NK-1R deficiency alleviates psoriasis by reducing the inflammatory response of dendritic cells
Authors: Wang Yan , Guo Jianning , Wang Yazhuo , Wang Tianyuan , Zhang Lu , Meng Yujiao , Di Tingting , Li Ping , Zhao Jingxia 
Published: March 2023

BACKGROUND: Abnormal neuroimmune regulation is involved in the occurrence and development of psoriasis. The elevated levels of neurotransmitters in the skin locally promote the activation of immune cells by binding to their corresponding receptors, leading to the inflammation of psoriasis lesions. As an important neurotransmitter receptor, Neurokinin-1 Receptors (NK-1R) can bind to a variety of ligands to intensify the activation of immune cells and maintain the inflammatory response in psoriasis. However, its specific role in psoriasis needs to be further elucidated.
METHODS：Immunohistochemistry was used to detect the expression levels of Substance P (SP) and NK-1R in human skin lesions. Mice with imiquimod (IMQ)-induced psoriasis were treated with NK-1R agonist or inhibitor, and NK-1R knockout (KO) mice were treated with IMQ to establish a psoriatic lesion model. The severity of skin lesions was scored using the Psoriasis Area Severity Index (PASI). The epidermal thickness of the mice was measured by hematoxylin–eosin staining. The levels of SP and NK-1R in the skin lesions were detected by fluorescence immunohistochemistry. The expression of inflammatory factors in the skin lesions and peripheral blood was detected using Luminex assay. Western blotting was used to investigate the expression levels of Akt/PKB (Protein kinase B), p-Akt, Rho family GTPase 3 (RND3), and vascular endothelial growth factor (VEGF). Flow cytometry was used to detect the number of dendritic cells (DCs), macrophages, T lymphocytes, and so on. The expression of CD80, CD86, and (major histocompatibility complex II, MHC II) molecules on CD11c+ DCs in ears, skin lesions, and spleens were also examined by flow cytometry. Bone marrow–derived DCs were cultured from the bone marrow of wild-type (WT) and NK-1R KO mice. Luminex assay was used to detect the cytokines secreted by DCs.
RESULTS: The expression levels of SP and NK-1R increased in human skin lesions. NK-1R agonist aggravated IMQ-induced psoriasis-like skin lesions in mice, while NK-1R inhibitor could alleviate skin lesions. NK-1R KO mice showed alleviated skin lesions, reduced epidermal thickness, decreased expression of proliferating cell nuclear antigen and CD3+, decreased levels of inflammatory cytokines in the skin and peripheral blood, decreased protein expression levels of SP, NK-1R, and p-Akt, RND3, and VEGF in the skin lesions. Further, the expression level of MHC II on CD11c+ DCs in ears decreased in the ears of NK-1R KO mice, the expression levels of CD80 and CD86 on CD11c+ DCs in the skin lesions decreased, and the expression levels of CD80 and MHC II on CD11c+ DCs were decreased in the spleen. The secretion of cytokines IL-1β, IL-12p70, IL-23, and tumor necrosis factor-α decreased in NK-1R KO mice when bone marrow–derived DCs were cultured in vitro.
CONCLUSIONS: NK-1R deficiency alleviated psoriasis by reducing the inflammatory response of DCs, which was also associated with SP/NK-1R/Akt and RND3/VEGF pathways. The results also suggested that NK-1R might be a key molecular target of psoriasis.