D2.425 - Type 2 neuro-immune signaling is upregulated in Candida albicans-driven itch

Itch is a distressing symptom negatively affecting patients with a range of inflammatory dermatoses. Candida albicans inhabits the skin as a harmless commensal that can trigger cutaneous inflammation via Th17/Il17A axis upon epithelial barrier function impairment. However, the intricate neuro-immune pathways underlying Candida albicans-driven itch remain to be elucidated.

We developed Candida albicans-induced itch mouse model and conducted the assessment of itch behavior with subsequent two-photon microscopy and VSDi (voltage-sensitive dye imaging) analysis to examine morphological and electrophysiological changes of neurons, single-cell transcriptomic analysis of skin, DRG (dorsal root ganglion) and lymph nodes along with whole-mount imaging of skin to explore neuro-immune interactions, ELISA for detection of Candida albicans-specific IgEs, flow cytometry and IF staining of skin to examine immune cell types and cytokines.

Itch-related behavior (p<0.0001) was increased on day 10 under daily epicutaneous application of Candida albicans (10⁵ CFU/mL). Increased nerve fiber thickness and density (p<0.01) along with enhanced responsiveness of DRG cells was observed upon Candida albicans application. Transcriptional markers of type 2 immune receptors were upregulated in itch-specific sensory neurons (NP1, NP2, NP3) while type 2 cytokine signature was upregulated in type 2 immune skin cells (p<0.001) in the experimental group. Moreover, whole-mount imaging showed close spatial proximity between nerve fibers and type 2 immune cells in skin. Additionally, Candida albicans-specific IgE levels were increased on day 10 (p<0.001) in Candida albicans-treated mice accompanied by upregulation of FcεRI in the mast cell population and heavy chain of IgE and IL-4 in lymph nodes.

Therefore, this study attempts to uncover mechanisms underlying Candida albicans-induced itch sensation.