Regulation Of Mast Cell Function Research Articles

Regulation of mast cells by overlapping but distinct protein interactions of Siglec-6 and Siglec-8.

Sialic acid-binding immunoglobulin-like lectin (Siglec)-6 and Siglec-8 are closely related mast cell (MC) receptors with broad inhibitory activity, but whose functional differences are incompletely understood. Proteomic profiling using quantitative mass spectrometry was performed on primary mouse MCs to identify proteins associated with Siglec-6 and Siglec-8. For functional characterization, each receptor was evaluated biochemically and in exvivo and invivo inhibition models of IgE and non-IgE-mediated MC activation in Siglec-6- or Siglec-8-expressing transgenic mice. Siglec-6 and Siglec-8 were found in MCs within large complexes, interacting with 66 and 86 proteins, respectively. Strikingly, Siglec-6 and Siglec-8 interacted with a large cluster of proteins involved in IgE and non-IgE-mediated MC activation, including the high affinity IgE receptor, stem cell factor (SCF) receptor KIT/CD117, IL-4 and IL-33 receptors, and intracellular kinases LYN and JAK1. Protein interaction networks revealed Siglec-6 and Siglec-8 had overlapping yet distinct MC functions, with a potentially broader regulatory role for Siglec-6. Indeed, Siglec-6 preferentially interacted with the mature form of KIT at the cell surface, and treatment with an anti-Siglec-6 antibody significantly inhibited SCF-mediated MC activation more in comparison to targeting Siglec-8. These data demonstrate a central role for Siglec-6 and Siglec-8 in controlling MC activation through interactions with multiple activating receptors and key signaling molecules. Our findings suggest that Siglec-6 has a role distinct from that of Siglec-8 in regulating MC function and represents a distinct potential therapeutic target in mast cell-driven diseases.

Dedicator of cytokinesis 8 (DOCK8) is a negative regulator of skin mast cell function

Abstract Dysregulated expansion and/or activation of mast cells have detrimental consequences in allergic disease. In humans, homozygous or compound heterozygous deletions of DOCK8 cause a combined immunodeficiency characterized by allergic disorders. Based on this evidence, we hypothesized that DOCK8 may be a negative regulator of mast cell function. To address this hypothesis, we used mice with a loss-of-function mutation in Dock8 (primuris, Dock8 pri/primice) and conditional mice in which DOCK8 is ablated in connective tissue mast cells (Mcpt5-Cre +; Dock8 fl/flmice). Dock8 pri/primice exhibited increased plasma levels of mast cell protease-1 (MCPT1) in homeostatic conditions. Furthermore, Dock8 pri/primice and Mcpt5-Cre +; Dock8 fl/flmice experienced a more severe IgE-dependent passive cutaneous anaphylactic reaction (PCA) than control mice. This data suggests that DOCK8 deficiency is linked to increased mast cell activation in homeostatic conditions and upon stimulation by IgE-dependent mechanisms. Fetal skin derived cultured mast cells (FSMCs) generated from Dock8 pri/primice released increased amounts of β-hexosaminidase upon IgE-dependent activation. Consistent with this finding, naïve DOCK8-deficient FSMCs exhibited alterations in cytoskeletal dynamics that may facilitate mast cell degranulation. Finally, we observed an increased number of tryptase positive cells in skin biopsies obtained from three pediatric patients diagnosed with hyper IgE syndrome (HIES) due to DOCK8 mutations, suggesting that DOCK8 immunodeficiency may contribute to skin mast cell expansion in humans. Our findings provide strong evidence that DOCK8 can contribute to negative regulation of skin mast cell activation and expansion. R01 AI140626-05

