Mast cells: a double-edged sword in inflammation and fibrosis.

As one of the key components of the immune system, mast cells are well known for their role in allergic reactions. However, they are also involved in inflammatory and fibrotic processes. Mast cells participate in all the stages of acute inflammatory responses, playing an immunomodulatory role in both innate and adaptive immunity. Mast cell-derived histamine, TNF-α, and IL-6 contribute to the inflammatory processes, while IL-10 mediates the suppression of inflammation. Crosstalk between mast cells and other immune cells is also involved in the development of inflammation. The cell-cell adhesion of mast cells and fibroblasts is crucial for fibrosis. Mast cell mediators, including cytokines and proteases, play contradictory roles in the fibrotic process. Here, we review the double-edged role of mast cells in inflammation and fibrosis.

Neutrophils on the mast cell menu.

A recent article in Cell reported a new peculiar interaction between mast cells and neutrophils. Upon IgE/Ag-mediated degranulation, mast cells (MCs) produce leukotriene B4 (LTB4), which attracts migrating neutrophils. Some neutrophils are able to establish close contact with MCs and end up trapped inside the MC, forming a cell-in-cell structure. While the neutrophil eventually dies inside the vacuole, the MC benefits from the remains of its prisoner, using it as a nutrient reserve and reusing its antimicrobial weapons.

Reduced microRNA-744 expression in mast cell-derived exosomes triggers epithelial cell ferroptosis in acute respiratory distress syndrome.

Acute respiratory distress syndrome (ARDS) is a critical disorder characterized by immune-related damage to epithelial cells; however, its underlying mechanism remains elusive. This study investigated the effects of alterations in microRNA (miRNA) expression in mast cell-derived exosomes on human bronchial epithelial (HBE) cells and ARDS development in cellular and mouse models challenged with lipopolysaccharide. Lipopolysaccharide-treated mast cell-derived exosomes reduced glutathione peroxidase 4 (GPX4) expression and increased long-chain acyl-CoA synthetase 4 (ACSL4), 15-lipoxygenase (ALOX15), and inflammatory mediator levels in HBE cells. miRNA sequencing revealed a reduction in mast cell-derived exosomal miR-744 levels, which was associated with the regulation of ACSL4, ALOX15, and GPX4 expression. This downregulation of exosomal miR-744 expression reduced miR-744 levels and promoted ferroptosis in HBE cells, whereas the experimental upregulation of miR-744 reversed these adverse effects. Down-regulation of miR-744 induced the expression of markers for ferroptosis and inflammation in HBE cells and promoted pulmonary ferroptosis, inflammation, and injury in LPS-stimulated mice. In vivo, treatment with ACSL4, ALOX15, and GPX4 inhibitors mitigated these effects, and experimental miR-744 expression rescued the lipopolysaccharide-induced changes in HBE cells and mouse lungs. Notably, miR-744 levels were reduced in the plasma and exosomes of patients with ARDS. We concluded that decreased mast cell-derived exosomal miR-744 levels trigger epithelial cell ferroptosis, promoting lung inflammation and damage in ARDS. This study provides new mechanistic insights into the development and sustained pulmonary damage associated with ARDS and highlights potential therapeutic strategies.

The evolving role of mast cells in wound healing: insights from recent research and diverse models.

Chronic wounds significantly burden health care systems worldwide, requiring novel strategies to ease their impact. Many physiological processes underlying wound healing are well studied but the role of mast cells remains controversial. Mast cells are innate immune cells and play an essential role in barrier function by inducing inflammation to defend the host against chemical irritants and infections, among others. Many mast cell-derived mediators have proposed roles in wound healing; however, in vivo evidence using mouse models has produced conflicting results. Recently, studies involving more complex wound models such as infected wounds, diabetic wounds and wounds healing under psychological stress suggest that mast cells play critical roles in these processes. This review briefly summarizes the existing literature regarding mast cells in normal wounds and the potential reasons for the contradictory results. Focus will be placed on examining more recent work emerging in the last 5 years that explores mast cells in more complex systems of wound healing, including infection, psychological stress and diabetes, with a discussion of how these discoveries may inspire future work in the field.

CysLT receptor-mediated NOX2 activation is required for IL-8 production in HMC-1 cells induced by Trichomonas vaginalis-derived secretory products.

