The skin is a highly innervated organ and contains numerous sensory afferent nerve fibers that respond to a diverse array of stimuli ranging from gentle touch to noxious, painful stimuli. There are also many skin-resident immune cells including several subsets of dendritic cells that direct effector responses from skin-resident innate and adaptive T cells. During C. albicans skin infection, cutaneous nociceptors (unmyelinated pain- sensing neurons) are able to directly sense C. albicans and are required for the resulting cascade of down- stream Type 17 immune events resulting in efficient clearance of C. albicans. In addition, in models of psoriasis-like skin inflammation, nociceptors are required for cutaneous Type 17 inflammation. A key step in this cascade is the interaction of nociceptors with cutaneous dendritic cells that drive both innate Type 17 inflammation and are required for the development of adaptive Th17 cells that provide long-term protection. This could explain why in human patients, loss of nerve innervation or spinal cord injury results in clearance of psoriatic lesions in denervated limbs as well as increased rates of superficial C. albicans infection. Thus, in both humans and mice, cutaneous nerves play a critical role in regulating the Type 17 immunity in the skin during both infection and autoimmunity. Despite this progress, a large number of important unanswered questions remain on how the nervous and immune systems communicate in response to immune challenges. The goal of this project is to define the mechanism(s) of neuronal activation and resulting neuronal influence on immune responses in the setting of host defense and autoimmunity. In particular, we will test how nociceptors are activated and the effect of isolated nociceptor activation. By dissecting these pathways in detail we expect to create a rational use for novel pharmacological agents that target peripheral nerve function in the treatment of skin diseases. We hypothesize that the nociceptive subset of cutaneous afferents identified by expression of TRPV1 directly recognize C. albicans and Imiquimod through engagement of the TLR pathway. We will test this hypothesis by comparing responses of dorsal root ganglion neurons isolated from mice with genetic defects in the TLR pathway to mutant strains of C. albicans in vitro. We will also determine whether activation of nociceptors in vivo is sufficient for the establishment of Type 17 immunity using optogenetics. Finally, using mice with genetic ablation of nociceptors, we will test whether nociception is required for the development of adaptive Th17 cells in vivo.

Public Health Relevance

The skin is a highly innervated organ and contains numerous sensory afferent nerve fibers. There are also many skin-resident immune cells including several subsets of dendritic cells that direct both innate and adaptive effector responses. During infection and in models of autoimmunity, some nerves directly detect the presence of the insult and direct the immune response. The goal of this project is to define the mechanism(s) of neuronal activation and resulting neuronal influence on immune responses in the setting of host defense and autoimmunity. By dissecting these pathways in detail we expect to create a rational use for novel pharmacological agents that target peripheral nerve function for the treatment of skin diseases.

Agency
National Institute of Health (NIH)
Institute
National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS)
Type
Research Project (R01)
Project #
5R01AR071720-03
Application #
9613224
Study Section
Special Emphasis Panel (ZRG1)
Program Officer
Cibotti, Ricardo
Project Start
2017-03-01
Project End
2021-12-31
Budget Start
2019-01-01
Budget End
2019-12-31
Support Year
3
Fiscal Year
2019
Total Cost
Indirect Cost
Name
University of Pittsburgh
Department
Dermatology
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Kashem, Sakeen W; Kaplan, Daniel H (2018) Isolation of Murine Skin Resident and Migratory Dendritic Cells via Enzymatic Digestion. Curr Protoc Immunol 121:e45
Kaplan, Daniel H (2017) Ontogeny and function of murine epidermal Langerhans cells. Nat Immunol 18:1068-1075