Anaphylaxis: Advances in the Past 10 Years

In the past ten years, anaphylaxis has grown into its own special area of study within Allergy-Immunology, both at the bench and at the bedside. This review focuses on some of the most clinically relevant advances over the past decade. These include simplified and more inclusive diagnostic criteria for adults and children, uniform definition of biphasic anaphylaxis, and improved systems for objective severity grading. Studies reported in the past decade have led to improved understanding of normal and abnormal regulation of mast cell function, translating into better diagnostic and therapeutic approaches to patients with anaphylaxis. Research has provided improved recognition and treatment of mast cell disorders, and has identified a new condition, hereditary alpha tryptasemia, that may impact anaphylactic syndromes. We have learned to recognize new causes (alpha-gal), new pathways (MRGPRX2), and many risk factors for severe anaphylaxis. The stability of epinephrine in autoinjectors was reported to be very good for several years after the labeled expiry date, and it can tolerate freezing and thawing. Repeated and prolonged exposure to excessive heat leads to degradation of epinephrine activity. New treatments to prevent severe anaphylaxis have been described, utilizing new ways to block the IgE receptor or modulate intracellular signaling pathways.

The Role of TGFβ and Other Cytokines in Regulating Mast Cell Functions in Allergic Inflammation.

Mast cells (MC) are a key effector cell in multiple types of immune responses, including atopic conditions. Allergic diseases have been steadily rising across the globe, creating a growing public health problem. IgE-mediated activation of MCs leads to the release of potent mediators that can have dire clinical consequences. Current therapeutic options to inhibit MC activation and degranulation are limited; thus, a better understanding of the mechanisms that regulate MC effector functions in allergic inflammation are necessary in order to develop effective treatment options with minimal side effects. Several cytokines have been identified that play multifaceted roles in regulating MC activation, including TGFβ, IL-10, and IL-33, and others that appear to serve primarily anti-inflammatory functions, including IL-35 and IL-37. Here, we review the literature examining cytokines that regulate MC-mediated allergic immune responses.

The ketone body β-hydroxybutyrate mitigates ILC2-driven airway inflammation by regulating mast cell function.

Ketone bodies are increasingly understood to have regulatory effects on immune cell function, with β-hydroxybutyrate (BHB) exerting a predominantly anti-inflammatory response. Dietary strategies to increase endogenous ketone body availability such as the ketogenic diet (KD) have recently been shown to alleviate inflammation of the respiratory tract. However, the role of BHB has not been addressed. Here, we observe that BHB suppresses group 2 innate lymphoid cell (ILC2)-mediated airway inflammation. Central to this are mast cells, which support ILC2 proliferation through interleukin-2 (IL-2). Suppression of the mast cell/IL-2 axis by BHB attenuates ILC2 proliferation and the ensuing type 2 cytokine response and immunopathology. Mechanistically, BHB directly inhibits mast cell function in part through GPR109A activation. Similar effects are achieved with either the KD or 1,3-butanediol. Our data reveal the protective role of BHB in ILC2-driven airway inflammation, which underscores the potential therapeutic value of ketone body supplementation for the management of asthma.

MiR-155 Is a Positive Regulator of FcεRI-Induced Cyclooxygenase-2 Expression and Cytokine Production in Mast Cells.

MicroRNA-155 (miR-155) has been implicated in IgE-dependent allergic disease including asthma and atopic dermatitis. A few roles for miR-155 have been described in mast cells and some specifically related to IgE receptor signaling, but it is not completely understood. Here, we demonstrate by miRNA seq profiling and quantitative RT-PCR that miR-155 expression is significantly increased in human skin-derived mast cells (SMCs) and mouse bone marrow-derived mast cells (BMMCs) following FcεRI crosslinking with antigen. We demonstrate that FcεRI-induced expression of cyclooxygenase-2 (COX-2) was significantly inhibited in miR-155 knockout (KO) BMMCs whereas arachidonate-5-lipoxygenase (ALOX-5) expression and leukotriene C4 (LTC4) biosynthesis, and degranulation were unaffected. FcεRI-induced cytokine production (TNF, IL-6, and IL-13) from miR-155 KO BMMCs was also significantly diminished. Correspondingly, Akt phosphorylation, but not protein expression, was inhibited in the absence of miR-155 whereas p38 and p42/44 were unaffected. Interesting, lipopolysaccharide (LPS)-induced cytokine production was increased in miR-155 KO BMMCs. Together, these data demonstrate that miR-155 specifically targets the FcεRI-induced prostaglandin and cytokine pathways, but not the leukotriene or degranulation pathways, in mast cells. The data further suggest that miR-155 acts indirectly by targeting a repressor of COX-2 expression and a phosphatase that normally blocks Akt phosphorylation. Overall, this study reveals the role of miR-155 as a positive regulator of mast cell function.

