Mast Cell Development Research Articles

Perinatal androgen exposure impacts mast cell development and sex differences in mast cell-mediated pathophysiology

Abstract Mast cell (MC)-associated diseases exhibit a sex bias with females often exhibiting more severe symptoms. Further, these sex biases exist in both prepubertal children and adults indicating that mechanisms other than adult sex hormones are involved. In previous studies, we showed that, compared with female MCs, male MCs store and release less histamine which coincided with reduced severity of MC-mediated anaphylaxis, and that these sex differences emerge prior to puberty. The early life mechanisms responsible for the emergence of sex differences in MC-associated disease remain poorly understood. Here we tested the hypothesis that perinatal androgen exposure, a major sexual organization event in males, drives sex differences in MC-mediated pathophysiology. Adult female mice that were previously exposed to high levels of androgens in the perinatal period (E16-PN7) via perinatal testosterone propionate administration had reduced IgE-mediated serum histamine levels and hypothermic responses compared with control females. In contrast, perinatal exposure of males to the endocrine disruptor DEHP, with known anti-androgenic effects, exacerbated IgE-mediated histamine levels and hypothermia. MC-deficient sash mice engrafted with BMMCs from adult perinatally androgenized females, exhibited reduced serum histamine and hypothermia responses compared with WT BMMC engrafted sash controls. Together, these data demonstrate that androgen exposure during the perinatal period shapes MC phenotype and MC-mediated anaphylaxis and thus could be an important determinant of differences in later life MC disease risk between the sexes.

Inhibition of JNK Signaling During Mast Cell Differentiation Promotes Altered Cytokine Secretion and Degranulation Profiles

Mast cells are large granulated leukocytes active in both innate and acquired immunity. These cells differentiate from hematopoietic stem cells, found in the medullary cavity of long trabecular bones. Increased inflammatory activity and numbers of mast cells contribute to allergic disease, which is of increasing concern worldwide. C‐jun N‐terminal kinase (JNK) is a major signaling node in the map kinase pathway that has been shown to contribute to IL‐3 signaling, known to promote murine mast cell differentiation. The aim of this research is to determine the role of JNK signaling in mast cell differentiation. Primary bone marrow‐derived mast cell (BMMC) cultures were established from C57BL/6 mice and differentiated for 7 weeks in the presence or absence of a JNK inhibitor (JNK‐IN‐8). Following removal of the inhibitor for 5 days, phenotypic and functional characteristics of BMMCs were probed using flow cytometry, ELISA, and β‐hexominidase release assays. Flow cytometric analysis of surface expression of the mast cell marker c‐kit, and levels of IgE bound to FcɛRI, a measure of mast cell sensitization, were unaffected by impaired JNK signaling compared to cells grown in the absence of inhibitor over mast cell differentiation, suggesting a normal mast cell phenotype with the potential to be activated via the allergen‐bound IgE‐dependent pathway. Cells differentiated under JNK inhibition showed a significant impairment in the secretion of IL‐6 (p<0.05) and IL‐13 (p<0.05) and a non‐significant impairment in TNF and CCL1 secretion at 24 hrs post‐activation compared to cells grown in the absence of inhibitor. Degranulation was also significantly decreased (by 25%; p<0.05) in BMMCs grown under JNK inhibition. To probe an epigenetic mechanistic role for histone acetylation changes in JNK‐impaired differentiation, expression of HDAC and HAT enzymes were considered by qPCR and western blotting, but were not modulated by JNK. These results suggest that JNK plays an important role in the development of a fully functional mast cell in the context of IgE‐mediated allergic inflammation and may warrant consideration as a strategy to regulate mast cell development in associated pathologies.Support or Funding InformationSupported by the Natural Sciences and Engineering Research Council of Canada (NSERC); Canada Foundation for Innovation (CFI); Government of Ontario and Brock University.

Immunohistochemical evaluation of CD117 in mast cell of aggressive periodontitis.

