By regulating immune responses, pain, and pruritus, sensory nerves play an essential role in the initiation or aggravation of chronic diseases like atopic dermatitis, inflammatory bowel disease, irritable bowel syndrome, asthma, and rheumatoid arthritis. Certain cytokines, notably Interleukin-31 (IL-31) and its related cytokine Oncostatin M (OSM), directly activate sensory neurons, thereby regulating neurogenic inflammation, pruritus, and/or pain. In addition, keratinocytes, which express classical "neuronal" receptors and release factors that subsequently modulate the function of sensory nerves (itch, pain) are a "forefront" of neuronal signaling in the skin. To test this hypothesis, we propose to investigate the impact of IL-31 and OSM as novel "neuromediators" with respect to inflammation, pain and pruritus. Understanding how immune cells "talk" to nerves and vice versa will lead to novel insights into how the nervous and the immune systems communicate in disease states and to new treatment strategies for these diseases, thus improving quality of life. Our knowledge how nerves and immune cells or keratinocytes communicate during inflammation and pruritic diseases, however, is still very poor. There is also a need for better therapies for pruritic and painful diseases in which cytokines are involved. Our preliminary results strongly indicate that skin sensory nerves are directly involved in IL-31-and OSM-induced signalling. In addition, IL-31 and OSM are capable of releasing factors from keratinocytes which subsequently regulate neuronal function during inflammation and pruritus/pain. Based on these new findings, we hypothesize that IL-31 and OSM alone and/or in combination, activate subsets of dorsal root ganglion (DRG) and spinal cord (SC) neurons and keratinocytes through their receptors, thereby regulating neurogenic inflammation, pruritus and/or pain. We will test this hypothesis in three specific aims:
Aim 1 : To test the hypothesis that receptors for IL-31 and OSM are expressed in neurochemically distinct subsets of primary afferents in mice and humans, and that these neurons innervate peripheral (skin) and central (spinal cord) tissues that express these cytokines.
Aim 2 : To test the hypothesis that IL-31 and OSM regulate inflammation, pruritus and pain via an action on primary afferent neurons as well as keratinocytes.
Aim 3 : To test the hypothesis that IL-31 and OSM contribute to neurogenic inflammation, pruritus, and pain using behavioral mouse models in vivo. The significance of this study is that it seeks to prove the concept that "classical immune" cytokine receptors act as important neuronal cytokine receptors on sensory nerves, thereby regulating skin inflammation, pruritus, and/or pain. This may lead to novel therapeutic strategies to combat skin diseases that have a neuronal component, like atopic dermatitis and other eczemas, or rosacea, and to reduce the adverse symptoms associated with these conditions, including pruritus and pain.

Public Health Relevance

The nervous and immune system in the skin share a common developmental origin with a close, bidirectional interaction throughout life, defining the skin as a neuro-immune organ. The proposed research is relevant to public health because understanding how immune or skin cells communicate with cutaneous nerves to release factors that induce neurogenic inflammation involved in various chronic inflammatory diseases could lead to new treatment strategies. The long-term objective will be to define the links between immune cells and nerves in inflammatory skin diseases and to develop new strategies against these diseases using a translational approach.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR059402-02
Application #
8290495
Study Section
Somatosensory and Chemosensory Systems Study Section (SCS)
Program Officer
Cibotti, Ricardo
Project Start
2011-07-01
Project End
2016-06-30
Budget Start
2012-07-01
Budget End
2013-06-30
Support Year
2
Fiscal Year
2012
Total Cost
$347,625
Indirect Cost
$122,625
Name
University of California San Francisco
Department
Dermatology
Type
Schools of Medicine
DUNS #
094878337
City
San Francisco
State
CA
Country
United States
Zip Code
94143
Braz, Joao M; Juarez-Salinas, Dina; Ross, Sarah E et al. (2014) Transplant restoration of spinal cord inhibitory controls ameliorates neuropathic itch. J Clin Invest 124:3612-6
Cevikbas, Ferda; Wang, Xidao; Akiyama, Tasuku et al. (2014) A sensory neuron-expressed IL-31 receptor mediates T helper cell-dependent itch: Involvement of TRPV1 and TRPA1. J Allergy Clin Immunol 133:448-60
Kido-Nakahara, Makiko; Buddenkotte, Jörg; Kempkes, Cordula et al. (2014) Neural peptidase endothelin-converting enzyme 1 regulates endothelin 1-induced pruritus. J Clin Invest 124:2683-95
Moore, Carlene; Cevikbas, Ferda; Pasolli, H Amalia et al. (2013) UVB radiation generates sunburn pain and affects skin by activating epidermal TRPV4 ion channels and triggering endothelin-1 signaling. Proc Natl Acad Sci U S A 110:E3225-34
Cattaruzza, Fiore; Johnson, Cali; Leggit, Alan et al. (2013) Transient receptor potential ankyrin 1 mediates chronic pancreatitis pain in mice. Am J Physiol Gastrointest Liver Physiol 304:G1002-12
Wang, Xidao; Zhang, Jie; Eberhart, Derek et al. (2013) Excitatory superficial dorsal horn interneurons are functionally heterogeneous and required for the full behavioral expression of pain and itch. Neuron 78:312-24
Feramisco, Jamison D; Goerge, Tobias; Schulz, Sarah E et al. (2012) Disseminated erosive pustular dermatosis also involving the mucosa: successful treatment with oral dapsone. Acta Derm Venereol 92:91-2
Suarez, Andrea L; Feramisco, Jamison D; Koo, John et al. (2012) Psychoneuroimmunology of psychological stress and atopic dermatitis: pathophysiologic and therapeutic updates. Acta Derm Venereol 92:7-15
Kempkes, Cordula; Rattenholl, Anke; Buddenkotte, Jorg et al. (2012) Proteinase-activated receptors 1 and 2 regulate invasive behavior of human melanoma cells via activation of protein kinase D1. J Invest Dermatol 132:375-84
Sulk, Mathias; Seeliger, Stephan; Aubert, Jerome et al. (2012) Distribution and expression of non-neuronal transient receptor potential (TRPV) ion channels in rosacea. J Invest Dermatol 132:1253-62

Showing the most recent 10 out of 13 publications