Atopic dermatitis (AD) is a chronic relapsing inflammatory condition of the skin that results from the interactions of the immune system with the structural cells in the skin. Cytokines produced by Th2 cells are critical promoters of atopic inflammation, and biological therapeutics that block the effects of IL-4, one of the Th2 cytokines, are efficacious in treatment of AD. Mechanistically, IL-4 potentiates inflammation by promoting chemokine production allowing increased recruitment of cells to the inflamed tissue, decreases expression of genes in keratinocytes that contribute to barrier function, and impairs innate pathogen defenses in the skin. We have added to our understanding of this process by demonstrating the ability of IL-4 to impair re- epithelialization of the skin after wounding. In a disease that is perpetuated by an itch-scratch-wound cycle, the inability to recover from wounds and restore barrier function is a critical component of chronic disease. Among the discoveries in our previous cycle of funding we demonstrated that keratinocytes exposed to IL-4 have impaired wound-healing responses both in vitro and in vivo using a model of atopic dermatitis. IL-4 stimulation repressed fibronectin expression in keratinocytes, and supplementing fibronectin either to cultures, or topically to wounded tissue in models of AD. Importantly, while wound healing has been studied extensively, how the atopic environment alters wound healing is completely unknown. In the next funding period we will define a re- epithelialization regulatory circuit that involves IL-4, ?? T cells, keratinocytes, and fibronectin. Experiments in the First Aim will define the IL-4-responsive cells that contribute to altered wound healing in models of AD. Based on preliminary data that there is a dramatic loss of ?? T cells in the skin of AD models, the Second Aim will determine how the ?? T cell contribution to wound healing is altered in an atopic environment. The final Third Aim will focus on testing the efficacy of topical fibronectin application in human skin transplant models. Together, the studies in these Aims will mechanistically define the interactions of immune and structural cells during a wound healing response in the context of an atopic environment, and will test potential new approaches to treating the pathology in AD.

Public Health Relevance

Atopic dermatitis is an itchy, rash-inducing skin disease that affects around 10% of children and up to 3% of adults in the US. We have discovered that healing of skin wounds is altered in a model of atopic dermatitis. In this proposal, we investigate the mechanisms of this altered healing response by defining the role of specific soluble mediators and cells present in the skin.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Project (R01)
Project #
5R01AI095282-07
Application #
9632682
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Minnicozzi, Michael
Project Start
2012-02-15
Project End
2023-01-31
Budget Start
2019-02-01
Budget End
2020-01-31
Support Year
7
Fiscal Year
2019
Total Cost
Indirect Cost
Name
Indiana University-Purdue University at Indianapolis
Department
Pediatrics
Type
Schools of Medicine
DUNS #
603007902
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

Showing the most recent 10 out of 28 publications