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

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.

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Granzyme D Is a Novel Murine Mast Cell Protease That Is Highly Induced by Multiple Pathways of Mast Cell Activation

Infection and Immunity ◽

10.1128/iai.00290-13 ◽

2013 ◽

Vol 81 (6) ◽

pp. 2085-2094 ◽

Cited By ~ 3

Author(s):

Elin Rönnberg ◽

Gabriela Calounova ◽

Bengt Guss ◽

Anders Lundequist ◽

Gunnar Pejler

Keyword(s):

T Cells ◽

Mast Cell ◽

Mast Cells ◽

Serine Proteases ◽

Cell Activation ◽

Calcium Ionophore ◽

Mast Cell Activation ◽

Activated T Cells ◽

Mast Cell Protease ◽

Murine Mast Cell

ABSTRACTGranzymes are serine proteases known mostly for their role in the induction of apoptosis. Granzymes A and B have been extensively studied, but relatively little is known about granzymes C to G and K to M. T cells, lymphohematopoietic stromal cells, and granulated metrial gland cells express granzyme D, but the function of granzyme D is unknown. Here we show that granzyme D is expressed by murine mast cells and that its level of expression correlates positively with the extent of mast cell maturation. Coculture of mast cells with live, Gram-positive bacteria caused a profound, Toll-like receptor 2 (TLR2)-dependent induction of granzyme D expression. Granzyme D expression was also induced by isolated bacterial cell wall components, including lipopolysaccharide (LPS) and peptidoglycan, and by stem cell factor, IgE receptor cross-linking, and calcium ionophore stimulation. Granzyme D was released into the medium in response to mast cell activation. Granzyme D induction was dependent on protein kinase C and nuclear factor of activated T cells (NFAT). Together, these findings identify granzyme D as a novel murine mast cell protease and implicate granzyme D in settings where mast cells are activated, such as bacterial infection and allergy.

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Both Host-Type and Donor-Type Mast Cells Protect Against Acute Graft-Versus-Host Disease

Blood ◽

10.1182/blood.v122.21.3248.3248 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3248-3248

Author(s):

Raita Araki ◽

Hideaki Maeba ◽

Rie Kuroda ◽

Shintaro Mase ◽

Toshihiro Fujiki ◽

...

Keyword(s):

Bone Marrow ◽

T Cells ◽

Mast Cell ◽

Mast Cells ◽

Acute Gvhd ◽

Dependent Manner ◽

Spleen Cells ◽

Graft Versus Host ◽

Donor Type ◽

Deficient Mice

Abstract Originally mast cells have been known as effector cells in the IgE-mediated allergic responses. In addition, recent studies demonstrated that mast cells exerted pro-inflammatory or anti-inflammatory effects in complicated immune response depending on the situation. In allogeneic hematopoietic stem cell transplantation (HSCT), exact role of mast cells in graft-versus-host disease (GVHD) remains unclear. First we investigated whether host mast cells protect acute GVHD or not in a murine HSCT model using mast cell deficient mice. When lethally irradiated wild type (WT) B6 or mast cell deficient mice were transplanted with bone marrow cells and spleen cells from WT Balb/c mice, mast cell deficient B6 host mice showed significantly lower survival rate than WT B6 mice (p<0.01) due to acute GVHD. Moreover when irradiated mast cell deficient host mice (B6 derived) were given BM cells and splenocytes from mast cell deficient Balb/c mice, these mice died much faster compared to the mice receiving WT BM plus splenocytes (p<0.01) as shown below. Next, we demonstrated that bone marrow derived cultured mast cells (BMCMCs) inhibited mixed lymphocyte reaction (MLR) in a dose-dependent manner, when added to the coculture (Stimulator: dendritic cells (DCs) from B6, Responder: spleen cells of Balb/c, BMCMCs from B6). In addition when mast cells generated from the same strain of responder cells (Stimulator: DCs from B6, Responder: spleen cells from Balb/c, BMCMCs from Balb/c) were added to the MLR mixture, MLR was also suppressed even in this condition. Taken together, we have clearly demonstrated that both host-type and donor-type mast cells suppressed alloreaction in vivo and in vitro. However when we used anti-CD3 and anti-CD28 monoclonal antibodies to stimulate T-cells instead of DCs, BMCMCs could not suppress the lymphoproliferation any more. It suggested that mast cells could suppress MLR via the regulation of DCs directly, not T-cells. Next we have shown that BMCMCs dominantly regulated the alloreaction in a cell contact-dependent manner by using transwell system, though mast cells contain many kinds of substances to regulate immune reactions such as IL-10. DCs highly expressed costimulatory molecules such as CD80, CD86, CD40, I-A, however expression level of these molecules was not changed during coculture of BMCMCs and DCs. Finally, we compared the MLR suppression rate between naïve and activated BMCMCs using IgE and specific antigens, however no difference was observed between them. In conclusion, both host and donor-type mast cells have a protective role against acute GVHD. Disclosures: No relevant conflicts of interest to declare.

