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Background: Mast cells play an important role in allergic reactions by releasing potent mediators, including histamine and platelet-activating factor (PAF), upon activation. We recently reported that a biotinylated heptapeptide (peptide 2), D-Lys(Biotinyl)-Trp-Tyr-Lys-Asp-Gly-Asp, which is highly stable in the plasma, inhibits PAF bioactivity and anaphylactic hypothermia in vivo. However, the effects of this peptide on allergy induction by mast cells have not been investigated. Methods and Results: Several biotinylated heptapeptides, including peptide 2, inhibited IgE/antigen-stimulated degranulation in RBL-2H3 cells. Peptide 2 also markedly inhibited the degranulation induced by calcium ionophore A23187. All peptides (peptide 1, 2 and 3) inhibited activating stimuli-induced increase in intracellular Ca2+ levels. The transforming growth factor-alpha shedding assay indicated that peptide 2 antagonized against the histamine H1 receptor. Furthermore, peptide 2 inhibited histamine-induced rat paw edema. Conclusion: These results highlight the potential of peptide 2 in the prevention and treatment of various allergic diseases mediated by mast cell activation. [ABSTRACT FROM AUTHOR]

AbstractObjectivesMethodsKey findingsConclusionsChitosan is widely used in medicine to regulate immune responses in T cells and dendritic cells. However, research on the regulation of mast cells (MCs) is scarce. Mas-related G-protein-coupled receptor X2 (MRGPRX2) is a key receptor that mediates MC activation. However, the inhibitory effects of chitosan on MRGPRX2 activation have not yet been reported. The aim of this study was to determine whether chitosan inhibits MRGPRX2-mediated MC activation and the molecular weight of chitosan with the best inhibitory effect.Cytotoxic and activating effects of chitosan on LAD2 cells were evaluated in vitro. An in vitro MC degranulation reaction model and in vivo C48/80-induced local passive anaphylaxis mouse model were used to evaluate the inhibitory effect of chitosan on MRGPRX2 activation.Chitosan inhibited MC degranulation mediated by MRGPRX2 in vitro and reduced histamine, β-hexosaminidase, and cytokine release. Chitosan inhibited local pseudo-allergy and inflammatory mediator release by inhibiting MRGPRX2-mediated MC activation. Moreover, low-molecular-weight chitosan exhibited superior inhibitory activity against MRGPRX2.Chitosan inhibited MRGPRX2-mediated MC degranulation in vivo and in vitro. Low molecular weight chitosan has the potential to be developed as a functional drug or food to assist in the treatment of MRGPRX2-regulated diseases. [ABSTRACT FROM AUTHOR]

Introduction: The role of mast cells (MCs) in clear cell renal carcinoma (ccRCC) is unclear, and comprehensive single-cell studies of ccRCC MCs have not yet been performed. Methods: To investigate the heterogeneity and effects of MCs in ccRCC, we studied single-cell transcriptomes from four ccRCC patients, integrating both single-cell sequencing and bulk tissue sequencing data from online sequencing databases, followed by validation via spatial transcriptomics and multiplex immunohistochemistry (mIHC). Results: We identified four MC signature genes (TPSB2, TPSAB1, CPA3, and HPGDS). MC density was significantly greater in ccRCC tissues than in normal tissues, but MC activation characteristics were not significantly different between ccRCC and normal tissues. Activated and resting MCs were defined as having high and low expression of MC receptors and mediators, respectively, whereas proliferating MCs had high expression of proliferation-related genes. The overall percentage of activated MCs in ccRCC tissues did not change significantly but shifted toward a more activated subpopulation (VEGFA+ MCs), with a concomitant decrease in proliferative MCs (TNF+ MCs) and resting MCs. An analysis of the ratio of TNF+/VEGFA+ MCs in tumors revealed that MCs exerted antitumor effects on ccRCC. However, VEGFA+MC was produced in large quantities in ccRCC tissues and promoted tumor angiogenesis compared with adjacent normal tissues, which aroused our concern. In addition, MC signature genes were associated with a better prognosis in the KIRC patient cohort in the TCGA database, which is consistent with our findings. Furthermore, the highest level of IL1B expression was observed in macrophages in ccRCC samples, and spatial transcriptome analysis revealed the colocalization of VEGFA+ MCs with IL1B+ macrophages at the tumor–normal interface. Discussion: In conclusion, this study revealed increased MC density in ccRCC. Although the proportion of activated MCs was not significantly altered in ccRCC tissues compared with normal tissues, this finding highlights a shift in the MC phenotype from CTSGhighMCs to more activated VEGFA+MCs, providing a potential therapeutic target for inhibiting ccRCC progression. [ABSTRACT FROM AUTHOR]

