scholarly journals Signal Transduction Pathways Activated by Innate Immunity in Mast Cells: Translating Sensing of Changes into Specific Responses

Cells ◽  
2020 ◽  
Vol 9 (11) ◽  
pp. 2411 ◽  
Author(s):  
Zyanya P. Espinosa-Riquer ◽  
Deisy Segura-Villalobos ◽  
Itzel G. Ramírez-Moreno ◽  
Marian Jesabel Pérez Rodríguez ◽  
Mónica Lamas ◽  
...  

Mast cells (MCs) constitute an essential cell lineage that participates in innate and adaptive immune responses and whose phenotype and function are influenced by tissue-specific conditions. Their mechanisms of activation in type I hypersensitivity reactions have been the subject of multiple studies, but the signaling pathways behind their activation by innate immunity stimuli are not so well described. Here, we review the recent evidence regarding the main molecular elements and signaling pathways connecting the innate immune receptors and hypoxic microenvironment to cytokine synthesis and the secretion of soluble or exosome-contained mediators in this cell type. When known, the positive and negative control mechanisms of those pathways are presented, together with their possible implications for the understanding of mast cell-driven chronic inflammation. Finally, we discuss the relevance of the knowledge about signaling in this cell type in the recognition of MCs as central elements on innate immunity, whose remarkable plasticity converts them in sensors of micro-environmental discontinuities and controllers of tissue homeostasis.


2009 ◽  
Vol 77 (9) ◽  
pp. 1506-1512 ◽  
Author(s):  
Jie Wan Kim ◽  
Jun Ho Lee ◽  
Bang Yeon Hwang ◽  
Se Hwan Mun ◽  
Na Young Ko ◽  
...  


2016 ◽  
Vol 8 (2) ◽  
pp. 143-155 ◽  
Author(s):  
Sanjeev Choudhary ◽  
Istvan Boldogh ◽  
Allan R. Brasier

The airway mucosa is responsible for mounting a robust innate immune response (IIR) upon encountering pathogen-associated molecular patterns. The IIR produces protective gene networks that stimulate neighboring epithelia and components of the immune system to trigger adaptive immunity. Little is currently known about how cellular reactive oxygen species (ROS) signaling is produced and cooperates in the IIR. We discuss recent discoveries about 2 nuclear ROS signaling pathways controlling innate immunity. Nuclear ROS oxidize guanine bases to produce mutagenic 8-oxoguanine, a lesion excised by 8-oxoguanine DNA glycosylase1/AP-lyase (OGG1). OGG1 forms a complex with the excised base, inducing its nuclear export. The cytoplasmic OGG1:8-oxoG complex functions as a guanine nucleotide exchange factor, triggering small GTPase signaling and activating phosphorylation of the nuclear factor (NF)κB/RelA transcription factor to induce immediate early gene expression. In parallel, nuclear ROS are detected by ataxia telangiectasia mutated (ATM), a PI3 kinase activated by ROS, triggering its nuclear export. ATM forms a scaffold with ribosomal S6 kinases, inducing RelA phosphorylation and resulting in transcription-coupled synthesis of type I and type III interferons and CC and CXC chemokines. We propose that ATM and OGG1 are endogenous nuclear ROS sensors that transmit nuclear signals that coordinate with outside-in pattern recognition receptor signaling, regulating the IIR.



2021 ◽  
Author(s):  
Rouven Schulz ◽  
Medina Korkut-Demirbaş ◽  
Gloria Colombo ◽  
Sandra Siegert