Regulation of Trafficking and Signaling of the High Affinity IgE Receptor by FcεRIβ and the Potential Impact of FcεRIβ Splicing in Allergic Inflammation.

Mast cells are tissue-resident immune cells that function in both innate and adaptive immunity through the release of both preformed granule-stored mediators, and newly generated proinflammatory mediators that contribute to the generation of both the early and late phases of the allergic inflammatory response. Although mast cells can be activated by a vast array of mediators to contribute to homeostasis and pathophysiology in diverse settings and contexts, in this review, we will focus on the canonical setting of IgE-mediated activation and allergic inflammation. IgE-dependent activation of mast cells occurs through the high affinity IgE receptor, FcεRI, which is a multimeric receptor complex that, once crosslinked by antigen, triggers a cascade of signaling to generate a robust response in mast cells. Here, we discuss FcεRI structure and function, and describe established and emerging roles of the β subunit of FcεRI (FcεRIβ) in regulating mast cell function and FcεRI trafficking and signaling. We discuss current approaches to target IgE and FcεRI signaling and emerging approaches that could target FcεRIβ specifically. We examine how alternative splicing of FcεRIβ alters protein function and how manipulation of splicing could be employed as a therapeutic approach. Targeting FcεRI directly and/or IgE binding to FcεRI are promising approaches to therapeutics for allergic inflammation. The characteristic role of FcεRIβ in both trafficking and signaling of the FcεRI receptor complex, the specificity to IgE-mediated activation pathways, and the preferential expression in mast cells and basophils, makes FcεRIβ an excellent, but challenging, candidate for therapeutic strategies in allergy and asthma, if targeting can be realized.

Purinergic regulation of mast cell function and allergic response via ionotropic P2X4 receptors

Purinergic regulation of mast cell function and allergic response via ionotropic P2X4 receptors

Тучные клетки при аллергическом и инфекционном воспалении

Functional characteristics of a heterogeneous population of innate immune cells, mast cells, account for their involvement in many inflammatory and autoimmune diseases and tumors. A diversity of mast cell receptors and secreted biologically active mediators, broad presence in barrier tissues, and close relation with blood and lymphatic vessels allow mast cells to realize many protective functions (including as effective participants of allergic reactions and primary effectors of the immune response to infections). The primary role of mast cells in immune- mediated inflammation is accounted for by the synthesis and secretion of numerous biologically active substances under their activation with various factors (e.g., allergens, cytokines, anaphylotoxins, neuropeptides, immune complexes, microbial antigens and toxins, some medications). Impaired regulation of mast cell functions may have a negative effect which determines a pattern of their involvement in the pathogenesis of chronic allergic, inflammatory, and autoimmune diseases and tumors. Despite a better understanding of the pathogenic role of mast cells in immune-mediated inflammatory disorders, studies on the mechanisms of their activation and regulation, pattern and im-portance of the interaction of their mediators with immune cells, and mechanisms of the implementation of mast cell pro-inflammatory effects are still relevant. The results of these studies are likely to optmise the treatment of a variety of diseases. KEYWORDS: mast cells, immune pathogenesis, mediators, allergic inflammation, infectious inflammation, atopic dermatitis. FOR CITATION: Kolesnikova N.V. Mast cells in allergic and infectious inflammation. Russian Medical Inquiry. 2022;6(2):79–84 (in Russ.). DOI: 10.32364/2587-6821-2022-6-2-79-84.

