Histamine is a critical mediator of IgE/mast cell-mediated anaphylaxis, a neurotransmitter and a regulator of gastric acid secretion. Histamine is a monoamine synthesized from the amino acid ...histidine through a reaction catalyzed by the enzyme histidine decarboxylase (HDC), which removes carboxyl group from histidine. Despite the importance of histamine, transcriptional regulation of
gene expression in mammals is still poorly understood. In this review, we focus on discussing advances in the understanding of molecular regulation of mammalian histamine synthesis.
Histamine is a critical mediator of IgE/mast cell–mediated anaphylaxis. Histamine is synthesized by decarboxylating the amino acid histidine, a reaction catalyzed by the histidine decarboxylase (Hdc) ...gene–encoded enzyme HDC. However, regulation of the Hdc gene in mast cells is poorly understood.
We sought to investigate the in vivo regulation of IgE/mast cell–mediated anaphylaxis by the transcription factors GATA2 and microphthalmia-associated transcription factor (MITF) and the mechanisms by which GATA2 and MITF regulate Hdc gene expression in mouse and human mast cells.
Mice deficient in the transcription factors Gata2, aryl hydrocarbon receptor (Ahr), aryl hydrocarbon receptor repressor (Ahrr), or basic helix-loop-helix family member E40 (Bhlhe40) were assessed for anaphylactic reactions. Chromatin immunoprecipitation sequencing analysis identified putative Hdc enhancers. Luciferase reporter transcription assay confirmed enhancer activities of putative enhancers in the Hdc gene. The short hairpin RNA knockdown approach was used to determine the role of MITF in regulating mouse and human HDC gene expression.
Connective tissue mast cell–specific Gata2-deficient mice did not have IgE/mast cell-mediated anaphylaxis. GATA2 induced the expression of Mitf, Ahr, Ahrr, and Bhlhe40 in mast cells. MITF, but not AHR, AHRR, or BHLHE40, was required for anaphylaxis. MITF bound to an enhancer located 8.8 kb upstream of the transcription start site of the Hdc gene and directed enhancer activity. MITF overexpression largely restored Hdc gene expression in the Gata2-deficient mast cells. In the human mast cell line LAD2, MITF was required for the HDC gene expression and histamine synthesis.
The transcription factors GATA2 and MITF regulate Hdc gene expression in mast cells and are required for IgE/mast cell–mediated anaphylaxis.
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This paper presents millimeter‐wave (mmWave) propagation characteristics and channel model parameters including path loss, delay, and angular properties based on 28 GHz and 38 GHz field measurement ...data. We conducted measurement campaigns in both outdoor and indoor at the best potential hotspots. In particular, the model parameters are compared to sub‐6 GHz parameters, and system design issues are considered for mmWave 5G Giga communications. For path loss modeling, we derived parameters for both the close‐in free space model and the alpha–beta–gamma model. For multipath models, we extracted delay and angular dispersion characteristics including clustering results.
Macrophages as a principal component of immune system play an important role in the initiation, modulation, and final activation of immune response against pathogens including schistosomes. Classical ...(M1) or alternative (M2) activation states of macrophage have different functions during infections. Previously, we report that the schistosomal-derived anti-inflammatory molecule coding gene (named Sj16) was isolated and the recombinant Sj16 (rSj16) was expressed in
Escherichia coli
. rSj16 has been demonstrated to have definite anti-inflammatory effect in vivo and in vitro on rodent model. To study the molecular basis on anti-inflammatory of rSj16, in the present paper, we investigate the effects of rSj16 on the lipopolysaccharide (LPS)-induced activated RAW264.7, a murine macrophage cell line. We found that rSj16 inhibited LPS-induced activation of RAW264.7, as evidenced by impacting the proliferation, phagocytosis, and migration of the RAW264.7. After pretreated with rSj16, it showed the most potent inhibitory effects of rSj16 on the nitric oxide production in RAW264.7 cells. Furthermore, rSj16 also significantly decreased the levels of proinflammatory cytokines such as PGE2, IL-1β, IL-6, IL-12, IL-23, and TNF-α, whereas it increased the levels of immunosuppressive cytokine IL-10. rSj16 can also inhibit the LPS-induced activation of NF-κβ. These results further imply that Sj16 contributes to the immune evasion of
Schistosoma japonicum
through alternatively activated macrophage (M2), and rSj16 is expected to serve as a potential drug source for the medication of inflammatory disorders.
