PURPOSE OF THE STUDY.
Atopic dermatitis (AD) is a cutaneous disorder characterized by inflamed and pruritic (itchy) skin. The proallergic cytokine thymic stromal lymphopoietin (TSLP) is produced by keratinocytes and plays a central role in the pathogenesis of AD. Whether TSLP is directly responsible for the severe itching associated with AD is unclear.
STUDY POPULATION.
Studies were performed with mice and human cells.
METHODS.
TSLP-mediated neuronal signaling was assessed by using calcium imaging and electrophysiology. TSLP-inducing signaling pathways were studied in human primary epithelial cells.
RESULTS.
The authors observed that direct injection of TSLP into the skin of mice resulted in itching behavior. TSLP-induced itching occurred in mice genetically deficient for lymphocytes or mast cells, suggesting that the pruritic properties of TSLP were independent of its effects on the immune system. Interestingly, dorsal root ganglia from humans and mice were found to express the TSLP receptor, indicating that neurons may be biologically responsive to TSLP. Indeed, treatment of nerve cells with TSLP resulted in calcium influx in a subset of cells expressing the irritant receptor TRPA1, demonstrating that TSLP could act directly on the nervous system. Finally, the authors found that TSLP induction in keratinocytes was dependent on nuclear translocation of the nuclear factor of activated T cells transcription factor, which could be suppressed by the calcineurin inhibitor cyclosporine.
CONCLUSIONS.
TSLP acts directly on cutaneous sensory neurons to cause the itching associated with AD.
REVIEWER COMMENTS.
The incessant pruritus associated with AD is an important cause of morbidity and decreased quality of life. It is generally thought that AD-associated itching is primarily due to “pruritogens” released by TSLP-stimulated immune cells present in eczematous lesions. However, this study uncovers a novel pathway by which epithelial-derived TSLP can act directly on a subset of sensory neurons involved with the transmission of itch and pain signals. Because TSLP-responsive neurons also innervate the lung and gut, it is possible that the pathogenesis of asthma and food allergy may also involve epithelial–neuronal crosstalk. Finally, this study provides insight into the antipruritic mechanisms of cyclosporine, an agent often prescribed for the treatment of inflammatory skin disorders. Identifying other pharmaceuticals that target the epithelial–neuronal axis could lead to new and effective treatments for allergic disease.