Inflammatory skin conditions, such as psoriasis, atopic dermatitis and contact hypersensitivity are often associated with unpleasant sensations of pain and itch. It is unclear whether and to what extent these sensations of discomfort may play an active role in initiating and maintaining cutaneous inflammation. Work in this area must take into account that there are different subsets of nociceptive peripheral nerve fibers that transmit distinct painful stimuli, including noxious heat, cold, mechanical pressure and itch. In preliminary work for this project, we have discovered that a subset of sensory neurons responsive to specific painful stimuli is essential for the development of psoriasiform dermatitis in murine skin. In this model inflammation is initiated and sustained by the local production of the cytokines interleukin (IL)-23 and IL-17. Using both pharmacological and genetic models of selective nociceptor ablation, we observed that specific sensory neurons are in close proximity to skin-resident dendritic cells (DCs) and are critical for the production of IL-23 by DCs, which i necessary to promote subsequent IL-17 secretion by cutaneous T cells. Here we propose to test the hypothesis that dermal somatosensation by nociceptors plays an active role in regulating inflammatory skin responses by controlling the production of key cytokines by tissue-resident immune cells. Our experimental approach will allow us to define how distinct pain sensations contribute to regulating different branches of the innate and adaptive cutaneous immune system. If successful, these aims will enhance both our fundamental knowledge of neuro-immune interactions at a barrier tissue and also identify novel therapeutic targets to alleviate and treat inflammatory skin disease. To test our hypothesis, we propose two Aims that are supported by extensive preliminary data:
Aim 1 : To investigate the impact of nociceptive sensory neurons on cutaneous inflammatory responses. We will provide a comprehensive overview of the relationship between distinct pain modalities and inflammatory modules that drive Type 1, Type 2 or Type 17 responses in the skin Aim 2. To characterize the regulation of dendritic cells by nociceptors. We will phenotype and visualize dendritic cell behavior in response to neural modulation in the skin.

Public Health Relevance

Inflammatory skin conditions such as psoriasis, atopic dermatitis and contact hypersensitivity are severely debilitating in part due to the sensations of pain and itch that affect patients. Preliminary work for this project has shown that the peripheral nerves that transmit these sensations are actively involved in regulating inflammatory processes in the skin. This project seeks to understand how sensory neurons that transmit pain (nociceptors) communicate with the skin-resident immune system and orchestrate immunopathology. This has the potential to uncover new and specific targets for the treatment of inflammatory skin diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
1R01AR068383-01
Application #
8945517
Study Section
Special Emphasis Panel (ZRG1-IMM-D (90))
Program Officer
Cibotti, Ricardo
Project Start
2015-07-07
Project End
2020-04-30
Budget Start
2015-07-07
Budget End
2016-04-30
Support Year
1
Fiscal Year
2015
Total Cost
$372,900
Indirect Cost
$152,900
Name
Harvard Medical School
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
047006379
City
Boston
State
MA
Country
United States
Zip Code
02115
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