Trapping of
(
) eggs in host tissue, mainly in the intestine and liver, causes severe gastrointestinal and hepatic granulomatous immune responses and irreversible fibrosis. Although the gut ...microbiota plays a central role in regulating pathological responses in several diseases, the effect of the gut microbiota on the pathologenesis progression of schistosomiasis remains largely unknown. In this study, we aimed to investigate the regulatory function of the gut microbiota in schistosomiasis japonica. We found that the depletion of the gut microbiota significantly ameliorated egg granulomas formation and fibrosis in the intestine of infected mice. This role of the gut microbiota in intestinal granuloma formation and fibrosis was reinforced when normal and infected mice were housed together in one cage. Notably, changes in the gut microbiota induced by
infection were partly reversible with microbiota transfer in the cohousing experiment. Transfer of the gut microbiota from normal to infected mice attenuated the intestinal pathological responses. Depletion of the gut microbiota by antibiotics, or transfer of the gut microbiota from normal to infected mice decreased the levels of IL-4, IL-5, and IL-13 and promoted the production of cytokines and mRNA levels of IL-10 and TGF-β in infected mice. Our findings indicated a regulatory effect of the gut microbiota on intestinal pathological injury associated with schistosomiasis japonica in mice, and thus suggested a potential strategy for schistosomiasis treatment.
This paper presents millimeter-wave (mmWave) propagation characteristics and channel model parameters including path loss, delay, and angular properties based on 28 GHz and 38 GHz field measurement ...data. We conducted measurement campaigns in both outdoor and indoor at the best potential hotspots. In particular, the model parameters are compared to sub-6 GHz parameters, and system design issues are considered for mmWave 5G Giga communications. For path loss modeling, we derived parameters for both the close-in free space model and the alpha-beta-gamma model. For multipath models, we extracted delay and angular dispersion characteristics including clustering results.
Schistosomiasis is considered second only to malaria as the most devastating parasitic disease in tropical countries. Schistosome cercariae invade the host by penetrating the skin and migrate though ...the lungs and portal circulation to their final destination in the hepatic portal system and eventually the mesenteric veins. Previous studies have shown that the cytotoxic pathways that target schistosomulum in the lung-stage involve nitric oxide (NO) produced by macrophages. By contrast, skin-stage schistosomulas can evade clearance, indicating that they might be freed from macrophage NO-mediated cytotoxicity to achieve immune evasion; however, the critical molecules and mechanisms involved remain unknown.
Recombinant SjCa8 (rSjCa8), an 8-kDa calcium-binding protein that is stage-specifically expressed in cercaria and early skin-stage schistosomulas of Schistosoma japonicum, was incubated with mouse RAW264.7 macrophages. Effects on macrophage proliferation were determined using Cell Counting Kit-8. Next, transwell assay was carried out to further investigate the role of rSjCa8 in macrophage migration. The effects of rSjCa8 on macrophage apoptosis were evaluated using confocal microscopy and flow cytometry. Additional impacts of rSjCa8 on NO release by lipopolysaccharide (LPS)-stimulated macrophages as well as the underlying mechanisms were explored using fluorescent probe, nitric oxide signaling pathway microarray, quantitative real-time PCR, mutagenesis, and neutralizing antibody approaches.
rSjCa8 exhibited a striking inhibitory effect on macrophage migration, but did not markedly increase cell proliferation or apoptosis. Additionally, rSjCa8 potently inhibited NO release by LPS-stimulated macrophages in a dose- and time-dependent manner, and the inhibitory mechanism was closely associated with intracellular Ca(2+) levels, the up-regulation of catalase expression, and the down-regulation of the expression of 47 genes, including Myc, Gadd45a, Txnip, Fas, Sod2, Nos2, and Hmgb1. Vaccination with rSjCa8 increased NO concentration in the challenging skin area of infected mice and reduced the number of migrated schistosomula after skin penetration by cercariae.
Our findings indicate that SjCa8 might be a novel molecule that plays a critical role in immune evasion by S. japonicum cercaria during the process of skin penetration. The inhibitory impacts of rSjCa8 on macrophage migration and Ca(2+)i-dependent NO release suggest it might represent a novel vaccine candidate and chemotherapeutic target for the prevention and treatment of schistosomiasis.
