ATP/IL-33-Co-Sensing by Mast Cells (MCs) Requires Activated c-Kit to Ensure Effective Cytokine Responses
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PROVIDER: S-EPMC10705958 | biostudies-literature | 2023 Nov
REPOSITORIES: biostudies-literature
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Project description:The alarmin interleukin-33 (IL-33) is released upon cell stress and damage in peripheral tissues. The receptor for IL-33 is the Toll/Interleukin-1 receptor (TIR)-family member T1/ST2 (the IL-33R), which is highly and constitutively expressed on MCs. The sensing of IL-33 by MCs induces the MyD88-TAK1-IKK2-dependent activation of p65/RelA and MAP-kinases, which mediate the production of pro-inflammatory cytokines and amplify FcεRI-mediated MC-effector functions and the resulting allergic reactions. Therefore, the investigation of IL-33-induced signaling is of interest for developing therapeutic interventions effective against allergic reactions. Importantly, beside the release of IL-33, heat shock proteins (HSPs) are upregulated during allergic reactions. This maintains the biological functions of signaling molecules and/or cytokines but unfortunately also strengthens the severity of inflammatory reactions. Here, we demonstrate that HSP90 does not support the IL-33-induced and MyD88-TAK1-IKK2-dependent activation of p65/RelA and of mitogen-activated protein (MAP)-kinases. We found that HSP90 acts downstream of these signaling pathways, mediates the stability of produced cytokine mRNAs, and therefore facilitates the resulting cytokine production. These data show that IL-33 enables MCs to perform an effective cytokine production by the upregulation of HSP90. Consequently, HSP90 might be an attractive therapeutic target for blocking IL-33-mediated inflammatory reactions.
| S-EPMC9502846 | biostudies-literature
Project description:BackgroundIL-13 is a critical effector cytokine for allergic inflammation. It is produced by several cell types, including mast cells, basophils, and TH2 cells. In mast cells and basophils its induction can be stimulated by cross-linkage of immunoglobulin receptors or cytokines. The IL-1 family members IL-33 and IL-18 have been linked to induction of IL-13 production by mast cells and basophils. In CD4 TH2 cells IL-33-mediated production of IL-13 requires simultaneous signal transducer and activator of transcription (STAT) 5 activation.ObjectiveHere we have addressed whether cytokine-induced IL-13 production in mast cells and basophils follows the same logic as in TH2 cells: requirement of 2 separate signals.MethodsBy generating a bacterial artificial chromosome (BAC) transgenic IL-13 reporter mouse, we measured IL-13 production in mast cells and basophils.ResultsIn mast cells harvested from peritoneal cavities, 2 cytokine signals are required for IL-13 production: IL-33 and IL-3. In bone marrow mast cells IL-13 production requires IL-33, but the requirement for a STAT5 inducer is difficult to evaluate because these cells require the continuous presence of IL-3 (a STAT5 activator) for survival. Poorer STAT5 inducers in culture (IL-4 or stem cell factor) result in less IL-13 production on IL-33 challenge, but the addition of exogenous IL-3 enhances IL-13 production. This implies that bone marrow-derived mast cells, like peritoneal mast cells and TH2 cells, require stimulation both by an IL-1 family member and a STAT5 inducer to secrete IL-13. Basophils follow the same rule; splenic basophils produce IL-13 in response to IL-18 or IL-33 plus IL-3.ConclusionOptimal IL-13 production from mast cells and basophils requires 2 cytokine signals.
| S-EPMC3782850 | biostudies-literature
Project description:This SuperSeries is composed of the SubSeries listed below.