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Laminin-8 (alpha4beta1gamma1) is synthesized by lymphoid cells, promotes lymphocyte migration and costimulates T cell proliferation

Journal of Cell Science ◽

10.1242/jcs.114.2.423 ◽

2001 ◽

Vol 114 (2) ◽

pp. 423-433 ◽

Cited By ~ 1

Author(s):

T. Geberhiwot ◽

D. Assefa ◽

J. Kortesmaa ◽

S. Ingerpuu ◽

C. Pedraza ◽

...

Keyword(s):

T Cells ◽

Basement Membranes ◽

Lymphoid Cells ◽

T Cell Proliferation ◽

Expression Recognition ◽

Dependent Manner ◽

Lymphocyte Migration ◽

Cell Permeabilization ◽

Blood Lymphocytes ◽

Laminin 1

Laminins are a growing family of large heterotrimeric proteins with cell adhesive and signalling functions. They are major components of basement membranes and are found in many organs, including the vasculature and other compartments of bone marrow, thymus, lymph nodes and spleen. However, expression, recognition and use of laminin isoforms by lymphoid cells are poorly understood. In the present study, lymphoid T cells (Jurkat) were found to synthesize laminin alpha4, beta1 and gamma1 mRNAs and polypeptides and to assemble the chains into laminin-8. Lymphoblastoid B (NAD-20) cells, lymphoid NK (NKL) cells and blood lymphocytes also contained laminin-8 and, after cell permeabilization, practically all blood lymphocytes reacted with mAbs to laminin beta1 and gamma1 chains. Following stimulation, blood lymphocytes secreted laminin-8, and this laminin isoform, but not laminin-10/11(alpha5beta1gamma1/alpha5beta2gamma1), promoted chemokine-induced migration of the cells. In an activation-dependent manner, purified blood CD4 T cells adhered to immobilized laminin-8 and laminin-10/11 by using alpha6beta1 integrin, but minimally to laminin-1 (alpha1beta1gamma1). Accordingly, laminin-8 and laminin-10/11, but not laminin-1, strongly costimulated proliferation of the T cells via the same integrin. Thus, lymphoid cells are able to synthesize and secrete complete laminin molecules. In addition, synthesis of laminin-8 and recognition of laminin-8 and -10/11 by lymphocytes indicate relevance of these laminin isoforms in lymphocyte physiology.

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Immunologic mast cell-mediated responses and histamine release are attenuated by heparin

Journal of Applied Physiology ◽

10.1152/jappl.1992.73.3.1093 ◽

1992 ◽

Vol 73 (3) ◽

pp. 1093-1101 ◽

Cited By ~ 50

Author(s):

J. Lucio ◽

J. D'Brot ◽

C. B. Guo ◽

W. M. Abraham ◽

L. M. Lichtenstein ◽

...