Trichomoniasis is caused by a sexually transmitted flagellate protozoan parasite Trichomonas vaginalis. T. vaginalis-derived secretory products (TvSP) contain lipid mediators such as leukotriene B4 (LTB4) and various cysteinyl leukotrienes (CysLTs) which included LTC4, LTD4, and LTE4. However, the signaling mechanisms by which T. vaginalis-induced CysLTs stimulate interleukin (IL)-8 production in human mast cells remain unclear. In this study, we investigated these mechanisms in human mast cells (HMC-1). Stimulation with TvSP resulted in increased intracellular reactive oxygen species (ROS) generation and NADPH oxidase 2 (NOX2) activation compared to unstimulated cells. Pre-treatment with NOX2 inhibitors such as diphenyleneiodonium chloride (DPI) or apocynin significantly reduced ROS production in TvSP-stimulated HMC-1 cells. Additionally, TvSP stimulation increased NOX2 protein expression and the translocation of p47phox from the cytosol to the membrane. Pretreatment of HMC-1 cells with PI3K or PKC inhibitors reduced TvSP-induced p47phox translocation and ROS generation. Furthermore, NOX2 inhibitors or NOX2 siRNA prevented CREB phosphorylation and IL-8 gene expression or protein secretion induced by TvSP. Pretreatment with a CysLTR antagonist significantly inhibited TvSP-induced ROS production, CREB phosphorylation, and IL-8 production. These results indicate that CysLT-mediated activation of NOX2 plays a crucial role in ROS-dependent IL-8 production in human mast cells stimulated by T. vaginalis-secreted CysLTs. These findings enhance our understanding of the inflammatory response in trichomoniasis and may inform the development of targeted therapies to mitigate this response.

Lemon Juice and Peel Constituents Potently Stabilize Rat Peritoneal Mast Cells.

BACKGROUND/AIMS: Lemons (Citrus limon ) contain various nutrients and are among the most popular citrus fruit. Besides their antioxidant, anticancer, antibacterial, and anti-inflammatory properties, clinical studies have indicated their anti-allergic properties. METHODS: Using the differential-interference contrast (DIC) microscopy, we examined the effects of lemon juice and peel constituents, such as citric acid, ascorbic acid, hesperetin and eriodictyol, on the degranulation from rat peritoneal mast cells. Using fluorescence imaging with a water-soluble dye, Lucifer Yellow, we also examined their effects on the deformation of the plasma membrane. RESULTS: Lemon juice dose-dependently decreased the number of degranulated mast cells. At concentrations equal to or higher than 0.25 mM, citric acid, hesperetin, and eriodictyol significantly reduced the number of degranulating mast cells in a dose-dependent manner, while ascorbic acid required much higher doses to exert significant effects. At 1 mM, citric acid, hesperetin, and eriodictyol almost completely inhibited exocytosis and washed out the Lucifer Yellow trapped on the mast cell surface, while ascorbic acid did not. CONCLUSION: This study provides in vitro evidence for the first time that lemon constituents, such as citric acid, hesperetin, and eriodictyol, potently exert mast cell-stabilizing properties. These properties are attributable to their inhibitory effects on plasma membrane deformation in degranulating mast cells.

Role and mechanisms of mast cells in brain disorders.

Mast cells serve as crucial effector cells within the innate immune system and are predominantly localized in the skin, airways, gastrointestinal tract, urinary and reproductive tracts, as well as in the brain. Under physiological conditions, brain-resident mast cells secrete a diverse array of neuro-regulatory mediators to actively participate in neuroprotection. Meanwhile, as the primary source of molecules causing brain inflammation, mast cells also function as the "first responders" in brain injury. They interact with neuroglial cells and neurons to facilitate the release of numerous inflammatory mediators, proteases, and reactive oxygen species. This process initiates and amplifies immune-inflammatory responses in the brain, thereby contributing to the regulation of neuroinflammation and blood-brain barrier permeability. This article provides a comprehensive overview of the potential mechanisms through which mast cells in the brain may modulate neuroprotection and their pathological implications in various neurological disorders. It is our contention that the inhibition of mast cell activation in brain disorders could represent a novel avenue for therapeutic breakthroughs.