Carnosic acid inhibits mast cell pro‐inflammatory mediator release in allergic inflammation

Over the past several decades, developed countries have been plagued by the increasing prevalence of allergic disorders. This allergy epidemic has led to an exponential increase in health care‐associated costs, while significantly deteriorating quality of life for those affected. Allergic inflammation is a consequence of an excessive and undesirable immune response towards environmental allergens, mediated by immune sentinels known as mast cells. Mast cells are ubiquitously distributed in vascularized tissues, where they play an essential role in host defence, in addition to pathological contexts of inflammation. Allergen detection by the immune system results in IgE‐mediated mast cell activation, characterized by rapid degranulation during the early phase, and sustained release of newly synthesized pro‐inflammatory mediators in the late phase. Plant derived micronutrients, known as polyphenols, have been explored as therapeutic options in pathological models, due to the modulatory effects they have on pro‐inflammatory mediator release. We have recently established rosemary extract (RE); a mixture abundant in polyphenolic compounds, as a potent inhibitor of mast cell mediated allergic inflammation, through attenuation of essential signalling cascades required for pro‐inflammatory mediator secretion. The objective of this study was to evaluate the therapeutic potential of three major polyphenolic constituents of RE including: carnosic acid (CA), carnosol (CO), and rosmarinic acid (RA), assessing the ability of isolated polyphenols to inhibit pro‐inflammatory mediator release following mast cell activation. Bone marrow‐derived mast cells (BMMCs) were sensitized with IgE and stimulated with allergen, while simultaneously treated with various concentrations of CA, CO, or RA. Mast cell degranulation was measured via the β‐hexosaminidase release assay, while late phase pro‐inflammatory mediator release was quantified by enzyme‐linked immunosorbent assay. Following individual treatment with CA and CO, β‐hexosaminidase release was significantly inhibited dose‐dependently to 14% and 17% of control respectively (p < 0.001), while RA had no effect on β‐hexosaminidase release. ELISA analysis showed that CA significantly inhibited release of TNF (p<0.0001), IL‐6 (p<0.0001), IL‐13 (p<0.0001), CCL1 (p<0.001), and CCL2 (p<0.05), RA inhibited CCL2 (p<0.05), and treatment with CO did not inhibit the release of any cytokine examined. These results suggest that CA is a potent inhibitor of both the early and late phase of allergen‐induced mast cell activation. Further dissection of the mechanism behind CA mediated modulation of essential mast cell signalling and subsequent pro‐inflammatory mediator release will inform on its utility in regulation of mast cell function in numerous mast cell‐dependent inflammatory disorders.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.

3-Benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran-2(3H)-one suppresses FcεRI-mediated mast cell degranulation via the inhibition of mTORC2-Akt signaling

Mast cells express high-affinity IgE receptor (FcεRI) on their surface, cross-linking of which leads to the immediate release of proinflammatory mediators such as histamine but also late-phase cytokine secretion, which are central to the pathogenesis of allergic diseases. Despite the growing evidences that mammalian target of rapamycin (mTOR) plays important roles in the immune system, it is still unclear how mTOR signaling regulates mast cell function. In this study, we investigated the effects of 3-benzyl-5-((2-nitrophenoxy) methyl)-dihydrofuran-2(3H)-one (3BDO) as an mTOR agonist on FcεRI-mediated allergic responses of mast cells. Our data showed that administration of 3BDO decreased β-hexosaminidase, interleukin 6 (IL-6), and tumor necrosis factor-α (TNF-α) release in murine bone marrow-derived mast cells (BMMCs) after FcεRI cross-linking, which was associated with an increase in mTOR complex 1 (mTORC1) signaling but a decrease in activation of Erk1/2, Jnk, and mTORC2-Akt. In addition, we found that a specific Akt agonist, SC79, is able to fully restore the decrease of β-hexosaminidase release in 3BDO-treated BMMCs but has no effect on IL-6 release in these cells, suggesting that 3BDO negatively regulates FcεRI-mediated degranulation and cytokine release through differential mechanisms in mast cells. The present data demonstrate that proper activation of mTORC1 is crucial for mast cell effector function, suggesting the applicability of the mTORC1 activator as a useful therapeutic agent in mast cell-related diseases.

Coumarin alleviates ovalbumin-induced food anaphylaxis in a mouse model by affecting mast cell function.

