The primary goal of our research is to mechanistically characterize systemic immunosuppression induced by ultraviolet B radiation (UVB). The immunosuppressive effects of UVB are involved in the ability of this environmental stimulus to induce skin cancers. Moreover, UVB radiation treatments are used clinically to treat inflammatory skin disorders, in great part to its immunosuppressive effects. The planned research plans to take advantage of results of previous studies both in our laboratory and others indicating that UVB-mediated systemic immunosuppression involves novel glycerophosphocholine-derived lipids produced by epidermal cells in response to UVB. These compounds, some of which have not been structurally characterized, act as agonists for the Platelet-activating Factor (PAF) receptor. Accumulating evidence suggests that these PAF-R agonists exert immunosuppressive effects via a complex interplay of cell types and cytokines including mast cells, cyclooxygenase-2-produced eicosanoids, interleukin-10 and histamine.
Two specific aims are planned to mechanistically characterize the complex pathway of UVB-mediated systemic immunosuppression using a well-established murine model of contact hypersensitivity.
The first aim will use mass spectrometry to structurally characterize and quantitate PAF-R agonists produced by UVB in murine skin. The amounts of these novel PAF-R ligands produced enzymatically as well as through non- enzymatic free radical-mediated oxidation of glycerophosphosphocholines will be assessed using a mouse defective in PAF enzymatic synthesis and use of systemic antioxidants.
The second aim will characterize the roles of mast cells and regulatory T cells using novel murine transplantation studies. Completion of the planned studies to characterize the cell types and mediators involved in UVB-mediated systemic immunosuppression should result in an enhanced understanding of this important process intimately involved in skin cancer.
PROJECT NARRATIVE: The primary goal of our research is to mechanistically characterize the cell types and mediators involved in ultraviolet B radiation (UVB)-mediated systemic immunosuppression. The immunosuppressive effects of UVB are involved in the ability of this environmental stimulus to induce skin cancers. These skin cancers and pre- cancerous actinic keratoses induced by chronic sun exposure are the most common form of neoplastic disorders found in veterans. Though usually not associated with increased mortality, actinic neoplasias constitute an enormous burden of health care resources and increased morbidity. Moreover, UVB radiation treatments are used clinically to treat inflammatory skin disorders, in great part to its immunosuppressive effects. These studies should result in an enhanced understanding of this important process.
|Poon, Chien; Sunar, Ulas; Rohrbach, Daniel J et al. (2018) Early assessment of burn severity in human tissue ex vivo with multi-wavelength spatial frequency domain imaging. Toxicol In Vitro 52:251-254|
|DaSilva-Arnold, Sonia C; Thyagarajan, Anita; Seymour, Leroy J et al. (2018) Phenotyping acute and chronic atopic dermatitis-like lesions in Stat6VT mice identifies a role for IL-33 in disease pathogenesis. Arch Dermatol Res 310:197-207|
|Ocana, Jesus A; Romer, Eric; Sahu, Ravi et al. (2018) Platelet-Activating Factor-Induced Reduction in Contact Hypersensitivity Responses Is Mediated by Mast Cells via Cyclooxygenase-2-Dependent Mechanisms. J Immunol 200:4004-4011|
|Khan, Aiman Q; Travers, Jeffrey B; Kemp, Michael G (2018) Roles of UVA radiation and DNA damage responses in melanoma pathogenesis. Environ Mol Mutagen 59:438-460|
|Fahy, Katherine; Liu, Langni; Rapp, Christine M et al. (2017) UVB-generated Microvesicle Particles: A Novel Pathway by Which a Skin-specific Stimulus Could Exert Systemic Effects. Photochem Photobiol 93:937-942|
|Sahu, Ravi P; Harrison, Kathleen A; Weyerbacher, Jonathan et al. (2016) Radiation therapy generates platelet-activating factor agonists. Oncotarget 7:20788-800|
|Sahu, Ravi P; Ferracini, Matheus; Travers, Jeffrey B (2015) Systemic chemotherapy is modulated by platelet-activating factor-receptor agonists. Mediators Inflamm 2015:820543|
|Ferracini, Matheus; Sahu, Ravi P; Harrison, Kathleen A et al. (2015) Topical photodynamic therapy induces systemic immunosuppression via generation of platelet-activating factor receptor ligands. J Invest Dermatol 135:321-323|
|Travers, Jeffrey B (2014) Toxic interaction between Th2 cytokines and Staphylococcus aureus in atopic dermatitis. J Invest Dermatol 134:2069-2071|
|Sahu, Ravi P; Ocana, Jesus A; Harrison, Kathleen A et al. (2014) Chemotherapeutic agents subvert tumor immunity by generating agonists of platelet-activating factor. Cancer Res 74:7069-78|
Showing the most recent 10 out of 12 publications