Mast cell-5-HT-HTR2A axis involvement in chronic itch induced by SADBE

Area of Science:

• Immunology
• Neuroscience
• Dermatology

Background:

• 5-hydroxytryptamine (5-HT) is implicated in allergic contact dermatitis (ACD) pruritus.
• The specific roles of mast cell (MC)-derived 5-HT and 5-HT2A receptor (HTR2A) expression in sensory neurons in chronic pruritus remain unclear.

Purpose of the Study:

• To investigate the involvement of the MC-5-HT-HTR2A axis in chronic pruritus induced by squaric acid dibutyl ester (SADBE) in a mouse model.
• To elucidate the expression and distribution of HTR2A in sensory neurons.

Main Methods:

• Established a SADBE-induced ACD mouse model.
• Evaluated pruritus behavior, MC activation, and 5-HT production.
• Utilized pharmacological interventions (MC stabilizer cromolyn, HTR2A antagonist Ketanserin) and FcεRIα-knockout (KO) mice.
• Employed single-cell RNA sequencing and RNAscope in situ hybridization.

Main Results:

• SADBE induced time-dependent MC recruitment and MC-derived 5-HT release, correlating with persistent pruritus.
• MC/IgE-dependent 5-HT release was confirmed, and inhibiting MC degranulation reduced pruritus.
• HTR2A was predominantly expressed in specific DRG neuron subsets (NF3/PEP2/NP3), with co-expression of Nppb and partial overlap with TRPV1/TRPA1.
• HTR2A antagonists effectively alleviated SADBE-induced pruritus.

Conclusions:

• The MC-5-HT-HTR2A axis plays a significant role in chronic pruritus associated with SADBE-induced ACD.
• Targeting this axis presents a promising therapeutic avenue for managing chronic itch in ACD.