The pro-tumor effects of mast cell (MC) in the tumor microenvironment (TME) are becoming increasingly clear. Recently, MC were shown to contribute to tumor malignancy by supporting the migration of tumor-associated macrophages (TAMs), suggesting a relationship with tumor immunity. In the current study, we aimed to examine the correlation between MC infiltration and neoadjuvant chemoradiotherapy (nCRT) response for locally advanced rectal cancer (LARC). Ninety-five LARC patients who recieved nCRT were enrolled in this study. Protein levels of the MC marker tryptase and TAM marker CD206 were evaluated with immunohistochemistry (IHC). The correlation between MC infiltration and prognostic factors was evaluated. The effects of MCs on the malignant potential were examined using in vitro proliferation and invasion assays with a colorectal cancer (CRC) cell line (HCT-116). Following nCRT, 31.6% of resected LARC patient specimens were positive for MC infiltration by tryptase IHC analysis. MC infiltration was significantly correlated with nCRT response. The 5-year disease-free survival (DFS) rate was significantly lower in the MC-positive group compared with the MC-negative group (52.3% vs. 76.8%). Univariate and multivariate analyses revealed that MC infiltration was the independent prognostic indicator for DFS. MC infiltration was significantly correlated with CD206 expression, and therefore TAMs. In vitro experiments suggested that tumor activated mast cells could promote CRC cell malignant behavior via production of macrophage inhibitory factor. MC infiltration in LARC patients was positively correlated with TAM infiltration and resistance to nCRT, and was also an independent poor prognostic indicator. [ABSTRACT FROM AUTHOR]

Upon stimulation and activation, mast cells (MCs) release soluble mediators, including histamine, proteases, and cytokines. These mediators are often stored within cytoplasmic granules in MCs and may be released in a granulated form. The secretion of cytokines and chemokines occurs within hours following activation, with the potential to result in chronic inflammation. In addition to their role in allergic inflammation, MCs are components of the tumor microenvironment (TME). MicroRNAs (miRNAs) are small RNA molecules that do not encode proteins, but regulate post-transcriptional gene expression by binding to the 3' non-coding regions of mRNAs. This plays a crucial role in the function of MC, including the key processes of MC proliferation, maturation, apoptosis, and activation. It has been demonstrated that miRNAs are also present in extracellular vesicles (EVs) secreted by MCs. EVs derived from MCs mediate intercellular communication by carrying miRNAs, affecting various diseases including allergic diseases, intestinal disorders, neuroinflammation, and tumors. These findings provide important insights into the therapeutic mechanisms and targets of miRNAs in MCs that affect diseases. This review discusses the relevance of miRNA production by MCs in regulating their own activity and the effect of miRNAs putatively produced by other cells in the control of MC activity and their participation in selected pathologies. [ABSTRACT FROM AUTHOR]

Purpose of Review: Clinical interest in non-IgE activation of mast cells has been growing since the description of the human MRGPRX2 receptor. Its participation in many allergic and inflammatory conditions such as non histaminergic itch, urticaria, asthma and drug hypersensitivity has been growing. We present here an updated review of its structure, expression and biology to help understand conditions and diseases attributed to its activation and/or overpexression and the search for agonists and antagonists of clinical utility. Recent Findings: The description of patients presenting anaphylaxis when exposed to one or multiple MRGPRX2 agonists such as general anesthetics, antibiotics, opiods and other agents has provided evidence of potential heterogeneity in humans. Summary: This review provides the most recent developments into the receptor structure, tissue expression and signaling pathways including the potential enhancement of IgE-mediated mast cell activation. New insight into its agonists and antagonists is described and future developments to adress its modulations. [ABSTRACT FROM AUTHOR]

Neurology and connective tissue are intimately interdependent systems and are critical in regulating many of the body's systems. Unlocking their multifaceted relationship can transform clinical understanding of the mechanisms involved in multisystemic regulation and dysregulation. The fascial system is highly innervated and rich with blood vessels, lymphatics, and hormonal and neurotransmitter receptors. Given its ubiquity, fascia may serve as a "watchman," receiving and processing information on whole body health. This paper reviews what constitutes fascia, why it is clinically important, and its contiguous and interdependent relationship with the nervous system. Unquestionably, fascial integrity is paramount to human locomotion, interaction with our environment, bodily sense, and general physical and emotional wellbeing, so an understanding of the fascial dysregulation that defines a range of pathological states, including hypermobility syndromes, autonomic dysregulation, mast cell activation, and acquired connective tissue disorders is critical in ensuring recognition, research, and appropriate management of these conditions, to the satisfaction of the patient as well as the treating practitioner. [ABSTRACT FROM AUTHOR]

