mice Infected with Giardia intestinalis

The contribution of mast cells to bacterial and fungal infection immunity

Frontline Science: Corticotropin-releasing factor receptor subtype 1 is a critical modulator of mast cell degranulation and stress-induced pathophysiology

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