Rong Hua, Yang Hai, Liu Qingqing, Zhang Hui, Wang Shaolin
Department of Ophthalmology, Shanghai Jiangong Hospital, Shanghai, China.
Department of Ophthalmology, Shanghai East Hospital Affiliated to Tongji University, Shanghai, China.
Scand J Immunol. 2025 Jan;101(1):e13434. 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.
干眼症（DED）是一种炎症性疾病，其中CD4 T细胞在其发病机制中起重要作用。一种称为产生粒细胞-巨噬细胞集落刺激因子的辅助性T细胞（ThGM细胞）的CD4 T细胞亚群会促成DED的发病机制。然而，ThGM细胞活性被调节的机制尚未完全了解。在本研究中，我们在小鼠DED模型中表征了神经激肽1受体（NK1R）和神经激肽2受体（NK2R）对ThGM细胞和辅助性T细胞1（Th1细胞）的影响。我们发现ThGM细胞表达NK1R和NK2R，而Th1细胞主要表达NK1R。此外，NK1R和NK2R的配体P物质和神经激肽A（NKA）在DED后的淋巴结和结膜中上调。P物质显著促进粒细胞-巨噬细胞集落刺激因子（GM-CSF）的表达，同时轻度上调ThGM细胞中干扰素-γ（IFN-γ）和白细胞介素2（IL-2）的表达。相比之下，NKA没有改变GM-CSF的表达，但显著增加了ThGM细胞中IFN-γ的表达。重要的是，表达NK1R的ThGM细胞的过继转移显著加剧了DED，而NK1R敲低的ThGM细胞的转移则轻度加重了DED。ThGM细胞中NK2R的敲低不影响DED的进展。总之，本研究确定P物质-NK1R轴是一种加强ThGM细胞在DED中致病性的新机制。