Primary human mast cells (MC) obtained through culturing of blood-derived MC progenitors are the preferred model for the ex vivo study of MRGPRX2- vs. IgE-mediated MC activation. In order to assess the impact of culture conditions on functional MRGPRX2 expression, we cultured CD34+-enriched PBMC from peripheral whole blood (PB) and buffy coat (BC) samples in MethoCult medium containing stem cell factor (SCF) and interleukin (IL)-3, modified through variations in seeding density and adding or withholding IL-6, IL-9 and fetal bovine serum (FBS). Functional expression of MRGPRX2 was assessed after 4 weeks via flow cytometry. We found similar proportions of CD34+ MC-committed progenitors in BC and PB. Higher seeding densities (≥ 1x105 cells/mL) and exposure to IL-9 and FBS suppressed functional MRGPRX2 expression at 4 weeks, while leaving MC yield largely unaffected. IL-6 had no impact on MRGPRX2 expression. MRGPRX2-expressing MC upregulated CD63 upon stimulation with polyclonal anti-IgE, substance P and compound 48/80 at 4 weeks. Ketotifen and dasatinib but not cromolyn sodium inhibited both IgE- and MRGPRX2-dependent pathways. Our results confirm the feasibility of functional MC activation studies on PB-derived MC after a short 4-week culture and highlight the impact of culture conditions on functional MRGPRX2 expression. [ABSTRACT FROM AUTHOR]

Background: Mast cells are implicated in the pathogenesis and severity of asthma in children and adults. The release of proinflammatory mediators and cytokines from activated mast cells (MC) is associated with Type 2 (T2) cell-skewed inflammation. Methods: We obtained the airway tissues of Balb/c mice with or without intra-tracheal diesel exhaust particles (DEP) instillation to measure the extent of tryptase+ MCs infiltration and interleukin (IL)-33 expression. Cultured human mast cells (HMC-1) were stimulated with DEP to determine the role of aryl hydrocarbon receptor (AhR) in mediating the synthesis and release of IL-33 and type-2 cytokines. Results: In the control animals, most of the MC accumulated in the submucosal vessels without expression of IL-33. Intra-tracheal DEP installation increased the number of IL-33+ MC infiltrating in the epithelial and sub-epithelial areas of mice. Human MC exposed to DEP upregulated mRNA and protein expression of IL-33. These effects were abolished by knockdown of expression of the AhR or AhR nuclear translocator (ARNT) by small interfering (si)RNA transfection. DEP also activated nuclear factor-kappa B (NF-κB) to facilitate nuclear translocation of the AhR. DEP increased MC migration and induced the synthesis and release of IL-4, IL-5, and IL-13 in MCs, and these effects were abolished by anti-ST2 antibodies. Conclusions: Airborne pollutants may activate MCs to produce IL-33 via the AhR/NF-κB pathway, leading to type 2 cytokines production and enhancing MC airway epithelium-shifted migration through the autocrine or paracrine IL-33/ST2 axis. [ABSTRACT FROM AUTHOR]

Kallikrein-related peptidase 7 (KLK7) is one of 15 members of the tissue kallikrein family and is primarily expressed in the skin epidermis. The activity of KLK7 is tightly regulated by multiple stages of maturation and reversible inhibition, similar to several other extracellular proteases. In this work, we used protease-specific inhibitors and active site variants to show that KLK7 undergoes autolysis at two separate sites in the 170 and 99 loops (chymotrypsinogen numbering), resulting in a loss of enzymatic activity. A protein BLAST search using the autolyzed KLK7 loop sequences identified mast cell chymase as a potential KLK7 substrate. Indeed, KLK7 cleaves chymase resulting in a concomitant loss of activity. We further demonstrate that KLK7 can hydrolyze other mast cell proteases as well as several cytokines. These cytokines belong mainly to the interferon and IL-10 families including IFN-α, IFN-β, IFN-γ, IL-28A/IFN-λ2, IL-20, IL-22, and IL-27. This is the first study to identify a possible molecular interaction link between KLK7 and mast cell proteases and cytokines. Although the precise biological implications of these findings are unclear, this study extends our understanding of the delicate balance of proteolytic regulation of enzyme activity that maintains physiological homeostasis, and facilitates further biological investigations. [ABSTRACT FROM AUTHOR]