Preventive and Therapeutic Effects of Lactiplantibacillus plantarum HD02 and MD159 through Mast Cell Degranulation Inhibition in Mouse Models of Atopic Dermatitis.

As the relationship between the gut microbiome and allergies becomes better understood, targeted strategies to prevent and treat allergies through gut microbiome modulation are being increasingly developed. In the study presented herein, we screened various probiotics for their ability to inhibit mast cell degranulation and identified Lactiplatibacillus plantarum HD02 and MD159 as effective candidates. The two strains significantly attenuated vascular permeability induced by mast cell degranulation in a passive cutaneous anaphylaxis (PCA) model and, in the MC903-induced murine atopic dermatitis (AD) model, demonstrated comparable preventive effects against allergies, reducing blood levels of MCPT-1 (mast cell protease-1) and total IgE. In the house dust mite (HDM)-induced murine AD model, both L. plantarum HD02 and MD159 showed therapeutic effects, with L. plantarum HD02 demonstrating superior efficacy. Nevertheless, L. plantarum MD159 better suppressed transepidermal water loss (TEWL). Furthermore, L. plantarum HD02 and MD159 significantly increased the number of splenic Foxp3+ regulatory T cells, with L. plantarum MD159 having a more pronounced effect. However, only L. plantarum HD02 achieved a reduction in immune cells in the draining lymph nodes. Our findings highlight L. plantarum HD02 and MD159 as promising candidates for the prevention and treatment of allergies, demonstrating significant efficacy in suppressing mast cell degranulation, reducing the number of allergy biomarkers, and modulating immune responses in experimental models of AD. Their distinct mechanisms of action suggest potential complementary roles in addressing allergic diseases, underscoring their therapeutic promise in clinical applications.

Clustering of clinical symptoms using large language models reveals low diagnostic specificity of proposed alternatives to consensus mast cell activation syndrome criteria.

BACKGROUND: The rate of diagnosis of mast cell activation syndrome (MCAS) has increased since the disorder's original description as a mastocytosis-like phenotype. While a set of consortium MCAS criteria is well described and widely accepted, this increase occurs in the setting of a broader set of proposed alternative MCAS criteria. OBJECTIVE: Effective diagnostic criteria must minimize the range of unrelated diagnoses that can be erroneously classified as the condition of interest. We sought to determine if the symptoms associated with alternative MCAS criteria result in less concise or consistent diagnostic alternatives, reducing diagnostic specificity. METHODS: We used multiple large language models, including ChatGPT, Claude, and Gemini, to bootstrap the probabilities of diagnoses that are compatible with consortium or alternative MCAS criteria. We utilized diversity and network analysis to quantify diagnostic precision and specificity compared to control diagnostic criteria including systemic lupus erythematosus (SLE), Kawasaki disease, and migraines. RESULTS: Compared to consortium MCAS criteria, alternative MCAS criteria are associated with more variable (Shannon diversity 5.8 vs. 4.6, respectively; p-value=0.004) and less precise (mean Bray-Curtis similarity 0.07 vs 0.19, respectively; p-value=0.004) diagnoses. The diagnosis networks derived from consortium and alternative MCAS criteria had lower between-network similarity compared to the similarity between diagnosis networks derived from two distinct SLE criteria (cosine similarity 0.55 vs. 0.86, respectively; p-value=0.0022). CONCLUSION: Alternative MCAS criteria are associated with a distinct set of diagnoses compared to consortium MCAS criteria and have lower diagnostic consistency. This lack of specificity is pronounced in relation to multiple control criteria, raising the concern that alternative criteria could disproportionately contribute to MCAS overdiagnosis, to the exclusion of more appropriate diagnoses.

Camel Whey Protein and Baicalein Suppressed Mast Cell Degranulation in Mice Models of IgE- and Non-IgE-Mediated Anaphylaxes: Potential Mechanisms on Downstream Cell Signaling of Mast Cells.