Coumarin is an important organic heterocyclic compound with a wide range of sources in nature. It plays an important role in the drug discovery process due to its existence in diverse biologically active compounds and its broad bioactivity. In this study, the anti-allergic activity of coumarin was evaluated using an ovalbumin (OVA)-induced mouse food allergy model and an immunoglobulin (Ig)E mediated mouse bone marrow-derived mast cell (BMMC) model. Coumarin could alleviate the OVA-induced allergic symptoms, decrease the diarrhea rates, and promote the rectal temperature rise in allergic mice. Moreover, coumarin had the ability to reduce the levels of histamine and mouse mast cell proteinases, inhibit OVA-specific IgE, and significantly decrease the population of mast cells in the spleen and mesenteric lymph nodes. Coumarin could also significantly suppress mast cell-dependent passive cutaneous anaphylaxis. Additionally, the number of mature BMMCs was decreased as coumarin caused the suppression of c-KIT receptors. Furthermore, coumarin up-regulated the apoptosis of OVA-activated BMMCs in a concentration-dependent manner. In conclusion, coumarin displayed effective anti-food allergy activity via the regulation of mast cell function and numbers. Coumarin and its derivatives provide a new direction for the development of anti-food allergic drug components.

Deep-Sea-Derived Butyrolactone I Suppresses Ovalbumin-Induced Anaphylaxis by Regulating Mast Cell Function in a Murine Model.

Deep-sea-derived butyrolactone I (BTL-I), which was identified as a type of butanolide, was isolated from Aspergillus sp. Ovalbumin (OVA)-induced BALB/c anaphylaxis was established to explore the antifood allergic activity of BTL-I. As a result, BTL-I was able to alleviate OVA-induced allergy symptoms, reduce the levels of histamine and mouse mast cell proteinases, inhibit OVA-specific IgE, and decrease the population of mast cells in the spleen and mesenteric lymph nodes. BTL-I also significantly suppressed mast-dependent passive cutaneous anaphylaxis. Additionally, the maturation of bone marrow-derived mast cells (BMMCs) declined as BTL-I caused down-regulation of c-KIT receptors. Furthermore, molecular docking analyses revealed that BTL-I interacted with the inhibitory receptor, FcγRIIB. In conclusion, the reduction of mast cell function by deep-sea-derived BTL-I as well as its interactions with the inhibitory receptor, FcγRIIB, may contribute to BTL-I-related protection against food anaphylaxis.

Epigenetic regulation of mast cell function via inhibition of histone acetylation results in suppression of mast cell responses

Abstract Mast cells are highly versatile cells that perform a variety of functions depending on the immune trigger, context of activation and cytokine stimulus. Antigen-mediated mast cell responses are regulated by transcriptional processes that result in the induction of numerous genes contributing to mast cell function. Recently, we also showed that exposure to dietary agents with known epigenetic actions such as curcumin can suppress mast cell-mediated food allergy, suggesting that mast cell responses in vivo may be epigenetically regulated. To further assess the effects of epigenetic modifications on mast cell function, we examined the behavior of bone marrow-derived mast cells (BMMCs) in response to trichostatin A (TSA) treatment, a well-studied histone deacetylase inhibitor. IgE-mediated BMMC activation resulted in enhanced expression and secretion of IL-4, IL-6, TNF-a and IL-13. In contrast, pretreatment with either curcumin or TSA resulted in altered cytokine secretion. This was accompanied by decreased expression of FceRI and mast cell degranulation. Interestingly, exposure to non-IgE stimuli such as IL-33, was also affected by TSA treatment. Furthermore, long-term TSA exposure contributed to mast cell apoptosis and a decrease in survival. Further examination revealed a decrease in phospho-relA levels in TSA-treated BMMCs, suggesting that TSA alters transcriptional processes, resulting in decreased NF-kB activation. These data therefore suggest that the epigenetic regulation of mast cell activation during immune responses may occur via regulation of histone acetylation, and that exposure to dietary substances such as curcumin may induce epigenetic modifications that modulate mast cell function.

