Browsing by Subject "mast cells"

Now showing 1 - 7 of 7
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    A Case of Mast Cell Leukemia: A Review of the Pathophysiology of Systemic Mastocytosis and Associated Psychiatric Symptoms
    (Elsevier, 2018) Jamison, Nathan K.; Holmes, Emily G.; Psychiatry, School of Medicine
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    Downregulation of hepatic stem cell factor by Vivo-Morpholino treatment inhibits mast cell migration and decreases biliary damage/senescence and liver fibrosis in Mdr2−/− mice
    (Elsevier, 2019) Meadows, Vik; Kennedy, Lindsey; Hargrove, Laura; Demieville, Jennifer; Meng, Fanyin; Virani, Shohaib; Reinhart, Evan; Kyritsi, Konstantina; Invernizzi, Pietro; Yang, Zhihong; Wu, Nan; Liangpunsakul, Suthat; Alpini, Gianfranco; Francis, Heather; Medicine, School of Medicine
    Introduction Primary sclerosing cholangitis (PSC) is characterized by increased mast cell (MC) infiltration, biliary damage and hepatic fibrosis. Cholangiocytes secrete stem cell factor (SCF), which is a chemoattractant for c-kit expressed on MCs. We aimed to determine if blocking SCF inhibits MC migration, biliary damage and hepatic fibrosis. Methods FVB/NJ and Mdr2−/− mice were treated with Mismatch or SCF Vivo-Morpholinos. We measured (i) SCF expression and secretion; (ii) hepatic damage; (iii) MC migration/activation and histamine signaling; (iv) ductular reaction and biliary senescence; and (v) hepatic fibrosis. In human PSC patients, SCF expression and secretion were measured. In vitro, cholangiocytes were evaluated for SCF expression and secretion. Biliary proliferation/senescence was measured in cholangiocytes pretreated with 0.1% BSA or the SCF inhibitor, ISK03. Cultured HSCs were stimulated with cholangiocyte supernatant and activation measured. MC migration was determined with cholangiocytes pretreated with BSA or ISK03 loaded into the bottom of Boyden chambers and MCs into top chamber. Results Biliary SCF expression and SCF serum levels increase in human PSC. Cholangiocytes, but not hepatocytes, from SCF Mismatch Mdr2−/− mice have increased SCF expression and secretion. Inhibition of SCF in Mdr2−/− mice reduced (i) hepatic damage; (ii) MC migration; (iii) histamine and SCF serum levels; and (iv) ductular reaction/biliary senescence/hepatic fibrosis. In vitro, cholangiocytes express and secrete SCF. Blocking biliary SCF decreased MC migration, biliary proliferation/senescence, and HSC activation. Conclusion Cholangiocytes secrete increased levels of SCF inducing MC migration, contributing to biliary damage/hepatic fibrosis. Targeting MC infiltration may be an option to ameliorate PSC progression.
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    The interplay between mast cells, pineal gland, and circadian rhythm: Links between histamine, melatonin, and inflammatory mediators
    (Wiley, 2021-03) Pham, Linh; Baiocchi, Leonardo; Kennedy, Lindsey; Sato, Keisaku; Meadows, Vik; Meng, Fanyin; Huang, Chiung-Kuei; Kundu, Debjyoti; Zhou, Tianhao; Chen, Lixian; Alpini, Gianfranco; Francis, Heather; Medicine, School of Medicine
    Our daily rhythmicity is controlled by a circadian clock with a specific set of genes located in the suprachiasmatic nucleus in the hypothalamus. Mast cells (MCs) are major effector cells that play a protective role against pathogens and inflammation. MC distribution and activation are associated with the circadian rhythm via two major pathways, IgE/FcεRI- and IL-33/ST2-mediated signaling. Furthermore, there is a robust oscillation between clock genes and MC-specific genes. Melatonin is a hormone derived from the amino acid tryptophan and is produced primarily in the pineal gland near the center of the brain, and histamine is a biologically active amine synthesized from the decarboxylation of the amino acid histidine by the L-histidine decarboxylase enzyme. Melatonin and histamine are previously reported to modulate circadian rhythms by pathways incorporating various modulators in which the nuclear factor–binding near the κ light-chain gene in B cells, NF-κB, is the common key factor. NF-κB interacts with the core clock genes and disrupts the production of pro-inflammatory cytokine mediators such as IL-6, IL-13, and TNF-α. Currently, there has been no study evaluating the interdependence between melatonin and histamine with respect to circadian oscillations in MCs. Accumulating evidence suggests that restoring circadian rhythms in MCs by targeting melatonin and histamine via NF-κB may be promising therapeutic strategy for MC-mediated inflammatory diseases. This review summarizes recent findings for circadian-mediated MC functional roles and activation paradigms, as well as the therapeutic potentials of targeting circadian-mediated melatonin and histamine signaling in MC-dependent inflammatory diseases.