G protein-coupled receptors (GPCRs) regulate multiple processes ranging from cell growth and immune responses to neuronal signal transmission. However, ligands for many GPCRs remain unknown, suffer from off-target effects or have poor bioavailability. Additional challenges exist to dissect cell type-specific responses when the same GPCR is expressed on different cells within the body. Here, we overcome these limitations by engineering DREADD-based GPCR chimeras that selectively bind their agonist clozapine-N-oxide (CNO) and mimic a GPCR-of-interest. We show that the chimeric DREADD-β2-adrenergic receptor (β2AR/ADRB2) triggers comparable responses to levalbuterol on second messenger and kinase activity, post-translational modifications, and protein-protein interactions. Moreover, we successfully recapitulate β2AR-mediated filopodia formation in microglia, a β2AR-expressing immune cell that can drive inflammation in the nervous system. To further dissect microglial inflammation, we compared DREADD-β2AR with two additionally designed DREADD-based chimeras mimicking GPR65 and GPR109A/HCAR2, both enriched in microglia. DREADD-β2AR and DREADD-GPR65 modulate the inflammatory response with a similar profile as endogenously expressed β2AR, while DREADD-GPR109A had no impact. Our DREADD-based approach allows investigation of cell type-dependent signaling pathways and function without known endogenous ligands.



2001 ◽  
Vol 194 (1) ◽  
pp. 57-70 ◽  
Author(s):  
David A. Ingram ◽  
Kelly Hiatt ◽  
Alastair J. King ◽  
Lucy Fisher ◽  
Rama Shivakumar ◽  
...  

Mutations in the NF1 tumor suppressor gene cause neurofibromatosis type I (NF1), a disease characterized by the formation of cutaneous neurofibromas infiltrated with a high density of degranulating mast cells. A hallmark of cell lines generated from NF1 patients or Nf1-deficient mice is their propensity to hyperproliferate. Neurofibromin, the protein encoded by NF1, negatively regulates p21ras activity by accelerating the conversion of Ras-GTP to Ras-GDP. However, identification of alterations in specific p21ras effector pathways that control proliferation in NF1-deficient cells is incomplete and critical for understanding disease pathogenesis. Recent studies have suggested that the proliferative effects of p21ras may depend on signaling outputs from the small Rho GTPases, Rac and Rho, but the physiologic importance of these interactions in an animal disease model has not been established. Using a genetic intercross between Nf1+/− and Rac2−/− mice, we now provide genetic evidence to support a biochemical model where hyperactivation of the extracellular signal–regulated kinase (ERK) via the hematopoietic-specific Rho GTPase, Rac2, directly contributes to the hyperproliferation of Nf1-deficient mast cells in vitro and in vivo. Further, we demonstrate that Rac2 functions as mediator of cross-talk between phosphoinositide 3-kinase (PI-3K) and the classical p21ras-Raf-Mek-ERK pathway to confer a distinct proliferative advantage to Nf1+/− mast cells. Thus, these studies identify Rac2 as a novel mediator of cross-talk between PI-3K and the p21ras-ERK pathway which functions to alter the cellular phenotype of a cell lineage involved in the pathologic complications of a common genetic disease.



2019 ◽  
Vol 31 (4) ◽  
pp. 969-974
Author(s):  
Mire Spasov ◽  
Icko Gjorgoski

The allergic reaction or type I hypersensitivity is a hypersensitive disorder to the immune system, which occurs by ingress of non-pathogenic agents from the external environment in the body. Antigens, in this case allergens, are substances from the environment that are harmless to most people. In allergies there is an inherent tendency to inherit the genes that make these people susceptible to allergies. Rapid sensitization may occur as a local reaction, which is just unpleasant (seasonal rhinitis or hay fever), severe exhaustion (asthma), or culminating in a fatal systemic disorder (anaphylaxis). Allergens in the body are inserted by inhalation, ingestion or injection, and move to mucous membranes, where they are accepted by T-lymphocytes. TN2 lymphocytes produce IL-4, which stimulate B-lymphocytes to differentiate into plasma cells. These cells excrete IgE, which recognize allergens. Excreted IgE antibodies sensitize mast cells that originate from the bone marrow. When sensitized individuals again expose themselves to an allergen from the external environment, they bind to specific IgE-antibodies to the mast cells (memory cells), whereby various mediators are excreted, causing inflammatory response, mucus secretion, vasoconstriction of blood vessels, and spasm of the airways. The aim of the study was to investigate the allergenic effect of Daucus carotte on the change in the number of leukocytes, lymphocytes, monocytes, granulocytes, basophils, and immunoglobulins as important components of the immune system. From the pollen of this plant, recombinant allergen is extracted, in the form of injections with a volume of 150μI. In the experiments, as experimental models were used Wistar white rats at the age of 6 to 9 weeks. We injected the allergen into the first, second, third and fourth week in a group of 6 rats in an amount of 5 μl and a second group of 6 rats in an amount of 2.5 μl allergen absorbed in 100 μl AI (OH) 3 (Serva, Heidelburg, Germany, 2 μg / mI) in a total volume of 150μI sterile PbS. The third group of 6 rats was a control group. The results showed that the Dacus carota causes an allergic reaction in Wistar white rats and its intensity depends directly on the volume of the allergen and the individuals that come into contact with it. Once we compared the values of blood parameters, leukocytes, lymphocytes, monocytes, granulocytes, and basophils, as well as the IgG, IgG1, IgG2a, and IgE IgG, IgG1, IgG2a, and IgE concentrations, we concluded that the higher concentration of Daucus carota causes a higher elevation in blood parameters and concentrations of immunoglobulins, compared to the smaller concentration of the same allergen. From the studies conducted over a period of one month, it was found that Dacus carota causes an allergic reaction, which is classified in Type I hypersensitivity in white laboratory rats of the Wistar strain.