Soluble Transforming Growth Factor Beta-1 enhances murine mast cell cytokine release

Abstract TGF-β1 is traditionally known as an immunosuppressive cytokine. Previous studies have investigated its effects on FcɛRI-dependent mast cell activation, yet there is an incomplete understanding of TGF-β1 on mast cell function, for example, without sensitization to IgE. We investigated the effects of soluble TGF-β1 on IL-6 and IL-13 cytokine production in C57BL/6 bone marrow-derived mast cells in the presence and absence of FcɛRI-mediated activation. Our experiments found IL-6 production to be significantly enhanced independent of IgE sensitization or FcɛRI crosslinking; this was similar to treatment with stem cell factor (SCF), which also enhanced IL-6 production in this resting state. Additionally, IL-13 production was significantly enhanced following IgE-mediated stimulation of TGF-β1 treated mast cells; an effect independent of IgE was not observed, and treatment with SCF had no significant impact. Lastly, via confocal microscopy, we interrogated the cell-surface expression of FcɛRI, CD117 (c-Kit; SCF receptor), and TGFβRII with and without soluble TGF-β1 and/or FcɛRI crosslinking. This experiment revealed no apparent effect of TGF-β1 on FcɛRI and CD117 receptor co-localization – in both treatments we observed an equivalent decline in co-localization following IgE-mediated activation. TGFβRII was also found to weakly co-localize with those receptors, however this co-localization was unchanged across all treatments. Together, our findings provide novel insight into the stimulatory role of TGF-β1 on mast cell function both in the presence and absence of an allergic-like stimulus, suggesting alternative pathways play a pivotal role in regulating mast cell function beyond that of a canonical IgE-mediated pathway.

Mast cell corticotropin releasing factor receptor CRF2 regulates mast cell function in response to psychological and immunological stress

Abstract Psychological stress is a significant risk factor in a number of inflammatory and allergic diseases. We have previously demonstrated that CRF1 receptors expressed on mast cells (MCs) can potentiate psychological stress-induced MC degranulation intestinal permeability, and IgE-mediated anaphylaxis. In this study, we investigated the role of the CRF2 receptors in regulating MC activation in response to psychological and immunological stress. CRF2-deficient (CRF2−/−) bone marrow derived MCs exhibited enhanced IgE-and c48/80-mediated mast cell degranulation, determined by β-hex and histamine release. Heightened degranulation in CRF2−/− MCs were mediated by enhanced intracellular Ca2+ mobilization from endoplasmic reticulum stores. Similar results were obtained with human LAD2 mast cells treated with the CRF2 antagonist Astressin 2B. In vitro findings translated to in vivo studies as MC-deficient KitW-sh/W-sh mice systemically engrafted with CRF2−/− BMMCs exhibited a 3-fold increase in serum histamine levels and intestinal permeability following acute restraint stress or passive systemic anaphylaxis. Contrasting effects of CRF2 were observed with de novo synthesized mediator release as IL-4, IL-6, MCP-1 and prostaglandin D2 release were reduced (by ~40–50%) in CRF2−/− BMMCs following stimulation with IgE-antigen, LPS and IL-33. In summary, these data show that CRF2 signaling inhibits MC degranulation and associated pathophysiology induced by acute psychological stress and IgE-mediated anaphylaxis, while enhancing the release of de novo synthesized mediators. Therefore, targeting CRF2 may represent a novel therapeutic approach for preventing stress-related allergic and inflammatory disease flares.

Epigenetic and transcriptional control of mast cell responses.

Mast cells are tissue-resident, innate immune cells present in most tissues of the body and are important effector and immunomodulatory cells. Differentiated mast cells typically are characterized by the surface expression of the receptors KIT and FcεRI, the latter especially being important for stimulation through IgE antibodies, although these cells have the ability to respond to a wide variety of environmental signals, to which they can variably react by releasing pre-stored or de novo–synthesized mediators or both. Since mast cells terminate their differentiation in their tissue of residence in response to specific microenvironmental cues, each tissue may comprise unique mast cell subtypes, and responses are tailored to the danger signals that are likely to be encountered in each anatomical location. From a transcriptional point of view, these cells therefore must be endowed with epigenetic and transcriptional programs that allow them to maintain a stable identity and at the same time allow sufficient plasticity to adapt to different environmental challenges. In this commentary, we highlight some of the recent findings that advanced our understanding of the transcriptional and epigenetic programs regulating mast cell functions.