Basophils and mast cells (MCs) play an important role in immune responses against allergens and parasitic infection. To elucidate the mechanisms that determine the commitment between basophils and mast cell (MCs), transcription factors and epigenetic modifications regulating the gene expression of basophil‐specific enzymes, Mcpt8 and Mcpt11, were analyzed using bone marrow‐derived (BM) cells containing basophils and MCs. Knockdown (KD) and overexpression experiments revealed that the transcription factor C/EBPα positively regulated the gene expression of Mcpt8 and Prss34 (encoding Mcpt11). Cebpa, Mcpt8, and Prss34 mRNAs levels were upregulated by histone deacetylases and downregulated by DNA methyltransferases. Gata2 KD significantly reduced the mRNA levels of Mcpt8 and Prss34, while TGF‐β treatment increased those of Mcpt8 and Prss34. These results show that basophil‐specific protease genes were transactivated by C/EBPα, GATA2, and TGF‐β signaling and modified with epigenetic regulation. [ABSTRACT FROM AUTHOR]

Mas-related G protein-coupled receptor b2 (Mrgprb2) binding to its cationic endogenous and exogenous ligands induces mast cell degranulation and promotes inflammation in mice. However, the physiological roles of its human homologue MRGPRX2 remain unclear. Here we aimed to elucidate the mechanisms by which MRGPRX2 regulates vascular permeability, and generated MRGPRX2 knock-in (MRGPRX2-KI) and Mrgprb2 knockout (Mrgprb2-KO) mice. Substance P (SP) and ciprofloxacin strongly degranulated MRGPRX2-KI peritoneal mast cells (PMCs) better than WT PMCs, whereas Dermatophagoides pteronyssinus (Der p) extract and phenol-soluble modulin α3 (PSMα3) did not degranulate PMCs. SP-stimulated MRGPRX2-KI PMCs released large amounts of histamine and mast cell protease 4 (MCPT4) chymase. Der p extract, PSMα3, and MCPT4, but not histamine, induced SP release from dorsal root ganglion (DRG) cells. However, this effect of Der p extract/PSMα3 was suppressed by a transient receptor potential vanilloid 1 (TRPV1) antagonist. SP-, ciprofloxacin-, Der p extract-, PSMα3-, and MCPT4-induced vascular permeability was highest in MRGPRX2-KI mice, which depended on SP. In addition, SP-, ciprofloxacin- and PSMα3-induced MRGPRX2-dependent vascular hyperpermeability was suppressed by antihistamine and chymase inhibitor. TRPV1 antagonist also inhibited PSMα3-induced MRGPRX2-dependent vascular hyperpermeability. Both Mrgprb2-KO and MRGPRX2-KI did not influence the histamine-induced murine vascular hyperpermeability. Overall, our results suggest that neuronal SP induces MRGPRX2-dependent mast cell degranulation, releasing histamine and chymase, which promote vascular hyperpermeability directly or indirectly via DRG cell activation. Importantly, the worsening cycle (MRGPRX2 → mast cell degranulation → chymase → DRG activation → SP → MRGPRX2) seems to play an important role in human MRGPRX2-depdendent inflammation. [ABSTRACT FROM AUTHOR]

Purpose: Mast cells, their serine proteinase tryptase, and immunoglobulin E (IgE) can be involved in cutaneous carcinogenesis. Materials and methods: To study the association of tryptase+ and IgE+ cells with photodamage and skin cancers 385 adult patients (201 males, 184 females, 75 with immunosuppression) at risk of any type of skin cancer were examined. Skin biopsies were taken from the sun-protected medial arm and from the photodamaged dorsal forearm skin followed by immunohistochemical staining for tryptase and IgE. Results: The results show that tryptase+ and IgE+ cells are significantly higher in number in the photodamaged than sun-protected skin, both in immunocompetent and -compromised subjects, and there is a strong correlation between tryptase+ and IgE+ cells. The numbers of forearm tryptase+ and especially IgE+ cells associated significantly with the forearm photodamage severity. In the logistic regression analysis, the forearm to upper arm ratio of IgE+ cells produced a univariate odds ratio of 1.521 (p =.010) and a multivariate one of 3.875 (p =.047) for the history of squamous cell carcinoma. The serum level of total IgE correlated significantly to the IgE to tryptase ratio in both skin sites. Conclusions: Therefore, IgE+ mast cells participate in photodamage and carcinogenesis, though it is unclear whether they are tumor-protective or -causative. [ABSTRACT FROM AUTHOR]

Cetylpyridinium chloride (CPC) is a quaternary ammonium antimicrobial used in numerous personal care products, human food, cosmetic products, and cleaning solutions. Yet, there is minimal published data on CPC effects on eukaryotes, immune signaling, and human health. Previously, it was shown that low-micromolar CPC inhibits rat mast cell function by inhibiting antigen (Ag)-stimulated Ca2+ mobilization, microtubule polymerization, and degranulation. In the current study, these findings are extended to human mast cells (LAD2); this paper presents data indicating that a mechanism of action for CPC might center on its positively-charged quaternary nitrogen in its pyridinium headgroup. The inhibitory effect of CPC was independent of signaling platform receptor architecture. Tyrosine phosphorylation events are a trigger of Ca2+ mobilization necessary for degranulation. CPC inhibits global tyrosine phosphorylation in Ag-stimulated mast cells. Specifically, CPC inhibits tyrosine phosphorylation of specific key players Syk kinase and LAT, a substrate of Syk. In contrast, CPC did not affect Lyn kinase phosphorylation. Thus, a root mechanism for CPC effect might be electrostatic disruption of particular tyrosine phosphorylation events essential for signaling. This work presented here outlines biochemical mechanisms underlying the effects of CPC on immune signaling. [ABSTRACT FROM AUTHOR]

