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

  • Mol Pain. 2026 Jan-Dec:22:17448069251410452. doi: 10.1177/17448069251410452.
Limin Fan  1  2 ,  Xiuyu Nong  1 ,  Manting Ni  1  3 ,  Xi Chen  1 ,  Liping Zeng  1 ,  Huifang Chen  1 ,  Jian Wang  4  5 ,  Xuan Ouyang  4 ,  Ailin Tao  1 ,  Xueting Liu  1
Affiliations
  • 1. The Second Affiliated Hospital, The State Key Laboratory of Respiratory Disease, Guangdong Provincial Key Laboratory of Allergy & Clinical Immunology, GMU-GIBH Joint School of Life Sciences of Guangzhou Medical University, Guangzhou Medical University, Guangzhou, China.
  • 2. Dermatology Hospital, Southern Medical University, Guangzhou, China.
  • 3. The Third Affiliated Hospital of Southern Medical University, Guangzhou, China.
  • 4. State Key Laboratory of Respiratory Diseases, National Center for Respiratory Medicine, Guangdong Key Laboratory of Vascular Diseases, National Clinical Research Center for Respiratory Diseases, Guangzhou Institute of Respiratory Health, the First Affiliated Hospital of Guangzhou Medical University, Guangzhou, China.
  • 5. Guangzhou National Laboratory, Guangzhou, China.
PMID: 41378780 DOI: 10.1177/17448069251410452
Abstract

Although 5-hydroxytryptamine (5-HT) contributes to pruritus associated with allergic contact dermatitis (ACD), the role of 5-HT derived from mast cells (MC) in chronic pruritus induced by squaric acid dibutyl ester (SADBE), and the expression and distribution of 5-HT2A receptor (HTR2A) in sensory neurons remain unclear. In this study, a SADBE-induced ACD mouse model was established to evaluate pruritus behavior, MC activation, and 5-HTproduction. The mechanism was verified through pharmacological intervention (MC stabilizer cromolyn, HTR2A antagonist Ketanserin) and FcεRIα-KO mice. It was found that SADBE triggered time-dependent MC recruitment (peaking at Day 14-21) and Mc-derived 5-HT release, which were associated with persistent pruritus. The intervention of MC stabilizer cromolyn and FcεRIα-KO mice confirmed MC/IgE-dependent 5-HT release, and inhibiting MC degranulation could reduce pruritus. Single-cell RNA Sequencing and RNAscope in situ hybridization techniques revealed that HTR2A was mainly expressed in the NF3/PEP2/NP3 subsets of DRG neurons. The co-expression level of HTR2A and Nppb was relatively high, partially overlapping with TRPV1/TRPA1. HTR2A antagonists can relieve SADBE-induced pruritus. In conclusion, we have determined that the MC-5-HT-HTR2A axis is involved in chronic pruritus in SADBE-induced ACD, and targeting this axis provides a very promising therapeutic strategy.

Keywords
5-HT; HTR2A; Itch; allergic contact dermatitis; dorsal root ganglion; mast cells.
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