Context:Aggressive periodontitis is a type of inflammatory response in periodontal tissues that is differentiated from chronic by its earlier onset, its high rate of progression, subgingival microbial composition, the difference in the host's immune response, and family history of the disease. Mast cells live in tissues and contribute to the various allergic and inflammatory conditions, including periodontal diseases, through the release of cytokines, chemokines, and proteolytic enzymes. CD117, the receptor of the stem cell factor expressed by the mast cells, is the hallmark of mast cell development. This study aimed to determine the expression level of CD117 in the mast cells of aggressive periodontitis using immunohistochemistry.Aims:This study aimed to determine the expression level of CD117 in the mast cells of aggressive periodontitis using immunohistochemistry.Subjects and Methods:The study was conducted on tissue samples from 15 patients with aggressive periodontitis and 15 patients with healthy gingival tissue. Samples were stained for CD117 markers using immunohistochemistry. After the microscopic examination of samples, all data were entered into SPSS 20 and analyzed.Statistical Analysis Used:Statistical data were analyzed using Kolmogorov–Smirnov test and independent t-test.Results:According to the results, the mean expression levels of CD117 in the aggressive periodontitis and normal gingival groups were 19.08 ± 6.9 and 18.2 ± 8.1, respectively, which were not statistically significant (P = 0.75). The Kolmogorov–Smirnov test verified the normality of distribution of CD117 expression level. Given the normal distribution of the scores, the independent t-test was used to compare the CD117 expression level in the two study groups.Conclusions:There was no significant difference in the level of CD117 expression between the control and aggressive periodontitis groups.

Wnt-3a Induces Cytokine Release in Human Mast Cells

Mast cells are well known for their detrimental effects in allergies and asthma, and Wnt signaling has recently been implicated in asthma and other airway diseases. However, it is not known if or how Wnts affect human mast cells. Since Wnt expression is elevated in individuals with asthma and is linked to a Th2 profile, we hypothesized that mast cells could be affected by Wnts in the context of asthma. We therefore sought to investigate the role of Wnt signaling in human mast cell development and activation. We first examined the expression of the 10 main Wnt receptors, Frizzled 1–10 (FZD1–10), and found expression of several FZDs in human mast cells. Treatment with purified recombinant Wnt-3a or Wnt-5a did not affect the proliferation or maturation of CD34+ progenitors into mast cells, as indicated by cellular expression of CD117 and FcεRI, activation by FcεRI crosslinking, and histamine and tryptase release. Furthermore, Wnt treatment did not change the phenotype from MCT to MCTC, since MrgX2 expression, compound 48/80-mediated activation, and carboxypeptidase A3 content were not affected. However, Wnt-3a activated WNT/β-catenin signaling in mature human mast cells, as revealed by stabilization of β-catenin, upregulation of IL-8 and CCL8 mRNA expression, and release of IL-8 protein. Thus, our data suggest that Wnt-3a activation of mast cells could contribute to the recruitment of immune cells in conditions associated with increased Wnt-3a expression, such as asthma.

Human Mast Cell Development from Hematopoietic Stem Cells in a Connective Tissue-Equivalent Model.

Mast cells (MCs) play critical roles in the pathogenesis of IgE- and non-IgE-mediated immune responses, as well as host defense against parasites, bacteria, and viruses. Due to the effect of extracellular matrix components on tissue morphogenesis and cell behavior, utilizing a tissue model that mimics MC microenvironmental conditions in vivo has greater relevance for in vitro studies. For this work, MCs were developed within a connective tissue-equivalent model and cell function was examined in response to an allergen. MCs are located in proximity to fibroblasts and endothelial cells (ECs) that play a role in MC development and maturity. Accordingly, MC progenitors isolated from human peripheral blood were co-cultured with human primary fibroblasts in a 3D collagen matrix to represent the connective tissue. The matrix was coated with type IV collagen and fibronectin before seeding with primary human ECs, representing the capillary wall. The stem cell-derived cells demonstrated MC characteristics, including typical MC morphology, and the expression of cytoplasmic granules and phenotypic markers. Also, the generated cells released histamine in IgE-mediated reactions, showing typical MC functional phenotype in an immediate-type allergenic response. The created tissue model is applicable to a variety of research studies and allergy testing. Impact Statement Mast cells (MCs) are key effector and immunoregulatory cells in immune disorders; however, their role is not fully understood. Few studies have investigated human ex vivo MCs in culture, due to the difficulties in isolating large numbers. Our study demonstrates, for the first time, the generation of cells exhibiting MC phenotypic and functional characteristics from hematopoietic stem cells within a connective tissue-equivalent model with ancillary cells. Utilizing the 3D matrix-embedded cells can advance our understanding of MC biological profile and immunoregulatory roles. The tissue model can also be used for studying the mechanism of allergic diseases and other inflammatory disorders.