INTRODUCTION: Novel treatments are being researched to develop more safe and effective protective medications for anaphylaxis. Camel whey protein (CWP) and baicalein (BAC, one of the major flavones) have multiple beneficial properties including anti-inflammatory and antioxidant activities. METHODS: The current study investigated/compared the therapeutic protection of repeated intragastric administration of CWP (100 mg/kg body weight, as an animal extract) and BAC (10 mg/kg body weight, as a plant extract), before the challenge with ovalbumin (OVA) or receiving the compound 48/80 (C48/80), against mice models for IgE-independent and dependent anaphylaxes. Besides, their effects on mast cells (MCs) downstream cell signaling were explored. RESULTS: The results revealed that CWP and BAC reduced the mortality rate, as compared with a MCs stabilizer "sulfasalazine (SSZ, 100 mg/kg body weight, intraperitoneally)," in both mice models. Furthermore, they prevented the MCs degranulation and significantly reduced (p < .05) lung tissue levels of cell signaling (p-AKT, p-ERK, and p-IκBα). Additionally, they decreased histamine, tryptase, leukotriene C4, prostaglandin D2, interleukin (IL)-4, and IL-10 levels in broncho-alveolar and peritoneal lavages in systemic anaphylaxis mice models. They also restored the stabilization of peritoneal MCs membrane in inverted light microscopy results accompanied by amelioration of the lung histology. DISCUSSION: The present study provided evidence for the protective therapeutic effect of CWP and BAC against anaphylaxis. As a result, CWP and BAC may be used as preventative supplemented regimens for both non-vegetarian and vegetarian consumers to treat allergy through downregulation of MCs signal transduction pathways, and hence controlling the production of inflammatory mediators.

Epidemiology, Risk Factors, and Management of Biphasic Anaphylaxis.

PURPOSE OF REVIEW: Biphasic anaphylaxis is a variant of anaphylaxis characterized by recurrence of symptoms after initial resolution of anaphylaxis. It was first described in the mid 1990s by Popa and Lerner. Our understanding of the pathophysiology and epidemiology of the condition has advanced considerably since then. The purpose of this manuscript is to review the literature surrounding biphasic anaphylaxis while highlighting key works and recent advances. RECENT FINDINGS: Prior studies have estimated biphasic anaphylaxis occurs in 0.4-20% of anaphylaxis episodes. The wide range may be related to differences in anaphylaxis diagnostic criteria which was inconsistent across studies. Recently identified risk factors for occurrence of biphasic anaphylaxis include severe initial symptoms including hypotension or hypoxia, delay in epinephrine use, and greater than one dose of epinephrine required to treat symptoms. Despite our progress to better understand biphasic anaphylaxis, there remain gaps in the literature. This article aims to review the recent literature including, epidemiology, risk factors, and management of biphasic anaphylaxis.

No signs of mast cell involvement in long-COVID: A case-control study.

Long-COVID caused by SARS-CoV-2 infection has significant and increasing effects on human health worldwide. Although a unifying molecular or biological explanation is lacking, several pathophysiological mechanisms have been proposed. Involvement of mast cells-evolutionary old "multipurpose" innate immune cells-was reported recently in studies of acute infection and post-acute-COVID-19 syndrome. Mast cell activity has been suggested in long-COVID. In this case-control study, we compared data from 24 individuals with long-COVID (according to the NICE criteria) and 24 age- and sex-matched healthy individuals with a history of SARS-CoV-2 infection without developing sequelae. Serum levels of the proteases beta-tryptase (TPSB2) and carboxypeptidase (CPA3), which are mast cell specific, were measured using immunoassays. The values were compared between the two groups and correlated to measures of physical exertional intolerance. TPSB2 and CPA3 levels were median (range) 26.9 (2.0-1000) and 5.8 (1.5-14.0) ng/mL, respectively, in the long-COVID group. The corresponding values in the control group were 10.9 (2.0-1000) (p = 0.93) and 5.3 (3.5-12.9) ng/mL (p = 0.82). No significant correlations between TPSB2 or CPA3 levels and scores on the ten physical subscales of SF-36, 3.1-3.10 were revealed. We found no significant differences in the levels of mast cell activation markers TPSB2 and CPA3 between the long-COVID and control groups and no correlations with proxy markers of exercise intolerance. Mast cell activation does not appear to be part of long-term pathogenesis of long-COVID, at least in the majority of patients.

Expression of the cellular prion protein by mast cells in white-tailed deer carotid body, cervical lymph nodes and ganglia.