Bidirectional interactions between eosinophils and mast cells (MCs) have been reported in various allergic diseases. Bone marrow (BM) eosinophilia, and to a lesser extent blood eosinophilia, is common in systemic mastocytosis (SM), but its significance remains unknown. We described blood and BM eosinophil characteristics in SM. A large collection of BM biopsy samples was analyzed using immunohistochemical staining and whole-slide imaging. Eosinophil and extracellular granules were detected by eosinophil peroxidase (EPX) staining and MCs by KIT staining. Complementary analyses were conducted using flow cytometry and immunofluorescence. Eosinophil infiltrates and large areas of eosinophil degranulation were observed within or around BM MC infiltrates in SM. EPX staining surface, highlighting intact eosinophils and eosinophil degranulation, was higher in nonadvanced SM (n = 37 BM biopsy samples) compared with both controls (n = 8, P =.0003) and advanced SM (n = 24, P =.014). In nonadvanced SM, positive correlations were observed between serum tryptase levels and percentages of eosinophil counts in BM aspirations (Spearman r coefficient r = 0.38, P =.038), eosinophils count in BM biopsy samples (r = 0.45, P =.007), EPX staining (r = 0.37, P =.035), and eosinophil degranulation (r = 0.39, P =.023). Eosinophil counts in BM biopsy samples also correlated with MC counts (r = 0.47, P =.006) and KIT staining surface (r = 0.49, P =.003). BM MCs expressed IL-5 receptor and other usual eosinophil cytokine/chemokine receptors, and blood eosinophils displayed several increased surface markers compared with controls, suggesting an activated state. Our data suggest possible cross talk between MCs and eosinophils, supporting MC tryptase release and MC activation-related symptoms. This suggests a rationale for targeting eosinophils in nonadvanced SM not fully controlled by other therapies. [ABSTRACT FROM AUTHOR]

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. Summary: 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. [ABSTRACT FROM AUTHOR]

Historically, the nervous and immune systems were studied as separate entities. The nervous system relays signals between the body and the brain by processing sensory inputs and executing motor outputs, whereas the immune system provides protection against injury and infection through inflammation. However, recent developments have demonstrated that these systems mount tightly integrated responses. In particular, the peripheral nervous system acts in concert with the immune system to control reflexes that maintain and restore homeostasis. Notwithstanding their homeostatic mechanisms, dysregulation of these neuroimmune interactions may underlie various pathological conditions. Understanding how these two distinct systems communicate is an emerging field of peripheral neuroimmunology that promises to reveal new insights into tissue physiology and identify novel targets to treat disease. [ABSTRACT FROM AUTHOR]

Mast cells are hematopoietic-derived immune cells that possess numerous cytoplasmic granules containing immune mediators such as cytokines and histamine. Antigen stimulation triggers mast cell granule exocytosis, releasing granule contents in a process known as degranulation. We have shown that Rho GTPase signaling is an essential component of granule exocytosis, however, the proteins that regulate Rho GTPases during this process are not well defined. Here we examined the role of Rho guanine-nucleotide dissociation inhibitors (RhoGDIs) in regulating Rho GTPase signaling using RBL-2H3 cells as a mast cell model. We found that RBL-2H3 cells express two RhoGDI isoforms which are primarily localized to the cytosol. Knockdown of RhoGDI1 and RhoGDI2 greatly reduced the levels of all Rho GTPases tested: RhoA, RhoG, Rac1, Rac2, and Cdc42. The reduction in Rho GTPase levels was accompanied by an increase in their membrane-localized fraction and an elevation in the levels of active Rho GTPases. All RhoGDI knockdown strains had altered resting cell morphology, although each strain was activation competent when stimulated. Live cell imaging revealed that the RhoGDI1/2 double knockdown (DKD) strain maintained its activated state for prolonged periods of time compared to the other strains. Only the RhoGDI1/2 DKD strain showed a significant increase in granule exocytosis. Conversely, RhoGDI overexpression in RBL-2H3 cells did not noticeably affect Rho GTPases or degranulation. Based on these results, RhoGDIs act as negative regulators of Rho GTPases during mast cell degranulation, and inhibit exocytosis by sequestering Rho GTPases in the cytosol. [ABSTRACT FROM AUTHOR]

