Eosinophils are innate immune leukocytes associated with asthma, allergies and other diseases. Despite the long recognition of eosinophilic involvement in asthma, specific, non-redundant roles for eosinophils in disease pathogenesis had been elusive. However, recent studies from several laboratories have revealed new functions of eosinophils in immunomodulation and airway remodeling, changing the classic paradigm of disease pathogenesis and reinvigorating the field with a promise of more specific therapeutic targets. Our overall goal is to identify and mechanistically define effector functions of eosinophils vital to the initiation and exacerbation of asthma. In line with this goal, this proposal builds upon our novel discovery that mature human eosinophils express fully functional Notch ligands and receptors, indicating eosinophils utilize Notch signaling pathways, both as signal-receiving """"""""target"""""""" cells and as signal- sending """"""""signaling"""""""" cells. Our preliminary data establishes our overlying hypothesis that Notch signaling underlies eosinophil functions critical to asthma. Our studies will specifically investigate two hypotheses: 1) Notch receptor activation is required in parallel with cytokine signals to achieve full and sustained activation of eosinophils in asthmatic airways;and 2) Eosinophils promote a Th2 milieu in asthma by Notch ligand-mediated juxtacrine interactions with T cells. While experimental approaches utilize predominantly human eosinophils, proposed studies also take full advantage of the manipulative benefits of mouse models. Our proposal may provide vital insights into the mechanistic basis for eosinophil functions pertinent to asthma, and by extension other inflammatory diseases of the lung involving eosinophilia, relevant to development of novel, targeted therapeutic approaches.
Asthma is a highly prevalent and costly disease. Eosinophils, innate immune leukocytes associated with asthma, allergies and other diseases, are the predominant cellular infiltrate in asthmatic airways. This proposal is designed to elucidate the mechanistic basis of eosinophil functions leading to asthma exacerbation. These studies may lead to the development of novel, targeted therapeutic approaches.
|Carmo, LÃvia A S; Bonjour, Kennedy; Ueki, Shigeharu et al. (2016) CD63 is tightly associated with intracellular, secretory events chaperoning piecemeal degranulation and compound exocytosis in human eosinophils. J Leukoc Biol 100:391-401|
|Smith, Kalmia M; Rahman, Raiann S; Spencer, Lisa A (2016) Humoral Immunity Provides Resident Intestinal Eosinophils Access to Luminal Antigen via Eosinophil-Expressed Low-Affinity FcÎ³ Receptors. J Immunol 197:3716-3724|
|Akuthota, Praveen; Carmo, LÃvia A S; Bonjour, Kennedy et al. (2016) Extracellular Microvesicle Production by Human Eosinophils Activated by ""Inflammatory"" Stimuli. Front Cell Dev Biol 4:117|
|Liu, L Y; Wang, H; Xenakis, J J et al. (2015) Notch signaling mediates granulocyte-macrophage colony-stimulating factor priming-induced transendothelial migration of human eosinophils. Allergy 70:805-12|
|Bettigole, Sarah E; Lis, Raphael; Adoro, Stanley et al. (2015) The transcription factor XBP1 is selectively required for eosinophil differentiation. Nat Immunol 16:829-37|
|Spencer, Lisa A; Bonjour, Kennedy; Melo, Rossana C N et al. (2014) Eosinophil secretion of granule-derived cytokines. Front Immunol 5:496|
|Ueki, Shigeharu; Melo, Rossana C N; Ghiran, Ionita et al. (2013) Eosinophil extracellular DNA trap cell death mediates lytic release of free secretion-competent eosinophil granules in humans. Blood 121:2074-83|
|Melo, R C N; Liu, L; Xenakis, J J et al. (2013) Eosinophil-derived cytokines in health and disease: unraveling novel mechanisms of selective secretion. Allergy 68:274-84|
|Akuthota, Praveen; Melo, Rossana C N; Spencer, Lisa A et al. (2012) MHC Class II and CD9 in Human Eosinophils Localize to Detergent-Resistant Membrane Microdomains. Am J Respir Cell Mol Biol 46:188-95|
|Shamri, Revital; Melo, Rossana C N; Young, Kristen M et al. (2012) CCL11 elicits secretion of RNases from mouse eosinophils and their cell-free granules. FASEB J 26:2084-93|
Showing the most recent 10 out of 12 publications