Chronic wasting disease (CWD) is a transmissible and fatal prion disease that affects cervids. While both oral and nasal routes of exposure to prions cause disease, the spatial and temporal details of how prions enter the central nervous system (CNS) are unknown. Carotid bodies (CBs) are structures that are exposed to blood-borne prions and are densely innervated by nerves that are directly connected to brainstem nuclei, known to be early sites of prion neuroinvasion. All CBs examined contained mast cells expressing the prion protein which is consistent with these cells playing a role in neuroinvasion following prionemia.

Corydalis yanhusuo extract and its pharmacological substances alleviate food allergy by inhibiting mast cells activation via PLC/PKC/STAT3 pathway.

ETHNOPHARMACOLOGICAL RELEVANCE: Food allergies have increasingly become a disease that affects global health and need for corresponding therapeutic drugs urgently. As a traditional Chinses medicine with a wide range of pharmacological effects, however, there was no clear research confirming therapeutic effect and pharmacological substances of Corydalis yanhusuo (YHS) on food allergies. Mast cells (MCs) are the main effector cells which mediate allergic and pseudo-allergic reactions. MATERIALS AND METHODS: In this study, we investigated the effect of YHS extract on treating food allergy and its underlying mechanism. The inhibitory effect of YHS on MCs activation in vitro was evaluated by Ca2+ influx, degranulation, and cytokine release detection. The in vivo effect was investigated using the passive cutaneous anaphylaxis (PCA), active systemic allergy as well as OVA-induced food allergy mice. Western blot was performed to reveal the signaling pathway. RESULTS: YHS extract showed an inhibitory effect on MCs activation and food allergy both in vitro and in vivo. PLC/PKC/STAT3 signaling pathway was suppressed by YHS extract in the disease. HPLC analysis revealed YHS extract contains corydaline and tetrahydropalmatine, and both compounds inhibited MCs activation induced by C48/80 in vitro. CONCLUSION: YHS extract inhibited the MCs activation and food allergy via PLC/PKC/STAT3 pathway.

Nutraceutical formulation based on a synergic combination of melatonin and palmitoylethanolamide for the management of allergic events.

The management of allergic events is a growing global health issue, especially in industrialized countries. This disease is an immune-mediated process, regulated by the interaction of IgE with an allergen, resulting in mast cell activation, which concerns the release of several immune-inflammatory modulators, i.e., histamine, ß-hexosaminidase, COX-2, IL-6, and TNF-α, responsible for the main allergic-reaction associated symptoms. The aim of the present study was the efficacy evaluation of an alternative remedy, an innovative nutraceutical formulation (NF) based on the synergic combination of melatonin (MEL) and palmitoylethanolamide (PEA) for the prevention and treatment of immune disease. At first, the intestinal bioaccessibility of PEA and MEL in NF was assessed at 1.6 and 36%, respectively. Then the MEL and PEA ability to modulate the release of immune-inflammatory modulators in the human mast cell line (HMC-1.2) at their bioaccessible concentration was investigated. Our results underline that NF treatment was able to reduce COX-2 mRNA transcription levels (-30% vs. STIM, p < 0.0001) in stimulated HMC-1.2 and to contract COX-2 enzymatic activity directly (IC50: 152 µg/mL). Additionally, NF showed valuable ability in reducing histamine and ß-hexosaminidase release in stimulated HMC-1.2, as well as in decreasing TNF-α and IL-6 mRNA transcription levels and protein production.

Tryptase: The Silent Witness of Past and Ongoing Systemic Events.

