Skin inflammation in Atopic Dermatitis (AD) patients includes dendritic cells, mast cells and T cells. Evidence for the function of several T helper subsets in AD exists both from patient samples and from mouse models. There is clearly a genetic component in disease;family history of allergy is one of the strongest predictors of AD, and mutations in the filaggrin (FLG) gene, a component of the Epidermal Differentiation Complex (EDC), have emerged as a predisposing factor for the development of AD. IL-4 and IL-13 promote atopic responses and decrease expression of a number of EDC genes, which are critical for barrier function. One of the primary questions that remain unanswered is whether the defect leading to AD is in the skin, in the atopic immune system, or whether disease requires defects in both systems. Central to answering this question is an understanding of how the immune system and the skin, particularly keratinocytes, interact at the molecular level. The overall goal of this Project is to define the interactions of cytokines that promote the development of atopic inflammation on keratinocyte gene expression and function, with the long-term goal of finding pathways that could be targeted for treatment of disease. Our hypothesis is that pro-allergic cytokines change the biology of keratinocytes and alter barrier function, facilitating increased allergen exposure. This hypothesis will be examined in two Aims that will examine the interactions of filaggrin mutations with increased Th2 immunity in a mouse model system, and define the function of STAT6 in regulating keratinocyte gene expression. Together, these studies will provide a detailed understanding of the effects of cytokines produced during allergic inflammation on skin barrier function.

Public Health Relevance

Skin provides a barrier to harmful components in the environment including infection. Atopic Dermatitis, an allergic disease of the skin alters the barrier function of the skin and increases allergic inflammation and infection. This proposal defines the mechanism of altered barrier function and examines the interactions of the immune system with genes involved in barrier function.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI095282-03
Application #
8603836
Study Section
Hypersensitivity, Autoimmune, and Immune-mediated Diseases Study Section (HAI)
Program Officer
Minnicozzi, Michael
Project Start
2012-02-15
Project End
2017-01-31
Budget Start
2014-02-02
Budget End
2015-01-31
Support Year
3
Fiscal Year
2014
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Pediatrics
Type
Schools of Medicine
DUNS #
City
Indianapolis
State
IN
Country
United States
Zip Code
46202
Cheon, In Su; Son, Young Min; Jiang, Li et al. (2018) Neonatal hyperoxia promotes asthma-like features through IL-33-dependent ILC2 responses. J Allergy Clin Immunol 142:1100-1112
Li, Yue; Liu, Weiren; Guan, Xiaqun et al. (2018) STAT6 and Furin Are Successive Triggers for the Production of TGF-? by T Cells. J Immunol 201:2612-2623
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
Imam, Tanbeena; Park, Sungtae; Kaplan, Mark H et al. (2018) Effector T Helper Cell Subsets in Inflammatory Bowel Diseases. Front Immunol 9:1212
Walker, Matthew T; Green, Jeremy E; Ferrie, Ryan P et al. (2018) Mechanism for initiation of food allergy: Dependence on skin barrier mutations and environmental allergen costimulation. J Allergy Clin Immunol 141:1711-1725.e9
Serezani, Ana P M; Bozdogan, Gunseli; Sehra, Sarita et al. (2017) IL-4 impairs wound healing potential in the skin by repressing fibronectin expression. J Allergy Clin Immunol 139:142-151.e5
Kälin, Stefanie; Becker, Maike; Ott, Verena B et al. (2017) A Stat6/Pten Axis Links Regulatory T Cells with Adipose Tissue Function. Cell Metab 26:475-492.e7
Krishnamurthy, Purna; Da-Silva-Arnold, Sonia; Turner, Matthew J et al. (2017) Poly-ADP ribose polymerase-14 limits severity of allergic skin disease. Immunology 152:451-461
Sehra, Sarita; Krishnamurthy, Purna; Koh, Byunghee et al. (2016) Increased Th2 activity and diminished skin barrier function cooperate in allergic skin inflammation. Eur J Immunol 46:2609-2613

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