Cohen, Jonathan A
(2024)
The Role of Sensory Neurons in Cutaneous Inflammation.
Doctoral Dissertation, University of Pittsburgh.
(Unpublished)
Abstract
Cutaneous TRPV1+ neurons directly sense noxious stimuli, inflammatory cytokines, and pathogen-associated molecules and are required for innate immunity against some skin pathogens. Important unanswered questions are whether TRPV1+ neuron activation in isolation is sufficient to initiate innate immune responses and what is the biological function for TRPV1+ neuron-initiated immune responses. We used TRPV1-Ai32 optogenetic mice and cutaneous light stimulation to activate cutaneous neurons in the absence of tissue damage or pathogen-associated products. We found that TRPV1+ neuron activation was sufficient to elicit a local type 17 immune response that augmented host defense to C. albicans and S. aureus. Moreover, local neuron activation elicited type 17 responses and augmented host defense at adjacent, unstimulated skin through a nerve reflex arc. These data show the sufficiency of TRPV1+ neuron activation for host defense and demonstrate the existence of functional anticipatory innate immunity at sites adjacent to infection that depends on antidromic neuron activation. In order to further understand the mechanism by which TRPV1 neurons drive cutaneous inflammation, detailed kinetic analysis of the immune response following neuron activated was performed. Neurons trigger inflammation via reorganization of skin-resident immune cells. We found that TRPV1 neuron activation triggered dermal dendritic cell clustering in a Substance P, mast cell, CCL2-depenadnt manner. These data provide greater clarity to the early events that trigger neuroinflammation in the skin and highlight targets with exciting therapeutic potential.
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| Item Type: |
University of Pittsburgh ETD
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| Status: |
Unpublished |
| Creators/Authors: |
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| ETD Committee: |
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| Date: |
14 October 2024 |
| Date Type: |
Publication |
| Defense Date: |
3 October 2022 |
| Approval Date: |
14 October 2024 |
| Submission Date: |
8 August 2024 |
| Access Restriction: |
No restriction; Release the ETD for access worldwide immediately. |
| Number of Pages: |
192 |
| Institution: |
University of Pittsburgh |
| Schools and Programs: |
School of Medicine > Immunology |
| Degree: |
PhD - Doctor of Philosophy |
| Thesis Type: |
Doctoral Dissertation |
| Refereed: |
Yes |
| Uncontrolled Keywords: |
neuroimmunology, optogenetics, nociception, neuroinflammation |
| Date Deposited: |
14 Oct 2024 15:54 |
| Last Modified: |
14 Oct 2024 15:54 |
| URI: |
http://d-scholarship.pitt.edu/id/eprint/46876 |
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