Reproduction ◽  
2005 ◽  
Vol 130 (4) ◽  
pp. 509-516 ◽  
Author(s):  
Angela Jeanes ◽  
Dagmar Wilhelm ◽  
Megan J Wilson ◽  
Josephine Bowles ◽  
Peter J McClive ◽  
...  

Despite the importance of peritubular myoid (PM) cells in the histogenesis of the fetal testis, understanding the origin and function of these cells has been hampered by the lack of suitable markers. The current study was aimed at identifying molecular markers for PM cells during the early stages of testis development in the mouse embryo. Expression of candidate marker genes was tested by section in situ hybridisation, in some instances followed by immunofluorescent detection of protein products. Collagen type-I, inhibinβA, caldesmon 1 and tropomyosin 1 were found to be expressed by early-stage PM cells. These markers were also expressed in subsets of interstitial cells, most likely reflecting their common embryological provenance from migrating mesonephric cells. Although not strictly specific for PM cells, these markers are likely to be useful in studying the biology of early PM cells in the fetal testis.



1997 ◽  
Vol 25 (01) ◽  
pp. 51-56 ◽  
Author(s):  
Young Mi Lee ◽  
Chang Young Kim ◽  
Youn Chul Kim ◽  
Hyung Min Kim

A study was carried out to examine the effect of an aqueous extract from immature fruit of Poncirus trifoliata L. (Rutaceae) (PTIFE) on the type I hypersensitivity reaction. Forty-eight hour PCA (passive cutaneous anaphylaxis) in rats was significantly inhibited by the oral administration of PTIFE (200 mg/kg). It also inhibited histamine release from rat peritoneal mast cells (RPMC) induced by mouse anti-dinitrophenyl (DNP)-lgE and dinitrophenyl-human serum albumin (DNP-HSA). These results suggest that PTIFE has anti-allergic action against the type I hypersensitivity reaction.



Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 3870-3870
Author(s):  
Eirini Trompouki ◽  
Teresa V. Bowman ◽  
Lee N Lawton ◽  
Zi Peng Fan ◽  
Anthony DiBiase ◽  
...  

