Chronic inflammation is often the result of treatment failure and drug resistance. Located around blood vessels, mast cells are primary responders in inflammation by releasing pre-formed as well as de novo synthesized various inflammatory mediators, including histamine, cytokines, and chemokines upon allergen cross-linking of high affinity receptors for IgE (Fc?RI). In addition, activated mast cells can release the sphingolipid metabolite sphingosine-1-phosphate (S1P), generated upon sphingosine kinase (SphK) activation. Secreted S1P can bind to its own receptors, such as the type 2 receptor (S1P2) expressed on mast cells. Several mouse models of chronic inflammatory disorders have established an early increase in mast cell number in inflammatory foci, suggesting their early intervention in the process. We have shown that mast cell S1P2 is essential to the early events associated with acute signs of allergic inflammation, among which edema surrounding the blood vessels in the lungs. Edema promotes subsequent recruitment of inflammatory cells, also favored by increased number of blood vessels, features commonly observed in chronic inflammation. We are proposing to study the contribution of mast cell-expressed S1P2 in the disease progression using mouse models of mast cell-mediated pulmonary inflammation and define how it could lead to persistent inflammation. Using pharmacological, molecular and genetic approaches, we have discovered a new signaling pathway linking S1P2 to Stat3 transcription factor and how disrupting this pathway may potentially abrogate aspects of remodeling observed in chronic inflammation. The objectives of this application are: to establish the role of S1P2 in initiating inflammatory cell infiltration and propagating inflammation~ to elucidate the newly identified signaling pathway and its relevance to remodeling~ to develop in vivo models targeting the mast cell/S1P/ S1P2 axis in an attempt to prevent features associated with chronic inflammatory disorders. Since targeting individual mediators has failed to prevent sustained inflammation, we anticipate our proposed studies will lead to a better understanding of its underlying mechanisms and pave the way for more mechanistically tailored therapies targeting local regulatory pathways in inflammation with a central role for mast cell expressed S1P2.
Chronic inflammation is prevalent in many diseases responsible for the majority of health-care costs associated with these drug-resistant diseases. We are proposing that the type 2 receptor for a multifunctional mediator, sphingosine-1-phosphate, and its expression on mast cells which are primary responders in allergic disorders, exert a central function in initiating and propagating many features observed in inflamed tissues. We anticipate this innovative concept will lead to tailored therapies targeting local regulatory pathways in chronic inflammation for which there is no cure.
|Wedman, P A; Aladhami, A; Chumanevich, A P et al. (2018) Mast cells and sphingosine-1-phosphate underlie prelesional remodeling in a mouse model of eczema. Allergy 73:405-415|
|Caslin, Heather L; Taruselli, Marcela T; Paranjape, Anuya et al. (2018) The Use of Human and Mouse Mast Cell and Basophil Cultures to Assess Type 2 Inflammation. Methods Mol Biol 1799:81-92|
|Ndaw, Victor S; Abebayehu, Daniel; Spence, Andrew J et al. (2017) TGF-?1 Suppresses IL-33-Induced Mast Cell Function. J Immunol 199:866-873|
|Kolawole, Elizabeth Motunrayo; McLeod, Jamie Josephine Avila; Ndaw, Victor et al. (2016) Fluvastatin Suppresses Mast Cell and Basophil IgE Responses: Genotype-Dependent Effects. J Immunol 196:1461-70|
|Rodriguez, Yamila I; Campos, Ludmila E; Castro, Melina G et al. (2016) Sphingosine-1 Phosphate: A New Modulator of Immune Plasticity in the Tumor Microenvironment. Front Oncol 6:218|
|Paranjape, Anuya; Chernushevich, Oksana; Qayum, Amina Abdul et al. (2016) Dexamethasone rapidly suppresses IL-33-stimulated mast cell function by blocking transcription factor activity. J Leukoc Biol 100:1395-1404|
|Chumanevich, Alena; Wedman, Piper; Oskeritzian, Carole A (2016) Sphingosine-1-Phosphate/Sphingosine-1-Phosphate Receptor 2 Axis Can Promote Mouse and Human Primary Mast Cell Angiogenic Potential through Upregulation of Vascular Endothelial Growth Factor-A and Matrix Metalloproteinase-2. Mediators Inflamm 2016:1503206|
|Abebayehu, Daniel; Spence, Andrew J; Qayum, Amina Abdul et al. (2016) Lactic Acid Suppresses IL-33-Mediated Mast Cell Inflammatory Responses via Hypoxia-Inducible Factor-1?-Dependent miR-155 Suppression. J Immunol 197:2909-17|
|Qayum, Amina Abdul; Paranjape, Anuya; Abebayehu, Daniel et al. (2016) IL-10-Induced miR-155 Targets SOCS1 To Enhance IgE-Mediated Mast Cell Function. J Immunol 196:4457-67|
|Oskeritzian, Carole A (2015) Mast cell plasticity and sphingosine-1-phosphate in immunity, inflammation and cancer. Mol Immunol 63:104-12|
Showing the most recent 10 out of 15 publications