China still has more than 30,000 patients of advanced schistosomiasis while new cases being reported consistently. D-dimer is a fibrin degradation product. As ascites being the dominating symptom in ...advanced schistosomiasis, the present study aimed to explore a prediction model of ascites with D-dimer and other clinical easy-achievable indicators. A case-control study nested in a prospective cohort was conducted in schistosomiasis-endemic area of southern China. A total of 291 patients of advanced schistosomiasis were first investigated in 2013 and further followed in 2014. Information on clinical history, physical examination, and abdominal ultrasonography, including the symptom of ascites was repeatedly collected. Result showed 44 patients having ascites. Most of the patients' ascites were confined in the kidney area with median area of 20 mm
. The level of plasma D-dimer and pertinent liver function indicators were measured at the initial investigation in 2013. Compared with those without ascites, cases with ascites had significantly higher levels of D-dimer (0.71±2.44 μg/L vs 0.48±2.12 μg/L,
=0.005), as well ALB (44.5 vs 46.2, g/L) and Type IV collagen (50.04 vs 44.50 μg/L). Receiver operating characteristic curve analyses indicated a moderate predictive value of D-dimer by its own area under curve (AUC) of 0.64 (95% CI: 0.54-0.73) and the cutoff value as 0.81 μg/L. Dichotomized by the cutoff level, D-dimer along with other categorical variables generated a prediction model with AUC of 0.76 (95% CI: 0.68-0.89). Risks of patients with specific characteristics in the prediction model were summarized. Our study suggests that the plasma D-dimer level is a reliable predictor for incident ascites in advanced schistosomiasis japonica patients.
Exosomes are 30–100-nm membrane vesicles of endocytic origin that are released into the extracellular space upon fusion of the multi-vesicular bodies (MVB) with the plasma membrane, while initial ...studies described that the role of exosomes was a reticulocyte cargo-disposal mechanism allowing remodeling of the plasma membrane during the maturation of reticulocytes to erythrocytes. Recent studies indicate that exosomes are secreted by most cells and pathogens and play an important role in intercellular signaling and exert regulatory function by carrying bioactive molecules. As numerous pathogens, adult worm of Schistosoma japonicum (S. japonicum) reside in mesenteric veins of definitive host including man and mammal animals. It was reported that the worms or the eggs also have specialized secretion systems to export effector proteins or other molecules into host target cells. However, the mechanisms involved remained unclear. This study investigated the isolation of the exosome-like vesicles secreted by S. japonicum adult worms and its immune activity on microphage in vitro. In this report, we identified exosome-based secretion as a new mechanism for protein secretion by S. japonicum. Electron microscopy tomography revealed the previously unidentified ultrastructural detail of exosome-like vesicles with high resolution; they were found to be typical spherical shape and to have a diverse population that varies in size of 30–100 nm. Exosome-like vesicles isolated from S. japonicum contained a significantly different protein compared with debris pelleted and the apoptosis body. We also demonstrate that macrophages were preferentially differentiated into the M1 subtype while being treated with S. japonicum exosome-like vesicles. This study reveals there are exosome-like vesicles derived by S. japonicum adult worms, and the exosome-like vesicles can mediate M1-type immune- activity of macrophage.
IL-13 plays a critical role in mediating many biological processes responsible for allergic inflammation. Mast cells express
mRNA and produce IL-13 protein in response to antigenic stimulation. ...Enhancers are essential in promoting gene transcription and are thought to activate transcription by delivering essential accessory cofactors to the promoter to potentiate gene transcription. However, enhancers mediating
have not been identified. Furthermore, which
enhancers detect signals triggered by antigenic stimulation have not yet been defined. In this study, we identified potential mouse
enhancers using histone modification monomethylation at lysine residue 4 on histone 3 (H3K4me1) chromatin immunoprecipitation sequencing and acetylation at lysine residue 27 on histone 3 (H3K27ac) chromatin immunoprecipitation sequencing. We used Omni-assay for transposase-accessible chromatin sequencing to determine which accessible regions within the potential
enhancers that responded to IgE receptor crosslinking. We also demonstrated that the transcription factor cluster consisting of the NFATC2, STAT5, GATA2, AP1, and RUNX1 binding sites at the proximal
enhancer and the transcription factor cluster consisting of the EGR2 binding site at the distal
E+6.5 enhancer are critical in sensing the signals triggered by antigenic stimulation. Those enhancers, which are responsive to antigenic stimulation and are constitutively active, cooperate to generate greater transcriptional outputs. Our study reveals a novel mechanism underlying how antigenic stimulation induces robust
mRNA expression in mouse mast cells.
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