2021-11-06 | GSE148273 | GEO
Project description:While IgE is considered the primary mediator of mast cell activation, IL-33 contributes substantially in asthma, allergic rhinitis, and atopic dermatitis. To develop effective treatments for allergic disease, it is important to understand the role of therapeutic agents on IL-33 activation. We examined the effect of Didox (3,4-dihydroxybenzohydroxamic acid), an antioxidant and ribonucleotide reductase (RNR) inhibitor, on IL-33-mediated mast cell activation. Didox suppressed IL-6, IL-13, TNF, and MIP-1α (CCL3) production in bone marrow derived mast cells following IL-33 activation. This suppression was observed in different genetic backgrounds and extended to peritoneal mast cells. The antioxidant N-acetylcysteine mimicked the suppression of Didox, albeit at a much higher dose, while the RNR inhibitor hydroxyurea had no effect. Didox substantially suppressed IL-33-mediated NFκB and AP-1 transcriptional activities. These results suggest that Didox attenuates IL-33-induced mast cell activation and should be further studied as a potential therapeutic agent for inflammatory diseases involving IL-33.
| S-EPMC5593780 | biostudies-literature
Project description:Hematopoiesis is maintained by a highly regulated and hierarchical system, whereas aberrant control of hematopoiesis is the underlying cause of severe hematological diseases. Here, we demonstrate the indispensable role of ARID4B in fetal hematopoiesis that recruits Ezh2 to transcriptionally downregulate the expression of KIT during erythroid cell differentiation. Functional analyses reveal that the aberration of Arid4b inhibits fetal hematopoiesis at the multipotent progenitors (MPPs) stage, which reactivates the KIT-Src-family kinase (Src) pathway and leads to pre-mature erythroblast proliferation. The differentiation defect caused by ARID4B aberration could be counteracted by the Src inhibitor PP2 or by KIT knockdown. In summary, we identify ARID4B as a master regulator in the KIT-Src pathway, thus providing a fundamental insight in hematopoiesis and stem cell regulation.
2021-11-09 | GSE148269 | GEO
Project description:Hematopoiesis is maintained by a highly regulated and hierarchical system, whereas aberrant control of hematopoiesis is the underlying cause of severe hematological diseases. Here, we demonstrate the indispensable role of ARID4B in fetal hematopoiesis that recruits Ezh2 to transcriptionally downregulate the expression of KIT during erythroid cell differentiation. Functional analyses reveal that the aberration of Arid4b inhibits fetal hematopoiesis at the multipotent progenitors (MPPs) stage, which reactivates the KIT-Src-family kinase (Src) pathway and leads to pre-mature erythroblast proliferation. The differentiation defect caused by ARID4B aberration could be counteracted by the Src inhibitor PP2 or by KIT knockdown. In summary, we identify ARID4B as a master regulator in the KIT-Src pathway, thus providing a fundamental insight in hematopoiesis and stem cell regulation.
2021-11-09 | GSE148272 | GEO
Project description:Resistant KIT mutations have hindered the development of KIT kinase inhibitors for treatment of patients with systemic mastocytosis. The goal of this research was to characterize the synergistic effects of a novel combination therapy involving inhibition of KIT and calcineurin phosphatase, a nuclear factor of activated T cells (NFAT) regulator, using a panel of KIT-mutant mast cell lines. The effects of monotherapy or combination therapy on the cellular viability/survival of KIT-mutant mast cells were evaluated. In addition, NFAT-dependent transcriptional activity was monitored in a representative cell line to evaluate the mechanisms responsible for the efficacy of combination therapy. Finally, shRNA was used to stably knockdown calcineurin expression to confirm the role of calcineurin in the observed synergy. The combination of a KIT inhibitor and a calcineurin phosphatase inhibitor (CNPI) synergized to reduce cell viability and induce apoptosis in six distinct KIT-mutant mast cell lines. Both KIT inhibitors and CNPIs were found to decrease NFAT-dependent transcriptional activity. NFAT-specific inhibitors induced similar synergistic apoptosis induction as CNPIs when combined with a KIT inhibitor. Notably, NFAT was constitutively active in each KIT-mutant cell line tested. Knockdown of calcineurin subunit PPP3R1 sensitized cells to KIT inhibition and increased NFAT phosphorylation and cytoplasmic localization. Constitutive activation of NFAT appears to represent a novel and targetable characteristic of KIT-mutant mast cell disease. Our studies suggest that combining KIT inhibition with NFAT inhibition might represent a new treatment strategy for mast cell disease.