Mast Cells and Their Progenitors in Allergic Asthma.

Mast cells and their mediators have been implicated in the pathogenesis of asthma and allergy for decades. Allergic asthma is a complex chronic lung disease in which several different immune cells, genetic factors and environmental exposures influence the pathology. Mast cells are key players in the asthmatic response through secretion of a multitude of mediators with pro-inflammatory and airway-constrictive effects. Well-known mast cell mediators, such as histamine and bioactive lipids are responsible for many of the physiological effects observed in the acute phase of allergic reactions. The accumulation of mast cells at particular sites of the allergic lung is likely relevant to the asthma phenotype, severity and progression. Mast cells located in different compartments in the lung and airways have different characteristics and express different mediators. According to in vivo experiments in mice, lung mast cells develop from mast cell progenitors induced by inflammatory stimuli to migrate to the airways. Human mast cell progenitors have been identified in the blood circulation. A high frequency of circulating human mast cell progenitors may reflect ongoing pathological changes in the allergic lung. In allergic asthma, mast cells become activated mainly via IgE-mediated crosslinking of the high affinity receptor for IgE (FcεRI) with allergens. However, mast cells can also be activated by numerous other stimuli e.g. toll-like receptors and MAS-related G protein-coupled receptor X2. In this review, we summarize research with implications on the role and development of mast cells and their progenitors in allergic asthma and cover selected activation pathways and mast cell mediators that have been implicated in the pathogenesis. The review places an emphasis on describing mechanisms identified using in vivo mouse models and data obtained by analysis of clinical samples.

Frontline Science: Mast cells regulate neutrophil homeostasis by influencing macrophage clearance activity.

The receptor tyrosine kinase cKit and its ligand stem cell factor are essential for mast cells (MC) development and survival. Strains with mutations affecting the Kit gene display a profound MC deficiency in all tissues and have been extensively used to investigate the role of MC in both physiologic and pathologic conditions. However, these mice present a variety of abnormalities in other immune cell populations that can affect the interpretation of MC-related responses. C57BL/6 KitW-sh are characterized by an aberrant extramedullary myelopoiesis and systemic neutrophilia. MC deficiency in KitW-sh mice can be selectively repaired by engraftment with in vitro-differentiated MC to validate MC-specific functions. Nevertheless, the impact of MC reconstitution on other immune populations has never been evaluated in detail. Here, we specifically investigated the neutrophil compartment in primary and secondary lymphoid organs of C57BL/6 KitW-sh mice before and after MC reconstitution. We found that, albeit not apparently affecting neutrophils phenotype or maturation, MC reconstitution of KitW-sh mice restored the number of neutrophils at a level similar to that of wild-type C57BL/6 mice. In vitro and ex vivo experiments indicated that MC can influence neutrophil clearance by increasing macrophages' phagocytic activity. Furthermore, the G-CSF/IL-17 axis was also influenced by the presence or absence of MC in KitW-sh mice. These data suggest that MC play a role in the control of neutrophil homeostasis and that this aspect should be taken into account in the interpretation of results obtained using KitW-sh mice.

Development of Human Mast Cells from Hematopoietic Stem Cells within a 3D Collagen Matrix: Effect of Stem Cell Media on Mast Cell Generation.

Mast cells (MCs) arise from hematopoietic stem cells (HSCs) that mature within vascularized tissues. Fibroblasts and endothelial cells (ECs) play a role in the maturation of HSCs in the tissues. Due to difficulties in isolating MCs from tissues, large numbers of committed MC precursors can be generated in 2D culture systems with the use of differentiation factors. Since MCs are tissue-resident cells, the development of a 3D tissue-engineered model with ancillary cells that more closely mimics the 3D in vivo microenvironment has greater relevance for MC studies. The goals of this study were to show that MCs can be derived from HSCs within a 3D matrix and to determine a media to support MCs, fibroblasts, and ECs. The results show that HSCs within a collagen matrix cultured in StemSpan media with serum added at the last week yielded a greater number of c-kit+ cells and a greater amount of histamine granules compared to other media tested. Media supplemented with serum were necessary for EC survival, while fibroblasts survived irrespective of serum with higher cell yields in StemSpan. This work demonstrates the development of functional MCs within a 3D collagen matrix using a stem cell media that supports fibroblast and ECs.

