Decoy receptor 3 (DcR3) is a soluble receptor belonging to tumor necrosis factor receptor (TNFR) superfamily as well as an inflammation biomarker. Since its discovery in cancer tissues in 1998, accumulating studies demonstrate high expression of DcR3 in various lineages of malignant tissues. High DcR3 serum level has been established as a poor prognostic index of cancer patients. Tumor cells expressing DcR3 has been speculated to help tumor cells to escape host immunosurveillance via its neutralizing action on FasL, LIGHT, and TL1A. Besides exerting ligand neutralization effects, DcR3 acts as an effector molecule to execute its non-decoy multifunctional actions via interacting with heparan sulfate proteoglycans (HSPGs), thus modulate the activation and differentiation of macrophages, dendritic cells, and osteoclasts. Recently we also demonstrate the role of DcR3 in inflammation-associated psoriasis, which can be upregulated by EGFR signaling and various proinflammatory cytokines in keratinocytes. Moreover, we show that DcR3 is increased in psoriatic lesions, and DcR3 can inhibit keratinocyte differentiation, which is a key process for normal skin cornification. Galectins are a family of proteins defined by their binding specificity for β-galactoside sugars, such as N-acetyllactosamine (Galβ1-3GlcNAc or Galβ1-4GlcNAc), which can be bound to proteins by either N-linked or O-linked glycosylation. Recent work highlights galectin-3 is a multifunctional molecule which can function both inside and outside the cells. Galectin-3 has been shown to regulate immune cell activities, induce immunosuppression in tumorigenesis, and involve in the pathogenesis of inflammatory skin diseases including psoriasis. Intriguingly our preliminary work indicates the interaction of DcR3 and galectin-3 in the cytosol of primary human normal keratainocytes (NEHK) and mouse bone marrow-derived macrophages (BMDM). We also observed that DcR3 expression in kerationocytes is attenuated when galecin-3 is knocked down. In this project, we are going to explore the intracellular functions of both glycans-binding proteins in keratinocytes and macrophages. We will dissect their respective intracellular targets to control signaling pathways for inducing inflammation responses and cell differentiation, and clarify the molecular interactive features which contribute to regulate cellular functions of keratinocytes and macrophages. The specific aims of this project include (1) To understand the binding motifs between DcR3 and galectin-3, intracellular localization and binding regulators in keratinocytes and macrophages; (2) To understand the roles of DcR3 and galectin-3 in keratinocyte differentiation and growth; (3) To understand the roles of DcR3 and galectin-3 in macrophages activation.
|Effective start/end date||10/1/14 → 9/30/15|