Abstract Background Sepsis is a systemic inflammatory response caused by infection. When this inflammatory response spreads to the lungs, it can lead to acute lung injury (ALI) or more severe acute respiratory distress syndrome (ARDS). Pulmonary fibrosis is a potential complication of these conditions, and the early occurrence of pulmonary fibrosis is associated with a higher mortality rate. The underlying mechanism of ARDS-related pulmonary fibrosis remains unclear. Methods To evaluate the role of mast cell in sepsis-induced pulmonary fibrosis and elucidate its molecular mechanism. We investigated the level of mast cell and epithelial-mesenchymal transition(EMT) in LPS-induced mouse model and cellular model. We also explored the influence of cromolyn sodium and mast cell knockout on pulmonary fibrosis. Additionally, we explored the effect of MC-derived IL-13 on the EMT and illustrated the relationship between mast cell and pulmonary fibrosis. Results Mast cell was up-regulated in the lung tissues of the pulmonary fibrotic mouse model compared to control groups. Cromolyn sodium and mast cell knockout decreased the expression of EMT-related protein and IL-13, alleviated the symptoms of pulmonary fibrosis in vivo and in vitro. The PI3K/AKT/mTOR signaling was activated in fibrotic lung tissue, whereas Cromolyn sodium and mast cell knockout inhibited this pathway. Conclusion The expression level of mast cell is increased in fibrotic lungs. Cromolyn sodium intervention and mast cell knockout alleviate the symptoms of pulmonary fibrosis probably via the PI3K/AKT/mTOR signaling pathway. Therefore, mast cell inhibition is a potential therapeutic target for sepsis-induced pulmonary fibrosis.

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.

Lactation anaphylaxis is extremely rare and has been scarcely reported in the literature. Breast feeding and/or milk expression immediately induces life-threatening anaphylactic reactions, including generalized urticaria, angioedema, respiratory symptoms, and hypotension. Six English-language case reports have described the clinical course in detail. The present report describes a case involving a 24-year-old woman with no history of allergic reactions or anaphylaxis who experienced anaphylactic reactions three times immediately after milk expression. Lactation anaphylaxis was suspected when a detailed medical history revealed lactation-related recurrent anaphylactic symptoms. The authors prescribed bromocriptine to stop lactation and switched her to formula feeding, which resulted in no further anaphylactic episodes. Based on a review of the relevant literature, this report describes the characteristics of lactation anaphylaxis and possible management strategies. The pathogenesis of lactation anaphylaxis has been inferred from various experimental results.

Abstract Background The relationship between the alarming cytokine interleukin-33 (IL-33) and lung autophagy in systemic anaphylaxis mouse models is not yet fully elucidated, hence, the current study attempts to explain the regulation of lung autophagy in systemic anaphylactic mouse models. IL-33 plays a critical role in endoplasmic reticulum (ER) stress and autophagy regulation via insulin-like growth factor-binding protein-3 (IGFBP-3). Results The results of the present study confirmed the induction of systemic anaphylaxis in mice through the elevated mast cell mediators in the peritoneal lavage. Consequently, lung stress triggered IL-33 secretion that influenced autophagy markers; IGFBP-3, activating transcription factor-6 (ATF-6), autophagy related gene 4B (ATG4B), p62, microtubule-associated protein light chain3-II (LC3-II) as well as DNA damage-regulated autophagy modulator 1 (DRAM1). Conclusion This research is a trial to investigate lung autophagy in compound 48/80 or ovalbumin-induced systemic anaphylaxis mouse models and pay a particular attention to the role of IL-33 in lung autophagy in such models. Graphical abstract