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    Mast Cells Regulate Bile Acid Signaling and Cholestasis via Alteration of Farnesoid X Receptor/Fibroblast Growth Factor 15 Axis in Mice
    (2022-03) Meadows, Victoria E.; Francis, Heather; Alpini, Gianfranco; Dong, X Charlie; Esker, Burcin; Ren, Hongxia
    Primary Sclerosing Cholangitis (PSC) is a rare and slow progressing cholangiopathy characterized by hepatic inflammation, fibrosis and ductular reaction with liver transplantation as the sole therapeutic option. PSC patients are at high risk of auto-immune comorbidities like irritable bowel disease (IBD), found in up to 80% of PSC patients (PSC-IBD). There are indications of genetic and environmental components for auto-immune development in IBD; however, its etiology remains unclear. Mast cells (MCs) infiltrate the liver and can become activated leading to degranulation and release of mediators, like histamine (HA), which result in increased intrahepatic bile duct mass, biliary senescence, hepatic inflammation, and hepatic stellate cell activation. Similarly, MCs infiltrate the intestine and increase inflammation which alters host-microbiome communication. MCs are necessary for successful liver regeneration and the combat of intestinal pathogens; however, chronic HA signaling exacerbates damage in cholangiopathies and IBD. Bile acid synthesis is tightly regulated by Farnesoid X Receptor (FXR) and its downstream mediator, fibroblast growth factor 15 (FGF15, -19 in humans). Cholangiocytes (i) are the target of cholangiopathies, (ii) modify and recycle bile acids through Apical Sodium Bile Acid Transporter (ASBT)-mediated cholehepatic shunting, which functions outside of enterohepatic circulation of bile acids and (iii) are capable of autocrine HA signaling. The complex relationship between hepatic and intestinal MC infiltration and bile acid signaling has not been established; therefore, identifying MC regulation of bile acid pool and FXR/FGF15 signaling pathway will provide insight into therapeutic treatment of PSC-IBD. Under the rationale that (i) cholestatic liver diseases are positively correlated with auto-immune comorbidities like IBD, (ii) during disease, MCs infiltrate the liver and intestine and release signaling factors like HA, and (iii) MCs express FXR and secrete FGF15/19; we propose the central hypothesis that MC activation regulates bile acid signaling and PSC progression through paracrine crosstalk with cholangiocytes in the liver and intestinal inflammation.
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    Neurofibromin-deficient Schwann cells secrete a potent migratory stimulus for Nf1+/– mast cells
    (2003-12) Yang, Feng-Chun; Ingram, David A; Chen, Shi; Hingtgen, Cynthia M; Ratner, Nancy; Monk, Kelly R; Clegg, Travis; White, Hilary; Mead, Laura; Wenning, Mary Jo; Williams, David A; Kapur, Reuben; Atkinson, Simon J; Clapp, D Wade
    The NF1 tumor suppressor gene encodes a GTPase-activating protein called neurofibromin that negatively regulates Ras signaling. Mutations in NF1 cause neurofibromatosis type 1 (NF1). The development of neurofibromas, which are complex tumors composed of multiple cell types, is a hallmark of NF1. Somatic inactivation of murine Nf1 in Schwann cells is necessary, but not sufficient, to initiate neurofibroma formation. Neurofibromas occur with high penetrance in mice in which Nf1 is ablated in Schwann cells in the context of a heterozygous mutant (Nf1+/–) microenvironment. Mast cells infiltrate neurofibromas, where they secrete proteins that can remodel the ECM and initiate angiogenesis. Thus, identification of mechanisms responsible for mast cell migration to tumor microenvironments is important for understanding tumorigenesis and for designing potential therapies. Here, we show that homozygous Nf1 mutant (Nf1–/–) Schwann cells secrete Kit ligand (KitL), which stimulates mast cell migration, and that Nf1+/– mast cells are hypermotile in response to KitL. Furthermore, we link hyperactivation of the Ras-class IA-PI3K-Rac2 pathway to increased Nf1+/– mast cell migration. Thus, these studies identify a novel interaction between Nf1–/– Schwann cells and Nf1+/– mast cells that is likely to be important in neurofibroma formation.
