Journal Club 26.08.14

Platelets Orchestrate a Neuroimmune Axis Driving Cutaneous Inflammation and Itch

Ximin Hu1,2,3, Fujun Wang1,4, Ting Wang2, Yifei Liu2, Lei Zhang2,
Libei Liu2,3, Liang Cao5, Shaofeng Pu6, Ronghua Yang1, and Jing Feng2,7*
1Department of Burn and Plastic Surgery, School of Medicine, the Second Affiliated Hospital of South
China University of Technology (Guangzhou First People’s Hospital), Guangzhou 510180, China. 2State
Key Laboratory of Chemical Biology, Shanghai Institute of Materia Medica, Shanghai 200000, China.
3Department of Dermatology, Xiangya Hospital, Central South University, Changsha, Hunan 410000,
China. 4School of Basic Medicine, Qiqihar Medical University, Qiqihar, Heilongjiang 161006, China.
5Department of Chinese Medicine, The Second Affiliated Hospital of Air Force Medical University, Xi’an,
Shaanxi 710038, China. 6Department of Pain Management, Shanghai Jiao Tong University Affiliated
Sixth People’s Hospital, 200000, Shanghai, China. 7University of Chinese Academy of Sciences, Beijing
100000, China.
*Address correspondence to: shaofpu@sjtu.edu.cn (S.P.); eyyangronghua@scut.edu.cn (R.Y.); fengjing@
simm.ac.cn (J.F.)

Platelets are traditionally recognized for their roles in hemostasis, but their involvement as active immune
modulators in cutaneous neuroimmune signaling remains poorly understood. In this study, we integrated
multi-modal genetic and pharmacological strategies to investigate the functional contribution of platelets
to skin inflammation and chronic itch. Optogenetic activation of platelets was sufficient to elicit localized
skin inflammation, erythema, and robust pruritus, with transcriptomic profiling of lesions showing strong
concordance with the clinical signatures of atopic dermatitis (AD). In experimental AD models, platelet
depletion markedly reduced scratching behavior, inflammatory cell infiltration, and C-fiber excitability,
whereas platelet activation exacerbated these phenotypes. Mechanistically, activated platelets release
serotonin [5-hydroxytryptamine (5-HT)], which compromises vascular integrity and facilitates platelet
extravasation into the dermis. This “neuroimmune hub” promotes macrophage recruitment and sensitizes
TRPV1+ pruriceptors. Transcriptomic analysis revealed that platelet-derived 5-HT drives these processes
via HTR2B and HTR7 signaling. Specifically, genetic ablation of HTR2B in TRPV1+ neurons selectively
impaired itch transmission. Furthermore, re-analysis of clinical datasets confirmed the enrichment of
HTR2B and HTR7 in skin macrophage populations during inflammation. Systemic administration of
HTR antagonists or the anti-platelet agent clopidogrel markedly attenuated both inflammation and
pruritus across multiple models. Our findings identify the platelet–immune–neuron axis as a key driver
of cutaneous dysfunction and a promising therapeutic target for chronic inflammatory skin disorders.