Substance P and neurokinin 1 receptor boost the pathogenicity of granulocyte‐macrophage colony‐stimulating factor‐producing T helper cells in dry eye disease

• Published in: Scandinavian journal of immunology Vol. 101; no. 1; pp. e13434 - n/a
• Main Authors: Rong, Hua, Yang, Hai, Liu, Qingqing, Zhang, Hui, Wang, Shaolin
• Format: Journal Article
• Language: English
• Published: England Wiley Subscription Services, Inc 01.01.2025
• Subjects: Adoptive transfer; Animals; CD4 antigen; Cerebrospinal fluid; Conjunctiva - pathology; Disease Progression; dry eye disease; Dry Eye Syndromes - immunology; Dry Eye Syndromes - pathology; Eye diseases; Female; Granulocyte-Macrophage Colony-Stimulating Factor - pharmacology; Granulocytes; Helper cells; inflammation; Inflammatory diseases; Interferon; Interleukin 2; Leukocytes (granulocytic); Lymph Nodes - pathology; Lymphocytes T; Macrophages; Mice, Inbred C57BL; Neurokinin; neurokinin 1 receptor; Neurokinin A; Neurokinin A - metabolism; Neurokinin NK1 receptors; Neurokinin NK2 receptors; Pathogenesis; Pathogenicity; Receptors, Neurokinin-1 - metabolism; Receptors, Neurokinin-2 - metabolism; Substance P; Substance P - metabolism; T cells; T-Lymphocytes, Helper-Inducer - drug effects; T-Lymphocytes, Helper-Inducer - immunology; dry eye disease; T cells; substance P; inflammation; neurokinin 1 receptor
• ISSN: 0300-9475; 1365-3083; 1365-3083
• DOI: 10.1111/sji.13434

Dry eye disease (DED) is an inflammatory disorder in which CD4+ T cells play a significant role in its pathogenesis. A CD4+ T cell subset termed granulocyte‐macrophage colony‐stimulating factor‐producing T helper (ThGM) cells would contribute to DED pathogenesis. However, the mechanisms by which the activity of ThGM cells is modulated are not thoroughly understood. In this research, we characterized the effects of neurokinin 1 receptor (NK1R) and neurokinin 2 receptor (NK2R) on ThGM cells and T helper 1 (Th1) cells in a murine DED model. We found that ThGM cells expressed NK1R and NK2R, whereas Th1 cells predominantly expressed NK1R. Furthermore, substance P and neurokinin A (NKA), the ligands of NK1R and NK2R, were upregulated in post‐DED LNs and conjunctivae. Substance P significantly promoted granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) expression while mildly upregulating the expression of interferon‐gamma (IFN‐γ) and interleukin 2 (IL‐2) in ThGM cells. By contrast, NKA did not change GM‐CSF expression but significantly increased IFN‐γ expression in ThGM cells. Importantly, the adoptive transfer of NK1R‐expressing ThGM cells significantly exacerbated DED, whereas the transfer of NK1R‐knockdown ThGM cells weakly aggravated DED. NK2R knockdown in ThGM cells did not affect DED progression. In conclusion, this study identifies the substance P‐NK1R axis as a novel mechanism that reinforces the pathogenicity of ThGM cells in DED. Substance P (SP) binds to neurokinin 1 receptor (NK1R) to significantly promote granulocyte‐macrophage colony‐stimulating factor (GM‐CSF) expression while mildly upregulating the expression of interferon‐gamma (IFN‐γ) and interleukin 2 (IL‐2) in ThGM cells, and ultimately exacerbate the development of dry eye disease (DED).