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    p21-activated kinase regulates mast cell degranulation via effects on calcium mobilization and cytoskeletal dynamics
    (2009-03) Allen, Jayme D; Jaffer, Zahara M; Park, Su-Jung; Burgin, Sarah; Hofmann, Clemens; Sells, Mary A; Chen, Shi; Derr-Yellin, Ethel; Michels, Elizabeth G; McDaniel, Andrew; Bessler, Waylan K; Ingram, David A; Atkinson, Simon J; Travers, Jeffrey B; Chemoff, Jonathan; Clapp, D Wade
    Mast cells are key participants in allergic diseases via activation of high-affinity IgE receptors (FcϵRI) resulting in release of proinflammatory mediators. The biochemical pathways linking IgE activation to calcium influx and cytoskeletal changes required for intracellular granule release are incompletely understood. We demonstrate, genetically, that Pak1 is required for this process. In a passive cutaneous anaphylaxis experiment, Wsh/Wsh mast cell–deficient mice locally reconstituted with Pak1−/− bone marrow–derived mast cells (BMMCs) experienced strikingly decreased allergen-induced vascular permeability compared with controls. Consistent with the in vivo phenotype, Pak1−/− BMMCs exhibited a reduction in FcϵRI-induced degranulation. Further, Pak1−/− BMMCs demonstrated diminished calcium mobilization and altered depolymerization of cortical filamentous actin (F-actin) in response to FcϵRI stimulation. These data implicate Pak1 as an essential molecular target for modulating acute mast cell responses that contribute to allergic diseases.
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    ROCK1 via LIM kinase regulates growth, maturation and actin based functions in mast cells
    (Impact Journals, LLC, 2016-03-29) Kapur, Reuben; Shi, Jianjian; Ghosh, Joydeep; Munugalavadla, Veerendra; Sims, Emily; Martin, Holly; Wei, Lei; Mali, Raghuveer Singh; Department of Pediatrics, IU School of Medicine
    Understanding mast cell development is essential due to their critical role in regulating immunity and autoimmune diseases. Here, we show how Rho kinases (ROCK) regulate mast cell development and can function as therapeutic targets for treating allergic diseases. Rock1 deficiency results in delayed maturation of bone marrow derived mast cells (BMMCs) in response to IL-3 stimulation and reduced growth in response to stem cell factor (SCF) stimulation. Further, integrin-mediated adhesion and migration, and IgE-mediated degranulation are all impaired in Rock1-deficient BMMCs. To understand the mechanism behind altered mast cell development in Rock1-/- BMMCs, we analyzed the activation of ROCK and its downstream targets including LIM kinase (LIMK). We observed reduced activation of ROCK, LIMK, AKT and ERK1/2 in Rock1-deficient BMMCs in response to SCF stimulation. Further, loss of either Limk1 or Limk2 also demonstrated altered BMMC maturation and growth; combined deletion of both Limk1 and Limk2 resulted in further reduction in BMMC maturation and growth. In passive cutaneous anaphylaxis model, deficiency of Rock1 or treatment with ROCK inhibitor Fasudil protected mice against IgE-mediated challenge. Our results identify ROCK/LIMK pathway as a novel therapeutic target for treating allergic diseases involving mast cells.