Veterans suffer from several common skin conditions in which TNFa plays a key role. For example, this cytokine is induced in photodamage, which is a growing problem because UV is used therapeutically, and because our troops are serving or have returned from areas of the world where sunlight is particularly intense. TNFa excess is associated with short-term damage (sunburn), but also serious long-term problems, such as premature aging and fragility of the skin, photosensitive autoimmune diseases, pre-cancerous lesions, and skin cancer. In the other direction, new medicines to inhibit TNFa are widely used therapeutically in Veterans with psoriasis, rheumatoid arthritis, and inflammatory bowel disease. Unfortunately, TNFa inhibition also promotes skin cancers and may interfere with skin integrity owing to the normal role of this cytokine in promoting hyaluronan synthesis. Based on these data, our overall hypothesis is that too much or too little TNFa in the skin harms cutaneous health and integrity. We propose to characterize the processes mediating collagen loss caused by TNFa excess during cutaneous photodamage (Aim 1), determine the molecular mechanisms for TNFa overproduction during UV exposure (Aim 2), and most importantly, evaluate potential mechanisms for skin matrix disruption in humans during therapy with TNFa inhibition and/or UV (Aim 3).
Aim 1 : Characterization of processes mediating the collagen loss induced by excess TNFa. We will determine the roles of TNFa in UV-induced collagen change and inflammation by comparing the activation of collagenases and related enzymes, as well as populations of infiltrating cells, in th skin of mice treated with UVB alone versus UVB+etanercept. Using genetic and other methods to manipulate specific types of infiltrating immune cells, we will characterize their roles in vivoin UV-induced collagen loss, MMP induction, and recruitment of other inflammatory cells.
Aim 2 : Molecular mechanisms by which UVB induces excess TNFa. We previously found strong, wavelength-specific synergy between UVB and IL-1a in the induction of TNFa gene transcription and that this synergy depends on activation of AP-1 by UVB and NFKB by IL-1a. Here, we will use mega-DNase I hypersensitivity analysis (MDHA) of the endogenous TNFa gene to discover distal cis-acting control sequences. TNFa promoter/CAT reporter constructs will be used to recapitulate the synergistic response to UVB+IL-1a, pinpoint regulatory sites, and determine if they bind NFKB directly or factors induced by NFKB.
Aim 3 : Mechanisms of cutaneous matrix disruption in Veterans exposed to acute UV and/or chronic blockade of TNFa. We will extend the findings from Aim 1 to examine the mechanism of collagen loss in human skin. MMPs and inflammatory cells in skin from patients with psoriasis treated with and without UV, with and without TNFa blockade, will be examined and correlated with our findings in mice. UV therapy and TNFa inhibitors are widely used in Veterans and may interfere with cutaneous integrity. We will examine the effects of these two treatment modalities on dermal thickness, type I collagen, and HAS2 expression. Overall, these Aims will provide a better understanding of the mechanism of TNFa-related collagen loss, nature of the inflammatory infiltrate recruited by TNFa into skin in response to UV, how UV induces TNFa expression, and the mechanisms for damage to human skin during therapies that alter TNFa. This information will facilitate evaluation and development of potential interventions to prevent these extensive and destructive changes in skin.

Public Health Relevance

TNF plays important roles in the skin. It is upregulated by ultraviolet light, causing many deleterious effects to the skin. Understanding these effects will help develop more specific approaches to blocking photo damage associated with long-term exposure to UV light. In particular, MMPs play a critical role in the degradation of collagen in the skin, but the source of these MMPs and their activation may well depend on pro-inflammatory cytokines produced by cells in the epidermis, dermis, as well as inflammatory cells that home to the skin in response to UV light. Overall, the goal is to define the critical pathways that participate in skin damage from UV, ultimately leading to different approaches for controlling and preventing these. In addition, blocking TNF, frequently used in Veterans, potentially has effects on skin thinning that needs systematic study.

Agency
National Institute of Health (NIH)
Institute
Veterans Affairs (VA)
Type
Non-HHS Research Projects (I01)
Project #
5I01BX000706-03
Application #
8803242
Study Section
Immunology A (IMMA)
Project Start
2013-04-01
Project End
2017-03-31
Budget Start
2015-04-01
Budget End
2016-03-31
Support Year
3
Fiscal Year
2015
Total Cost
Indirect Cost
Name
Philadelphia VA Medical Center
Department
Type
DUNS #
071609291
City
Philadelphia
State
PA
Country
United States
Zip Code
19104
Kim, H J; Zeidi, M; Bonciani, D et al. (2018) Itch in dermatomyositis: the role of increased skin interleukin-31. Br J Dermatol 179:669-678
Mittal, Lavanya; Zhang, Lingqiao; Feng, Rui et al. (2018) Antimalarial drug toxicities in patients with cutaneous lupus and dermatomyositis: A retrospective cohort study. J Am Acad Dermatol 78:100-106.e1
Ang, C C; Anyanwu, C O; Robinson, E et al. (2017) Clinical signs associated with an increased risk of interstitial lung disease: a retrospective study of 101 patients with dermatomyositis. Br J Dermatol 176:231-233
Caplan, A; Imadojemu, S; Werth, V P (2017) Importance of recognition and improved treatment for antimelanoma differentiation-associated protein 5-associated dermatomyositis. Br J Dermatol 177:1168-1169
George, M D; Shah, R; Kreider, M et al. (2017) Pulmonary function tests, interstitial lung disease and lung function decline in outpatients with classic and clinically amyopathic dermatomyositis. Br J Dermatol 176:262-264
Mittal, Lavanya; Werth, Victoria P (2017) The quinacrine experience in a population of patients with cutaneous lupus erythematosus and dermatomyositis. J Am Acad Dermatol 77:374-377
Alves, Paul; Bashir, Muhammad M; Wysocka, Maria et al. (2017) Quinacrine Suppresses Tumor Necrosis Factor-? and IFN-? in Dermatomyositis and Cutaneous Lupus Erythematosus. J Investig Dermatol Symp Proc 18:S57-S63
Robinson, Elizabeth S; Alves, Paul; Bashir, Muhammad M et al. (2017) Cannabinoid Reduces Inflammatory Cytokines, Tumor Necrosis Factor-?, and Type I Interferons in Dermatomyositis In Vitro. J Invest Dermatol 137:2445-2447
Chansky, P B; Mittal, L; Werth, V P (2017) Dermatological evaluation in patients with skin of colour: the effect of erythema on outcome measures in atopic dermatitis. Br J Dermatol 176:853-854
Tiao, J; Feng, R; Bird, S et al. (2017) The reliability of the Cutaneous Dermatomyositis Disease Area and Severity Index (CDASI) among dermatologists, rheumatologists and neurologists. Br J Dermatol 176:423-430

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