Abstract Abstract 3870 The BMP and WNT signaling pathways are two highly conserved signaling pathways that cooperate in many developmental processes, ultimately through alteration of transcription via SMAD and TCF transcription factors. These pathways elicit pleiotropic outcomes across cell types, yet only a few cell-specific direct target genes are known for the signaling transcription factors that mitigate these effects. We took a genome-wide approach to define the binding sites of BMP and WNT-directed transcription factors in different hematopoietic lineages. Using heat-shock inducible transgenic fish lines that overexpress BMP2 or WNT8, we demonstrated accelerated marrow recovery following irradiation. Irradiation recovery was blunted by heat shock induced overexpression of the respective inhibitors Chordin and DKK1. Similar to the zebrafish regeneration results, competitive transplants with mouse bone marrow treated with the WNT agonist BIO led to enhanced chimerism. Inhibition of BMP diminished peripheral blood contribution even in the presence of WNT stimulation, suggesting a conserved and cell intrinsic interaction for these signaling pathways in adult stress hematopoiesis. To examine potential target genes that could account for the synergy, we performed chromatin immunoprecipitation with WNT- and BMP-activated transcription factors followed by sequencing (ChIP-seq) in K562 cells. ChIP-seq was performed with TCF7L2/TCF4, a mediator of the WNT pathway, and SMAD1, a mediator of the BMP signaling pathway, and >2000 binding sites were identified for each factor. Motif discovery revealed that the DNA sequences bound by TCF7L2 and SMAD1 were not only enriched for TCF and SMAD binding elements, respectively, but were also enriched for a GATA motif. Comparison of the TCF7L2 and SMAD1 bound genes with published ChIP-Seq data for GATA1 and GATA2 in K562 cells revealed that both signaling factors bind more than 40% of GATA1 bound genes and greater than 70% of GATA2 bound genes. Ingenuity and GSEA analysis revealed that genes important for erythropoiesis were among the genes co-bound by these factors. To evaluate the effect of cell lineage on signaling factor binding, ChIP-seq of TCF7L2 and SMAD1 in U937, a monocytic leukemia cell line, was performed. Motif discovery of sequences bound in U937 found enrichment for an ETS motif, which is bound by the key myeloid transcription factor Pu.1. In addition, TCF7L2 and SMAD1 bound genes in U937 overlapped genes bound by C/EBPalpha in U937 by greater than 70%. These genes are implicated in monocytic development. The overlap of binding between TCF7L2 in K562 and U937 was less than 15% and the overlap of SMAD1 binding sites between the cell lines was less than 10%, indicating a substantial influence of cell lineage on transcription factor binding. Confirmation of cell type selective binding of TCF7L2 and SMAD1 in vivo was accomplished by ChIP of the transcription factors in zebrafish nucleated erythrocytes. Binding of TCF7L2 and SMAD1 in these cells showed that these factors co-bind with GATA1 in many genes with established roles in erythropoiesis. Together our data suggest the co-binding of WNT- and BMP-specific transcription factors with master regulators of each hematopoietic cell type results in regulation of distinct blood genes based on lineage. (First two authors contributed equally to this work) Disclosures: Zon: FATE, Inc.: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties; Stemgent: Consultancy, Equity Ownership, Membership on an entity's Board of Directors or advisory committees.



Pathogens ◽  
2020 ◽  
Vol 9 (4) ◽  
pp. 292 ◽  
Author(s):  
Irene Lo Cigno ◽  
Federica Calati ◽  
Silvia Albertini ◽  
Marisa Gariglio

The growth of human papillomavirus (HPV)-transformed cells depends on the ability of the viral oncoproteins E6 and E7, especially those from high-risk HPV16/18, to manipulate the signaling pathways involved in cell proliferation, cell death, and innate immunity. Emerging evidence indicates that E6/E7 inhibition reactivates the host innate immune response, reversing what until then was an unresponsive cellular state suitable for viral persistence and tumorigenesis. Given that the disruption of distinct mechanisms of immune evasion is an attractive strategy for cancer therapy, the race is on to gain a better understanding of E6/E7-induced immune escape and cancer progression. Here, we review recent literature on the interplay between E6/E7 and the innate immune signaling pathways cGAS/STING/TBK1, RIG-I/MAVS/TBK1, and Toll-like receptors (TLRs). The overall emerging picture is that E6 and E7 have evolved broad-spectrum mechanisms allowing for the simultaneous depletion of multiple rather than single innate immunity effectors. The cGAS/STING/TBK1 pathway appears to be the most heavily impacted, whereas the RIG-I/MAVS/TBK1, still partially functional in HPV-transformed cells, can be activated by the powerful RIG-I agonist M8, triggering the massive production of type I and III interferons (IFNs), which potentiates chemotherapy-mediated cell killing. Overall, the identification of novel therapeutic targets to restore the innate immune response in HPV-transformed cells could transform the way HPV-associated cancers are treated.



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