Male-specific IL-33 expression regulates sex-dimorphic EAE susceptibility

The cellular and molecular basis of sex-dimorphic autoimmune diseases, such as the CNS demyelinating disease multiple sclerosis (MS), remains unclear. Our studies in the SJL mouse model of MS, experimental autoimmune encephalomyelitis (EAE), reveal that sex-determined differences in Il33 expression by innate immune cells in response to myelin peptide immunization regulate EAE susceptibility. IL-33 is selectively induced in PLP139-151-immunized males and activates type 2 innate lymphoid cells (ILC2s), cells that promote and sustain a nonpathogenic Th2 myelin-specific response. Without this attenuating IL-33 response, females generate an encephalitogenic Th17-dominant response, which can be reversed by IL-33 treatment. Mast cells are one source of IL-33 and we provide evidence that testosterone directly induces Il33 gene expression and also exerts effects on the potential for Il33 gene expression during mast cell development. Thus, in contrast to their pathogenic role in allergy, we propose a sex-specific role for both mast cells and ILC2s as attenuators of the pathogenic Th response in CNS inflammatory disease.

Aspirin exacerbated respiratory disease: Current topics and trends.

Aspirin-exacerbated respiratory disease is a chronic and treatment-resistant disease, characterized by the presence of eosinophilic rhinosinusitis, nasal polyposis, bronchial asthma, and nonsteroidal anti-inflammatory drugs hypersensitivity. Alterations in arachidonic acid metabolism may induce an imbalance between pro-inflammatory and anti-inflammatory substances, expressed as an overproduction of cysteinyl leukotrienes and an underproduction of prostaglandin E2. Although eosinophils play a key role, recent studies have shown the importance of other cells and molecules in the development of the disease like mast cells, basophils, lymphocytes, platelets, neutrophils, macrophages, epithelial respiratory cells, IL-33 and thymic stromal lymphopoietin, making each of them promissory diagnostic and treatment targets. In this review, we summarize the most important clinical aspects of the disease, including the current topics about diagnosis and treatment, like provocation challenges and aspirin desensitization. We also discuss recent findings in the pathogenesis of the disease, as well as future trends in diagnosis and treatment, including monoclonal antibodies and a low salicylate diet as a treatment option.

KIT signaling is dispensable for human mast cell progenitor development

AbstractHuman hematopoietic progenitors are generally assumed to require stem cell factor (SCF) and KIT signaling during differentiation for the formation of mast cells. Imatinib treatment, which inhibits KIT signaling, depletes mast cells in vivo. Furthermore, the absence of SCF or imatinib treatment prevents progenitors from developing into mast cells in vitro. However, these observations do not mean that mast cell progenitors require SCF and KIT signaling throughout differentiation. Here, we demonstrate that circulating mast cell progenitors are present in patients undergoing imatinib treatment. In addition, we show that mast cell progenitors from peripheral blood survive, mature, and proliferate without SCF and KIT signaling in vitro. Contrary to the prevailing consensus, our results show that SCF and KIT signaling are dispensable for early mast cell development.

The transcription factor C/EBPγ regulates mast cell development and function

The transcription factor C/EBPγ regulates mast cell development and function

The emerging role of mast cells in liver disease.

The depth of our knowledge regarding mast cells has widened exponentially in the last 20 years. Once thought to be only important for allergy-mediated events, mast cells are now recognized to be important regulators of a number of pathological processes. The revelation that mast cells can influence organs, tissues, and cells has increased interest in mast cell research during liver disease. The purpose of this review is to refresh the reader's knowledge of the development, type, and location of mast cells and to review recent work that demonstrates the role of hepatic mast cells during diseased states. This review focuses primarily on liver diseases and mast cells during autoimmune disease, hepatitis, fatty liver disease, liver cancer, and aging in the liver. Overall, these studies demonstrate the potential role of mast cells in disease progression.

Carbonic anhydrase enzymes regulate mast cell-mediated inflammation

Abstract Type 2 cytokine responses are necessary for the development of protective immunity to helminth parasites but also cause the inflammation associated with allergies and asthma. Recent studies have found that peripheral hematopoietic progenitor cells contribute to type 2 cytokine-mediated inflammation through their enhanced ability to develop into mast cells. Here we show that carbonic anhydrase (Car) enzymes are upregulated in type 2-associated progenitor cells and demonstrate that Car enzyme inhibition is sufficient to prevent murine mast cell responses and inflammation following Trichinella spiralis infection or the induction of food allergy-like disease. Further, we employed CRISPR/Cas9 technology and illustrate that genetically editing Car1 is sufficient to selectively reduce mast cell development. Finally, we demonstrate that Car enzymes can be targeted to prevent human mast cell development. Collectively these studies identify a previously unrecognized role for Car enzymes in regulating mast cell lineage commitment and suggest that Car enzyme inhibitors may possess therapeutic potential that can be employed to treat mast cell-mediated inflammation.