Mast cell-dependent IL-33/ST2 signaling is protective against the development of airway hyperresponsiveness in a house dust mite mouse model of asthma.

Interleukin-33 (IL-33) and its receptor ST2 have been influentially associated with the pathophysiology of asthma. Due to the divergent roles of IL-33 in regulating mast cell functions, there is a need to further characterize IL-33/ST2-dependent mast cell responses and their significance in the context of asthma. This study aimed to investigate how IL-33/ST2-dependent mast cell responses contribute to the development of airway hyperresponsiveness (AHR) and airway inflammation in a mouse model of house dust mite (HDM)-induced asthma. Mast cell-deficient C57BL/6-KitW-sh (Wsh) mice engrafted with either wild-type (Wsh + MC-WT) or ST2-deficient bone marrow-derived mast cells (Wsh + MC-ST2KO) were exposed to HDM delivered intranasally. An exacerbated development of AHR in response to HDM was seen in Wsh + MC-ST2KO compared with Wsh + MC-WT mice. The contribution of this IL-33/ST2-dependent mast cell response to AHR seems to reside within the smaller airways in the peripheral parts of the lung, as suggested by the isolated yet marked effect on tissue resistance. Considering the absence of a parallel increase in cellular inflammation in bronchoalveolar lavage fluid (BALF) and lung, the aggravated AHR in Wsh + MC-ST2KO mice seems to be independent of cellular inflammation. We observed an association between the elevated AHR and reduced PGE2 levels in BALF. Due to the protective properties of PGE2 in airway responses, it is conceivable that IL-33/ST2-dependent mast cell induction of PGE2 could be responsible for the dampening effect on AHR. In conclusion, we reveal that IL-33/ST2-dependent mast cell responses can have a protective, rather than causative role, in the development of AHR.

The transcriptional program, functional heterogeneity, and clinical targeting of mast cells.

Mast cells are unique tissue-resident immune cells that express an array of receptors that can be activated by several extracellular cues, including antigen-immunoglobulin E (IgE) complexes, bacteria, viruses, cytokines, hormones, peptides, and drugs. Mast cells constitute a small population in tissues, but their extraordinary ability to respond rapidly by releasing granule-stored and newly made mediators underpins their importance in health and disease. In this review, we document the biology of mast cells and introduce new concepts and opinions regarding their role in human diseases beyond IgE-mediated allergic responses and antiparasitic functions. We bring to light recent discoveries and developments in mast cell research, including regulation of mast cell functions, differentiation, survival, and novel mouse models. Finally, we highlight the current and future opportunities for therapeutic intervention of mast cell functions in inflammatory diseases.

RETRACTED ARTICLE: Inhibition of airway inflammation in a cockroach allergen model of asthma by agonists of miRNA-33b

MicroRNAs (miRNAs) play powerful roles in immune function by regulating target genes that mediate cell behavior. It is well known that mast cells have essential effector and immune regulatory functions in IgE-associated allergic disorders and in innate and adaptive immune responses. However, the role of miRNAs in mediating mast cell functions and the relevant mechanisms require further exploration. The roles of miR-33b in airway inflammation and mast cell functions are still unknown. To examine the role of miR-33b in mouse mast cells in cockroach allergen-induced asthma, we developed a lentiviral system for miRNA-33b overexpression to examine whether miRNA-33b mediates airway inflammation by regulating mast cell function and to evaluate the underlying mechanism. The results showed that miR-33b inhibited cockroach allergen-induced asthma in vivo: in particular, it inhibited TH2 cytokine production. In addition, we found that in cells in which miRNA-33b had been transfected, mast cell degranulation was inhibited through suppression of the calcium release and IgE/FcεRI pathway. Our study provides new insight into the roles of miR-33b in asthma and mast cell biology and identifies novel mechanisms that may contribute to mast cell-related pathological conditions in airway inflammation.