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Histamine Release ◽

Immunoglobulin E ◽

Specific Antigen ◽

Calcium Ionophore ◽

Intradermal Injection ◽

Calcium Ionophore A23187 ◽

Ionophore A23187 ◽

Dependent Manner

Heparin has been shown to act as a competitive inhibitor of inositol 1,4,5-triphosphate (InsP3) receptors in various cell types. Because InsP3 is one of the second messengers involved in stimulus-secretion coupling in mast cells, it is possible that heparin may inhibit mast cell-mediated reactions. Therefore, in allergic sheep, we tested this hypothesis in two mast cell-mediated reactions induced by immunologic and nonimmunologic stimuli: immediate cutaneous reaction (ICR) and acute bronchoconstrictor response (ABR). In 12 sheep allergic to Ascaris suum antigen, the surface area of the skin wheal was determined 20 min after intradermal injection (0.05 ml) of increasing concentrations of specific antigen, compound 48/80, and histamine, without and after pretreatment with heparin (100, 300, or 1,000 U/kg i.v.). Antigen, compound 48/80, and histamine produced concentration-dependent increases in ICR. Heparin “partially” inhibited the ICR to antigen and compound 48/80 in a dose-dependent manner without modifying the ICR to histamine. The heparin preservative benzyl alcohol was ineffective. In 11 additional sheep, specific lung resistance was measured before and after inhalation challenges with antigen, compound 48/80, and histamine without and with aerosol heparin pretreatment (1,000 U/kg). Heparin blocked the antigen- and compound 48/80-induced bronchoconstriction without modifying the airway effects of histamine. In isolated human uterine mast cells, heparin inhibited the anti-immunoglobulin E- but not the calcium ionophore- (A23187) induced histamine release. These data suggest that heparin inhibits the ICR and ABR induced by stimuli that produce immunologic and nonimmunologic mast cell degranulation without attenuating the effects of histamine.(ABSTRACT TRUNCATED AT 250 WORDS)

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The transmembrane adaptor protein NTAL limits mast cell chemotaxis toward prostaglandin E2

Science Signaling ◽

10.1126/scisignal.aao4354 ◽

2018 ◽

Vol 11 (556) ◽

pp. eaao4354 ◽

Cited By ~ 1

Author(s):

Ivana Halova ◽

Monika Bambouskova ◽

Lubica Draberova ◽

Viktor Bugajev ◽

Petr Draber

Keyword(s):

Mast Cell ◽

Mast Cells ◽

T Cell Activation ◽

Cell Activation ◽

Adaptor Protein ◽

Prostaglandin E ◽

Dependent Manner ◽

And Function ◽

Cell Chemotaxis

Chemotaxis of mast cells is one of the crucial steps in their development and function. Non–T cell activation linker (NTAL) is a transmembrane adaptor protein that inhibits the activation of mast cells and B cells in a phosphorylation-dependent manner. Here, we studied the role of NTAL in the migration of mouse mast cells stimulated by prostaglandin E2 (PGE2). Although PGE2 does not induce the tyrosine phosphorylation of NTAL, unlike IgE immune complex antigens, we found that loss of NTAL increased the chemotaxis of mast cells toward PGE2. Stimulation of mast cells that lacked NTAL with PGE2 enhanced the phosphorylation of AKT and the production of phosphatidylinositol 3,4,5-trisphosphate. In resting NTAL-deficient mast cells, phosphorylation of an inhibitory threonine in ERM family proteins accompanied increased activation of β1-containing integrins, which are features often associated with increased invasiveness in tumors. Rescue experiments indicated that only full-length, wild-type NTAL restored the chemotaxis of NTAL-deficient cells toward PGE2. Together, these data suggest that NTAL is a key inhibitor of mast cell chemotaxis toward PGE2, which may act through the RHOA/ERM/β1-integrin and PI3K/AKT axes.

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Alisol B 23-Acetate Inhibits IgE/Ag-Mediated Mast Cell Activation and Allergic Reaction

International Journal of Molecular Sciences ◽

10.3390/ijms19124092 ◽

2018 ◽

Vol 19 (12) ◽

pp. 4092 ◽

Cited By ~ 1

Author(s):

Chen Shao ◽

Bingjie Fu ◽

Ning Ji ◽

Shunli Pan ◽

Xiaoxia Zhao ◽

...