Abstract Background Microbial infections, particularly those caused by rhinovirus (RV) and respiratory syncytial virus (RSV), are major triggers for asthma exacerbations. These viruses activate toll-like receptors (TLRs), initiating an innate immune response. To better understand microbial-induced asthma exacerbations, animal models that closely mimic human lung characteristics are essential. This study aimed to assess airway responses in guinea pigs exposed to TLR agonists, simulating microbial infections. Methods The agonists poly(I: C) (TLR3), lipopolysaccharide (LPS; TLR4) and imiquimod (TLR7), or the combination of poly(I: C) and imiquimod (P/I) were administered intranasally once a day over four consecutive days. The latter group received daily intraperitoneal injections of dexamethasone starting one day before the TLR agonists challenge. Respiratory functions were measured by whole-body plethysmography and forced oscillatory technique. Bronchoalveolar lavage fluid (BALF) cells and lungs were collected for analysis. Results The intranasal exposure of LPS and P/I caused an increase in enhanced pause (Penh) after challenge, whereas neither poly(I: C) nor imiquimod alone showed any effect. After the challenges of LPS, poly(I: C) or P/I, but not imiquimod alone, induced an increase of both Rrs (resistance of the respiratory system) and Ers (elastance of the respiratory system). LPS exposure caused an increase of neutrophils in BALF, whereas none of the other exposures affected the composition of cells in BALF. Exposure to LPS, poly (I: C), imiquimod, and P/I all caused a marked infiltration of inflammatory cells and an increase of mast cells around the small airways. For the expression of inflammatory mediators, LPS increased CXCL8, poly(I: C) and imiquimod decreased IL-4 and IL-5, and increased IFNγ. Imiquimod increased CXCL8 and IL-6, whereas P/I decreased IL-5, and increased IL-6 and IFNγ. The increases in Rrs, Ers, and airway inflammation, but not the altered expression of inflammatory cytokines, were attenuated by dexamethasone. Conclusions TLR agonists promote acute airway inflammation and induce airway obstruction and hyperresponsiveness in guinea pigs. The severity of these effects varies depending on the specific agonists used. Notably, dexamethasone reversed pulmonary functional changes and mitigated bronchial inflammation caused by the combined treatment of P/I. However, it had no impact on the expression of inflammatory mediators.

Abstract Mast cells are commonly found in pancreatic ductal adenocarcinoma (PDAC), yet their role in the disease remains uncertain. Although mast cells have been associated with depression in several diseases, their connection to PDAC in this context remains unclear. This study explored the correlation between mast cells and psychosocial stress in patients with PDAC. Prior to surgery, 40 patients with PDAC (n = 29 primary resected, n = 11 neoadjuvant treated) completed four questionnaires assessing stress and quality of life. Immunostaining was performed on the resected tumor tissue. Spearman analysis was employed to correlate mast cells with distress and neuropeptides serotonin and beta-endorphin serum and tissue levels. Patients with PDAC exhibited elevated levels of distress and worry. Lower number of mast cells within the tumor correlated with greater psychological burden. Among primary resected patients, mast cell count moderately correlated with joy and inversely with worries. Following neoadjuvant chemotherapy, strong inverse correlation was observed between anxiety, depression, and mast cell quantity. No correlation was found between mast cells and serotonin or beta-endorphin levels. In summary, mast cell presence inversely correlates with psychosocial stress, suggesting a link between immune cells and psychological well-being in pancreatic cancer. Targeting mast cells might offer therapeutic avenues for addressing cancer-induced depression and anxiety.

Abstract Although the cellular prion protein (PrPC) has been evolutionarily conserved, the role of this protein remains elusive. Recent evidence indicates that PrPC may be involved in neuroinflammation and the immune response in the brain, and its expression may be modified via various mechanisms. Histamine is a proinflammatory mediator and neurotransmitter that stimulates numerous cells via interactions with histamine receptors 1-4 (HRH1-4). Since microglia are the innate immune cells of the central nervous system, we hypothesized that histamine-induced stimulation regulates the expression of PrPC in human-derived microglia. The human microglial clone 3 (HMC3) cell line was treated with histamine, and intracellular calcium levels were measured via a calcium flux assay. Cytokine production was monitored by enzyme-linked immunosorbent assay (ELISA). Western blotting and quantitative reverse transcription-polymerase chain reaction were used to determine protein and gene expression of HRH1-4. Flow cytometry and western blotting were used to measure PrPC expression levels. Fluorescence microscopy was used to examine Iba-1 and PrPC localization. HMC3 cells stimulated by histamine exhibited increased intracellular calcium levels and increased release of IL-6 and IL-8, while also modifying PrPC localization. HMC3 stimulated with histamine for 6 and 24 hours exhibited increased surface PrPC expression. Specifically, we found that stimulation of the HRH2 receptor was responsible for changes in surface PrPC. Histamine-induced increases in surface PrPC were attenuated following inhibition of the HRH2 receptor via the HRH2 antagonist ranitidine. These changes were unique to HRH2 activation, as stimulation of HRH1, HRH3, or HRH4 did not alter surface PrPC. Prolonged stimulation of HMC3 decreased PrPC expression following 48 and 72 hours of histamine stimulation. HMC3 cells can be stimulated by histamine to undergo intracellular calcium influx. Surface expression levels of PrPC on HMC3 cells are altered by histamine exposure, primarily mediated by HRH2. While histamine exposure also increases release of IL-6 and IL-8 in these cells, this cytokine release is not fully dependent on PrPC levels, as IL-6 release is only partially reduced and IL-8 release is unchanged under the conditions of HRH2 blockade that prevent PrPC changes. Overall, this suggests that PrPC may play a role in modulating microglial responses.