Vitamin D supplementation modulates Th2 immune response by inducing T regulatory cells in allergic conjunctivitis

Abstract Allergic conjunctivitis (AC) is one of the most common diseases encountered in eye clinics. Recently, Vitamin D deficiency has been shown to be associated with allergic AC. This present study was designed to evaluate the efficacy of vitamin D to suppress ovalbumin (OVA)-sensitized AC in a murine model. BALB/c mice were sensitized with OVA and aluminum hydroxide. Two weeks later, mice were challenged by OVA eyedrops for 12 days with intraperitoneal injection of vehicle or 1,25(OH)2D3. We evaluated clinical signs, the infiltration of inflammatory cells, regulatory T cells (Treg), serum IgE, and Th2 cytokines through flow cytometry and ELISA. In addition, to evaluate inhibitory function of Treg cells, anti–CD25 blocking antibody or isotype control antibody was injected intravenously during topical OVA challenge. AC development and conjunctival infiltration of eosinophils and mast cells were significantly impaired with 1,25(OH)2D3 treatment. In addition, 1,25(OH)2D3 suppressed production of OVA-specific IgE in serum and Th2 cytokines in vitro T cell assays, such as IL-4 and IL-13, compared to vehicle group. Interestingly, 1,25(OH)2D3 led to increase Treg cells population in draining LNs and suppressive levels of clinical signs and inflammatory cells infiltration into conjunctivae were reversed by depleting Treg cells. Our results suggest that vitamin D supplement alleviate allergic conjunctivitis, indicated by suppressing Th2 response in draining LNs and inflammatory cells infiltration into conjunctiva through increasing population of Treg cells in draining LNs. Therefore our results demonstrated the therapeutic potential of vitamin D for allergic diseases including asthma or atopic dermatitis.

Pyruvate dehydrogenase has a major role in mast cell function and its activity is regulated by mitochondrial MITF

Abstract Background We have recently observed that OXPHOS mediated ATP production is essential for mast cell function. Pyruvate dehydrogenase (PDH) is the main regulator of the Krebs cycle and is located upstream to the electron transport chain. However, the role of PDH in mast cell function has not been described. Microphthalmia transcription factor (MITF) regulates the development, number and function of mast cells. The localization of MITF to the mitochondria and its interaction with mitochondrial proteins has not been explored. Objective To explore the role played by PDH in mast cell exocytosis and to determine whether MITF is localized in the mitochondria and is involved in the regulation of PDH activity. Methods Experiments were performed in vitro using human and mouse mast cells and RBL cells and in vivo in mice. The effect of PDH inhibition on mast cell function was examined. PDH interaction with MITF was measured before and after immunological activation. Furthermore, mitochondrial localization of MITF and its effect on PDH activity were determined. Results PDH is essential for immunologically mediated degranulation of mast cells. Following activation PDH is serine dephosphorylated. In addition, we show for the first time that MITF is partially located in the mitochondria and interacts with PDH. This interaction is dependent on the phosphorylation state of PDH. Furthermore, mitochondrial MITF regulates PDH activity. Conclusion The association of mitochondrial MITF with PDH emerges as an important regulator of mast cell function. Our findings indicate that PDH could arise as a new target for the manipulation of allergic diseases.