Keyword(s):

Mast Cell ◽

Mast Cells ◽

Allergic Reaction ◽

Nuclear Factor Kappa B ◽

Immunoglobulin E ◽

Mast Cell Activation ◽

Human Mast Cell ◽

Dependent Manner ◽

Nuclear Factor ◽

Nuclear Factor Kappa

Alisol B 23-acetate (AB23A), a natural triterpenoid, has been reported to exert hepatoprotective and antitumor activities. Aiming to investigate the anti-inflammatory activity, this study examined the effect of AB23A on mast cells and allergic reaction. AB23A inhibited the degranulation of mast cells stimulated by immunoglobulin E/antigen (IgE/Ag), and also decreased the synthesis of leukotriene C4 (LTC4), production of interlukin-6 (IL-6), and expression of cyclooxygenase-2 (COX-2) in a concentration-dependent manner with no significant cytotoxicity in bone marrow-derived mast cells (BMMCs). AB23A inhibited spleen tyrosine kinase (Syk) and the downstream signaling molecules including phospholipase Cγ (PLCγ), serine-threonine protein kinase/inhibitor of nuclear factor kappa-B kinase/nuclear factor kappa-B (Akt/IKK/NF-κB), and mitogen-activated protein kinases/cytosolic phospholipase A2 (MAPK/cPLA2). Furthermore, AB23A blocked mobilization of Ca2+. Similar results were obtained in other mast cell lines Rat basophilic leukemia (RBL)-2H3 cells and a human mast cell line (HMC-1). In addition, AB23A attenuated allergic responses in an acute allergy animal model, passive cutaneous anaphylaxis (PCA). Taken together, this study suggests that AB23A inhibits the activation of mast cells and ameliorates allergic reaction, and may become a lead compound for the treatment of mast cell-mediated allergic diseases.

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IL-17+ Mast Cell/T Helper Cell Axis in the Early Stages of Acne

Frontiers in Immunology ◽

10.3389/fimmu.2021.740540 ◽

2021 ◽

Vol 12 ◽

Author(s):

Yoan Eliasse ◽

Edouard Leveque ◽

Lucile Garidou ◽

Louise Battut ◽

Brienne McKenzie ◽

...

Keyword(s):

T Cells ◽

Mast Cell ◽

Mast Cells ◽

Immune Cell ◽

T Helper Cell ◽

Helper Cell ◽

T Helper ◽

Cell Axis ◽

Early Stages ◽

Cutibacterium Acnes

Acne is a multifactorial disease driven by physiological changes occurring during puberty in the pilosebaceous unit (PSU) that leads to sebum overproduction and a dysbiosis involving notably Cutibacterium acnes. These changes in the PSU microenvironment lead to a shift from a homeostatic to an inflammatory state. Indeed, immunohistochemical analyses have revealed that inflammation and lymphocyte infiltration can be detected even in the infraclinical acneic stages, highlighting the importance of the early stages of the disease. In this study, we utilized a robust multi-pronged approach that included flow cytometry, confocal microscopy, and bioinformatics to comprehensively characterize the evolution of the infiltrating and resident immune cell populations in acneic lesions, beginning in the early stages of their development. Using a discovery cohort of 15 patients, we demonstrated that the composition of immune cell infiltrate is highly dynamic in nature, with the relative abundance of different cell types changing significantly as a function of clinical lesion stage. Within the stages examined, we identified a large population of CD69+ CD4+ T cells, several populations of activated antigen presenting cells, and activated mast cells producing IL-17. IL-17+ mast cells were preferentially located in CD4+ T cell rich areas and we showed that activated CD4+ T cells license mast cells to produce IL-17. Our study reveals that mast cells are the main IL-17 producers in the early stage of acne, underlying the importance of targeting the IL-17+ mast cell/T helper cell axis in therapeutic approaches.

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Changes in numbers and types of mast cell colony-forming cells in the peritoneal cavity of mice after injection of distilled water: evidence that mast cells suppress differentiation of bone marrow-derived precursors

Blood ◽

10.1182/blood.v71.3.573.573 ◽

1988 ◽

Vol 71 (3) ◽

pp. 573-580 ◽

Cited By ~ 25

Author(s):

Y Kanakura ◽

A Kuriu ◽

N Waki ◽

T Nakano ◽

H Asai ◽

...