Background: The relationship between the alarming cytokine interleukin-33 (IL-33) and lung autophagy in systemic anaphylaxis mouse models is not yet fully elucidated, hence, the current study attempts to explain the regulation of lung autophagy in systemic anaphylactic mouse models. IL-33 plays a critical role in endoplasmic reticulum (ER) stress and autophagy regulation via insulin-like growth factor-binding protein-3 (IGFBP-3). Results: The results of the present study confirmed the induction of systemic anaphylaxis in mice through the elevated mast cell mediators in the peritoneal lavage. Consequently, lung stress triggered IL-33 secretion that influenced autophagy markers; IGFBP-3, activating transcription factor-6 (ATF-6), autophagy related gene 4B (ATG4B), p62, microtubule-associated protein light chain3-II (LC3-II) as well as DNA damage-regulated autophagy modulator 1 (DRAM1). Conclusion: This research is a trial to investigate lung autophagy in compound 48/80 or ovalbumin-induced systemic anaphylaxis mouse models and pay a particular attention to the role of IL-33 in lung autophagy in such models. [ABSTRACT FROM AUTHOR]

Background: Microbial infections, particularly those caused by rhinovirus (RV) and respiratory syncytial virus (RSV), are major triggers for asthma exacerbations. These viruses activate toll-like receptors (TLRs), initiating an innate immune response. To better understand microbial-induced asthma exacerbations, animal models that closely mimic human lung characteristics are essential. This study aimed to assess airway responses in guinea pigs exposed to TLR agonists, simulating microbial infections. Methods: The agonists poly(I: C) (TLR3), lipopolysaccharide (LPS; TLR4) and imiquimod (TLR7), or the combination of poly(I: C) and imiquimod (P/I) were administered intranasally once a day over four consecutive days. The latter group received daily intraperitoneal injections of dexamethasone starting one day before the TLR agonists challenge. Respiratory functions were measured by whole-body plethysmography and forced oscillatory technique. Bronchoalveolar lavage fluid (BALF) cells and lungs were collected for analysis. Results: The intranasal exposure of LPS and P/I caused an increase in enhanced pause (Penh) after challenge, whereas neither poly(I: C) nor imiquimod alone showed any effect. After the challenges of LPS, poly(I: C) or P/I, but not imiquimod alone, induced an increase of both Rrs (resistance of the respiratory system) and Ers (elastance of the respiratory system). LPS exposure caused an increase of neutrophils in BALF, whereas none of the other exposures affected the composition of cells in BALF. Exposure to LPS, poly (I: C), imiquimod, and P/I all caused a marked infiltration of inflammatory cells and an increase of mast cells around the small airways. For the expression of inflammatory mediators, LPS increased CXCL8, poly(I: C) and imiquimod decreased IL-4 and IL-5, and increased IFNγ. Imiquimod increased CXCL8 and IL-6, whereas P/I decreased IL-5, and increased IL-6 and IFNγ. The increases in Rrs, Ers, and airway inflammation, but not the altered expression of inflammatory cytokines, were attenuated by dexamethasone. Conclusions: TLR agonists promote acute airway inflammation and induce airway obstruction and hyperresponsiveness in guinea pigs. The severity of these effects varies depending on the specific agonists used. Notably, dexamethasone reversed pulmonary functional changes and mitigated bronchial inflammation caused by the combined treatment of P/I. However, it had no impact on the expression of inflammatory mediators. [ABSTRACT FROM AUTHOR]

COVID-19 is an infectious disease caused by SARS-CoV-2; over the course of the disease, a dysregulated immune response leads to excessive inflammation that damages lung parenchyma and compromises its function. One of the cell lineages classically associated with pathological inflammatory processes is mast cells (MCs). MCs and their mediators have been associated with COVID-19; we previously reported the role of carboxypeptidase A3 (CPA3) in severe COVID-19. However, sequelae of SARS-CoV-2 infection have been poorly studied. In patients who successfully resolve the infection, one of the reported sequelae is pulmonary fibrosis (PF). The etiology and exact mechanisms are unknown, and few studies exist. Therefore, the aim of this study was to evaluate whether MCs are associated with PF development after SARS-CoV-2 infection. Our findings demonstrate that during severe cases of SARS-CoV-2 infection, there is an increased amount of CPA3+ MCs in areas with pneumonia, around thrombotic blood vessels, and in fibrotic tissue. Moreover, higher numbers of CPA3-expressing MCs correlate with fibrotic tissue development (r = 0.8323; p = 0.001170). These results suggest that during COVID-19, exacerbated inflammation favors the recruitment or expansion of MCs and CPA3 expression in the lungs, which favors tissue damage and a failure of repair mechanisms, leading to fibrosis. [ABSTRACT FROM AUTHOR]