TGFβ Receptor mutations alter mast cell development and function

Abstract Mutations in TGFBRI, encoding the receptor for TGFβ, cause Loeys-Dietz syndrome (LDS), a Mendelian disorder associated with an increased risk of developing nearly all forms of allergic disease, including food allergy. To better understand the mechanisms responsible for this association, knock-in mice harboring LDS mutations have been developed, which recapitulate nearly all aspects of the human phenotype. Mast cells are the main effector cells of allergic disease and several studies have identified TGFβ as a critical mediator of mast cell development and function. We hypothesized that LDS mast cells are altered in a manner that would promote greater susceptibility to allergic outcomes. To address this possibility, in vitro assays were performed with peritoneal mast cells (pMCs) cultured in IL-3 and stem cell factor and stimulated with IL-33, TGFβ, or IgE crosslinking agents. LDS pMCs expressed higher levels of ST2, the receptor for IL-33, and greater secretion of IL-9 following IL-33 stimulation. Furthermore, LDS pMCs were more resistant to apoptosis, exhibited greater degranulation following IgE receptor crosslinking, and showed less downregulation of FcɛRI and c-kit following exposure to recombinant TGFβ1. This was associated with reduced pSmad2/3 levels, a key signaling molecule in the TGFβ pathway. Furthermore, we demonstrated that following food allergy induction, LDS mice exhibited greater MC hyperplasia in the small intestinal lamina propria as well as in the peritoneum where LDS peritoneal mast cells showed enhanced secretion of IL-9. In vivo studies are ongoing to further examine the role of altered mast cell frequency and/or function resulting from altered TGFβ signaling in promoting food-induced anaphylaxis.

SLC10A4 regulates IgE-mediated mast cell degranulation in vitro and mast cell-mediated reactions in vivo

Mast cells act as sensors in innate immunity and as effector cells in adaptive immune reactions. Here we demonstrate that SLC10A4, also referred to as the vesicular aminergic-associated transporter, VAAT, modifies mast cell degranulation. Strikingly, Slc10a4−/− bone marrow-derived mast cells (BMMCs) had a significant reduction in the release of granule-associated mediators in response to IgE/antigen-mediated activation, whereas the in vitro development of mast cells, the storage of the granule-associated enzyme mouse mast cell protease 6 (mMCP-6), and the release of prostaglandin D2 and IL-6 were normal. Slc10a4-deficient mice had a strongly reduced passive cutaneous anaphylaxis reaction and a less intense itching behaviour in response to the mast cell degranulator 48/80. Live imaging of the IgE/antigen-mediated activation showed decreased degranulation and that ATP was retained to a higher degree in mast cell granules lacking SLC10A4. Furthermore, ATP was reduced by two thirds in Slc10a4−/− BMMCs supernatants in response to IgE/antigen. We speculate that SLC10A4 affects the amount of granule-associated ATP upon IgE/antigen-induced mast cell activation, which affect the release of granule-associated mast cell mediators. In summary, SLC10A4 acts as a regulator of degranulation in vitro and of mast cell-related reactions in vivo.

Development of peripheral blood-derived human mast cells from patients with chronic spontaneous urticaria : comparison with normal controls

Development of peripheral blood-derived human mast cells from patients with chronic spontaneous urticaria : comparison with normal controls

Peroxisome proliferator-activated receptor γ agonist suppresses mast cell maturation and induces apoptosis.

Peroxisome proliferator-activated receptor gamma (PPAR γ), is important in the immunoregulation of the allergic response. Mast cells are the most important inflammatory cells in immediate hypersensitivity and allergic diseases. However, there is limited information regarding the effects of PPAR γ on mast cell maturation. In the present study, mouse bone marrow-derived mast cells (BMMCs) were cultured in interleukin (IL)-3 and stem cell factor (SCF), in the presence or absence of the PPAR γ agonist, pioglitazone (PIO). The expression levels of the tyrosine kinase receptor CD117 and the high affinity IgE receptor FcεRI α, were assessed by flow cytometry, cell viability was assessed by Alamar-Blue assay and histamine release was determined by measuring the activity of β-hexosaminidase. IL-3 and SCF are required for the development of mast cells in vitro. PIO dose-dependently inhibited the expression of CD117 and FcεRI α, and the maturation of BMMCs. Treatment with PIO additionally inhibited the formation of granules and reduced the expression of β-hexosaminidase. In addition, reverse transcription-polymerase chain reaction analysis revealed that BMMCs treated with PIO expressed a lower level of mast cell protease (MCP)-6 mRNA and PIO treatment enhanced the level of PPAR γ mRNA. Furthermore, PIO induced mast cell progenitor apoptosis. PPAR γ agonists may maintain mast cell homeostasis by inhibiting maturation of their precursors. The inhibitory effects of PPAR γ agonists include suppression of the activation of mast cells and a decrease in mast cell function in the inflammatory response. Therefore, PPAR γ agonists may serve as effective anti-inflammatory reagents in the treatment of allergic reactions.