Keyword(s):

Bone Marrow ◽

Mast Cell ◽

Mast Cells ◽

Peritoneal Cavity ◽

Bone Marrow Cells ◽

Water Injection ◽

Lymphoid Cells ◽

Distilled Water ◽

Peritoneal Mast Cells ◽

Chediak Higashi Syndrome

Abstract Two different types of cells in the peritoneal cavity of mice produce mast cell colonies in methylcellulose. “Large” mast cell colonies are produced by bone marrow-derived precursors resembling lymphoid cells by light microscopy (L-CFU-Mast), whereas “medium” and “small” mast cell colonies are produced by morphologically identifiable mast cells (M-CFU- Mast and S-CFU-Mast, respectively). In the present study we eradicated peritoneal mast cells by intraperitoneal (IP) injection of distilled water. The regeneration process was investigated to clarify the relationship between L-CFU-Mast, M-CFU-Mast, and S-CFU-Mast. After injection of distilled water, M-CFU-Mast and S-CFU-Mast disappeared, but L-CFU-Mast increased, and then M-CFU-Mast and S-CFU-Mast appeared, suggesting the presence of a hierarchic relationship. When purified peritoneal mast cells were injected two days after the water injection, the L-CFU-Mast did not increase. In the peritoneal cavity of WBB6F1-+/+ mice that had been lethally irradiated and rescued by bone marrow cells of C57BL/6-bgJ/bgJ (beige, Chediak-Higashi syndrome) mice, L-CFU-Mast were of bgJ/bgJ type, but M-CFU-Mast and S-CFU-Mast were of +/+ type. The injection of distilled water to the radiation chimeras resulted in the development of bgJ/bgJ-type M-CFU-Mast and then S-CFU-Mast. The presence of mast cells appeared to suppress the recruitment of L-CFU- Mast from the bloodstream and to inhibit the differentiation of L-CFU- Mast to M-CFU-Mast.

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Retinoic acid is a negative regulator for the differentiation of cord blood-derived human mast cell progenitors

Blood ◽

10.1182/blood.v95.9.2821.009k11_2821_2828 ◽

2000 ◽

Vol 95 (9) ◽

pp. 2821-2828 ◽

Cited By ~ 25

Author(s):

Tatsuya Kinoshita ◽

Kenichi Koike ◽

Hadija Hemed Mwamtemi ◽

Susumu Ito ◽

Shuichi Ishida ◽

...

Keyword(s):

Mast Cell ◽

Retinoic Acid ◽

Mast Cells ◽

Cord Blood ◽

Cell Development ◽

Negative Regulator ◽

Human Mast Cell ◽

Target Cells ◽

Dependent Manner ◽

Selective Agonist

We examined the effects of retinoids on the human mast cell development using a serum-deprived culture system. When 10-week cultured mast cells derived from CD34+ cord blood cells were used as target cells, both all-trans retinoic acid (ATRA) and 9-cis RA inhibited the progeny generation under stimulation with stem cell factor (SCF) in a dose-dependent manner (the number of progeny grown by SCF plus RA at 10−7 mol/L was one tenth of the value obtained by SCF alone). The early steps in mast cell development appear to be less sensitive to RA according to the single CD34+c-kit+ cord blood cell culture study. The optimal concentration of RAs also reduced the histamine concentration in the cultured mast cells (3.00 ± 0.47 pg per cell in SCF alone, 1.44 ± 0.18 pg per cell in SCF+ATRA, and 1.41 ± 0.10 pg per cell in SCF+9-cis RA). RT-PCR analyses showed the expression of RAR, RARβ, RXR, and RXRβ messenger ribonucleic acid (mRNA) in 10-week cultured mast cells. The addition of an RAR-selective agonist at 10−10 mol/L to 10−7 mol/L decreased the number of mast cells grown in SCF, whereas an RXR-selective agonist at up to 10−8 mol/L was inactive. Among RAR subtype selective retinoids used at 10−9 mol/L to 10−7 mol/L, only the RAR agonist was equivalent to ATRA at 10−7 mol/L in its ability to inhibit mast cell growth. Conversely, the addition of excess concentrations of a RAR antagonist profoundly counteracted the retinoid-mediated suppressive effects. These results suggest that RA inhibits SCF-dependent differentiation of human mast cell progenitors through a specific receptor.

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

Science Advances ◽

10.1126/sciadv.aav8152 ◽

2019 ◽

Vol 5 (7) ◽

pp. eaav8152 ◽

Cited By ~ 3

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.

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