| S-EPMC5026483 | biostudies-literature
Project description:Kit/CD117 plays a crucial role in the cell-cell and cell-matrix adhesion of mammalian mast cells (MCs); however, it is unclear whether other adhesion molecule(s) perform important roles in the adhesion of MCs. In the present study, we show a novel Kit-independent adhesion mechanism of mouse cultured MCs mediated by Notch family members. On stromal cells transduced with each Notch ligand gene, Kit and its signaling become dispensable for the entire adhesion process of MCs from tethering to spreading. The Notch-mediated spreading of adherent MCs involves the activation of signaling via phosphatidylinositol 3-kinases and mitogen-activated protein kinases, similar to Kit-mediated spreading. Despite the activation of the same signaling pathways, while Kit supports the adhesion and survival of MCs, Notch only supports adhesion. Thus, Notch family members are specialized adhesion molecules for MCs that effectively replace the adhesion function of Kit in order to support the interaction of MCs with the surrounding cellular microenvironments.
| S-EPMC8562337 | biostudies-literature
Project description:To investigate global changes in gene expression patterns following treatment with DSCG or MCS-01 we performed RNA-sequencing and nanostring profiling analyses on Day 10 wounds. Differential expression analysis on pre-MCS-01 samples compared to blank identified 649 significantly altered genes at p value <0.05 and absolute fold change >=2. Similarly, in post-MCS-01 samples 954 genes were differentially expressed, of which 566 were down- and 388 up-regulated. DCSG treatment resulted in differential expression of 91 genes. RT-qPCR corroborated increased expression of NFκB and STAT3 with post-MCS-01 treatment. In addition, we compared miRNA expression between MCS-01 samples and controls. Pre-treatment significantly altered expression of 11 miRNAs, while post-treatment altered expression of 28 miRNAs. RT-qPCR confirmed miR-34c upregulation, while significant inverse correlations were found between miR-34c and selected target genes Lef-1, Myb, and Mycn.
2019-10-25 | GSE135915 | GEO
Project description:BackgroundMast cell-deficient Kit(W)/Kit(W-v) mice are an important resource for studying mast cell functions in vivo. However, because they are compound heterozygotes in a mixed genetic background and are infertile, they cannot be crossed easily with other mice.ObjectiveTo overcome this limitation, we explored the use of Kit(W-sh)/Kit(W-sh) mice for studying mast cell biology in vivo.ResultsThese mice are in a C57BL/6 background, are fertile and can be bred directly with other genetically modified mice. Ten-week-old Kit(W-sh)/Kit(W-sh) are profoundly mast cell-deficient. No mast cells are detected in any major organ, including the lung. Gene microarrays detect differential expression of just seven of 16,463 genes in lungs of Kit(W-sh)/Kit(W-sh) mice compared with wild-type mice, indicating that resting mast cells regulate expression of a small set of genes in the normal lung. Injecting 10(7) bone marrow-derived mast cells (BMMC) into tail veins of Kit(W-sh)/Kit(W-sh) mice reconstitutes mast cell populations in lung, stomach, liver, inguinal lymph nodes, and spleen, but not in the tongue, trachea or skin. Injection of BMMC into ear dermis or peritoneum reconstitutes mast cells locally in these tissues. When splenectomized Kit(W-sh)/Kit(W-sh) mice are intravenously injected with BMMC, mast cells circulate longer and are found more often in the liver and inguinal lymph nodes, indicating that the spleen acts as a reservoir for mast cells following injection and limits migration to some tissues.ConclusionIn summary, these findings show that mast cell-deficient Kit(W-sh)/Kit(W-sh) mice possess unique attributes that favour their use for studying mast cell functions in vivo.
| S-EPMC2271075 | biostudies-literature