Introduction: Tryptase is an important biomarker widely used in the laboratory confirmation of severe hypersensitivity reactions, especially anaphylaxis. It also plays a crucial role in the diagnosis, risk stratification, management and prognostic evaluation of many other mast cell-related conditions. Aim: This paper aims to highlight the role of serum tryptase, both in allergic disorders and other mast cell-related conditions. Two clinical cases regarding timely serum tryptase acquisition (in drug hypersensitivity reactions during the imaging procedure and perioperative anaphylaxis) are meant to emphasize the clinical potential of this protease. Method: We performed a comprehensive literature search of the PubMed/Medline and Scopus databases. From a total of 640 subject related publications, dating from 1940 to 2024, 45 articles written in English were selected. Literature search results: Total serum tryptase is a simple, cost-effective analysis with a normal baseline tryptase (sBT) level below 8.4 µg/L. Elevated sBT can indicate hereditary alpha-tryptasemia (HαT), mastocytosis and other non-allergic disorders. Patients with higher sBT levels, especially with insect venom allergy, have an increased risk of severe reactions and thereby require a prolonged treatment. All immediate systemic hypersensitivity reactions require a correlation between serum acute tryptase (sAT) and sBT. According to the guidelines, measuring sAT 30 min to 2 h after the symptom onset and sBT 24 h after the resolution, using the 20 + 2 rule and an sAT/sBT ratio of 1.685, improves the diagnostic accuracy in anaphylaxis. Conclusions: Tryptase levels should be acquired in all cases with clinical suspicion of MC degranulation. Given the increasing clinical relevance, elevated baseline serum tryptase levels require a multidisciplinary approach and further investigation.

The common cold: The need for an effective treatment amid the FDA discussion on oral phenylephrine.

An episode of the common cold can have a significant negative impact on quality of life, mood, and daily activities. In line with this fact, there is a growing demand for health care and treatments associated with the common cold. Current treatments aim to (1) inhibit symptom severity and (2) shorten the duration of an episode of the common cold. These products include analgesics, antihistamines, and decongestants. In addition, various supplements, including vitamins, minerals, and herbs, are marketed to treat the common cold. The current products marketed for treating the common cold may reduce the severity of some (but not all) common cold symptoms, but they usually do not shorten the common cold episode. The recent indication that phenylephrine is not effective means that it will ultimately need to be removed from the over-the-counter monograph. Manufacturers will consequently need to reformulate their products and withdraw oral phenylephrine-containing products. Several newly developed common cold products are currently under investigation. These clinical trials should evaluate their efficacy and safety, as there remains a clear need for common cold products that significantly reduce both the symptom severity and the duration of episodes of the common cold.

Flow cytometric immunophenotypic features of acute myeloid leukemia with mast cell differentiation.

OBJECTIVES: Acute myeloid leukemia (AML) with mast cell (MC) differentiation was recently described as an aggressive subgroup of AML cases. The objectives of this study were to assess the flow cytometric immunophenotypic features of AML-MC cases. METHODS: We characterized the immunophenotypic features of 21 AML-MC cases by flow cytometry and compared them to 20 reactive/regenerating bone marrow specimens. RESULTS: The number of MCs detected by flow cytometry in AML-MC cases ranged from 0.4% to 21.1%, with a median of 3.5%, significantly higher than that of normal/reactive bone marrow (BM) (median, 0.01%; range, 0.000%-0.396%; P < .0001). Immunophenotypically, MCs in AML-MC cases demonstrated immaturity, differing from MCs in normal/reactive BMs, including dimmer CD45 (100% vs 0%), lower side scatter (100% vs 0%), more frequent CD34 (81% vs 20%), and CD123 (100% vs 10%) positivity, and more frequent uniform/increased CD38 expression (95% vs 20%) (all P ≤ .0001). CD2 (0/5) and CD25 (2/6, 1 uniform and 1 partial) were assessed in a subset of cases. The myeloblasts in AML-MC were typically CD34+CD117+HLA-DR+ with unusually frequent expression of CD56 (57%, all partial) and CD25 (63%, mostly partial), increased CD117 (62%), and decreased CD38 (86%). The MC percentage determined by flow cytometry correlated well with MCs detected by tryptase immunohistochemistry (r = 0.76, P < .001). CONCLUSIONS: The MCs in AML-MC cases are characterized by dim CD45, low side scatter, CD34 and CD123 positivity, and uniform and increased CD38 expression. Flow cytometry is an excellent tool for identifying AML-MC cases.

Unusual Equine Tumors.

There are a number of unusual tumors in the horse. Gross tumor characteristics, anatomical location, and signalment may assist with identification. Clinical pathology is often unrewarding with non-specific findings, while fine needle aspirates may not obtain sufficient tissue material to confirm a diagnosis. Although regular staining of biopsy material may be sufficient, immunohistochemistry markers may be required, especially in less differentiated tumors. The prognosis is dependent on the type, location, tumor size as well as on metastatic spread. A selection of unusual and rare tumors that the clinician is more likely to encounter is discussed.