Atopic dermatitis is a common chronic inflammatory skin disease. It is a significant medical problem and as much as 15-20% of children are affected by this disease in industrialized countries. Treatment of atopic dermatitis continues to be a challenge. The current model suggests that atopic dermatitis is attributable to a Th2-mediated inflammatory response and T cells, dendritic cells, and mast cells play important roles. This proposal aims at the establishment of the role of a member of the galectin family in atopic dermatitis with the long-term goal of developing a novel therapy for treatment of this disease. Galectin-3 is a member of a family of animal lectins defined by their affinity for 2-galactosides and consensus sequences. It is expressed by a number of cell types, including epithelial cells and various leukocytes. A number of extracellular functions have been demonstrated by using exogenously added galectin-3 and these are associated with its binding to and crosslinking cell surface glycans. However, there is a great deal of evidence that endogenous galectin-3 regulates various cellular functions through intracellular actions. By studying T cells from galectin-3-deficient mice, we have demonstrated that galectin-3 is an inhibitory regulator in Th1 cells and suppresses the T cell receptor (TCR)-mediated Th1 response by promoting TCR downregulation. Galectin-3 is localized intracellularly at the immunological synapse in T cells activated by TCR engagement. We have also demonstrated that galectin-3 suppresses the production of IL-12 by dendritic cells. In addition, we have demonstrated an important role of galectin-3 in mast cells. By yeast two-hybrid screening, we found Alix as a galectin-3-binding partner, which is known to be a component of the endosomal sorting complex required for transport (ESCRT) and the multivesicular body (MVB). We also have other information suggesting that galectin-3 is associated with MVBs and exosomes. In a mouse model of atopic dermatitis, we found that galectin-3 promotes the Th2 response and suppresses the Th1 response and this is in part through the protein's function in T cells and dendritic cells. In this proposal, we plan to test the hypothesis that galectin-3 1) suppresses the TCR-mediated Th1 response by functioning at the IS;2) is critical for the antigen-presenting function of dendritic cells by suppressing IL-12 production and functions as an exosome-associated protein;3) promotes allergic skin inflammation through dendritic cells and mast cells (in addition to T cells).

Public Health Relevance

Atopic dermatitis is a common chronic inflammatory skin disease. The prevalence of this disease has increased by two- to three-fold during the past three decades in industrialized countries, where the current prevalence in children is estimated to be 15-20%. The treatment of this disease continues to be a challenge. Elucidation of the cellular and molecular bases of this disease is important for development of novel therapeutic strategies. Galectin-3 is a member of a family of proteins that bind carbohydrates, called lectins. The galectin family defined by their binding of 2-galactosides and sharing of similar amino acid sequences. When galectin-3 is added to various cells, it can bind to cell surface proteins that have attached carbohydrates recognizable by the lectin. However, there is a great deal of evidence that galectin-3 that is present inside the cells regulates various cellular functions through intracellular actions (without the protein being secreted). We have obtained important information on the functions of galectin-3 by studying genetically engineered mice we generated that lack galectin-3. Most recently, we found that galectin-3 plays an important function in the response of T cells. We found that galectin-3 is clustered inside the cells in the area that is important for the T cell response called the immunological synapse. We also found that galectin-3 has an important function in another cell type called dendritic cells. We have previously demonstrated that galectin-3 promotes allergic airway inflammation. We now have a significant amount of data supporting the role of this protein in a mouse model of atopic dermatitis. Additional work is required for understanding how galectin-3 regulates these inflammatory processes and for advancing strategies for developing galectin-3-targeting therapies. In this proposal, we plan to establish the mechanism by which galectin-3 regulates the responses of T cell and dendritic cell, which are both key cell types in the development of allergic skin inflammation associated with atopic dermatitis. We also plan to elucidate the cellular basis for galectin-3's regulatory role in a mouse model of atopic dermatitis.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR056343-03
Application #
8206814
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Cibotti, Ricardo
Project Start
2010-01-15
Project End
2014-11-30
Budget Start
2011-12-01
Budget End
2012-11-30
Support Year
3
Fiscal Year
2012
Total Cost
$330,930
Indirect Cost
$104,409
Name
University of California Davis
Department
Dermatology
Type
Schools of Medicine
DUNS #
047120084
City
Davis
State
CA
Country
United States
Zip Code
95618
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