Nantes Université, CHU Nantes, Inserm, TENS, The Enteric Nervous System in Gut and Brain Diseases, IMAD, Nantes, France.
Institute for Health and Sport, Victoria University, Melbourne, VIC, Australia.
Cell Mol Gastroenterol Hepatol. 2024;18(1):133-153. doi: 10.1016/j.jcmgh.2024.02.016. Epub 2024 Feb 29.
BACKGROUND & AIMS: The presence of myenteric plexitis in the proximal resection margins is a predictive factor of early postoperative recurrence in Crohn's disease. To decipher the mechanisms leading to their formation, T-cell interactions with enteric neural cells were studied in vitro and in vivo.
T cells close to myenteric neural cells were retrospectively quantified in ileocolonic resections from 9 control subjects with cancer and 20 patients with Crohn's disease. The mechanisms involved in T-cell adhesion were then investigated in co-cultures of T lymphocytes with enteric glial cells (glia). Finally, the implication of adhesion molecules in the development of plexitis and colitis was studied in vitro but also in vivo in Winnie mice.
The mean number of T cells close to glia, but not neurons, was significantly higher in the myenteric ganglia of relapsing patients with Crohn's disease (2.42 ± 0.5) as compared with controls (0.36 ± 0.08, P = .0007). Co-culture experiments showed that exposure to proinflammatory cytokines enhanced T-cell adhesion to glia and increased intercellular adhesion molecule-1 (ICAM-1) expression in glia. We next demonstrated that T-cell adhesion to glia was inhibited by an anti-ICAM-1 antibody. Finally, using the Winnie mouse model of colitis, we showed that the blockage of ICAM-1/lymphocyte function-associated antigen-1 (LFA-1) with lifitegrast reduced colitis severity and decreased T-cell infiltration in the myenteric plexus.
Our present work argues for a role of glia-T-cell interaction in the development of myenteric plexitis through the adhesion molecules ICAM-1/LFA-1 and suggests that deciphering the functional consequences of glia-T-cell interaction is important to understand the mechanisms implicated in the development and recurrence of Crohn's disease.
在克罗恩病患者的近端切除边缘存在肌间神经丛炎是术后早期复发的预测因素。为了解释其形成的机制，我们研究了 T 细胞与肠神经细胞的体外和体内相互作用。
回顾性分析了 9 例癌症患者和 20 例克罗恩病患者的回肠结肠切除标本，定量分析了靠近肌间神经细胞的 T 细胞。然后，在 T 淋巴细胞与肠神经胶质细胞（胶质细胞）的共培养中研究了 T 细胞黏附的机制。最后，在体外和 Winnie 小鼠体内研究了黏附分子在神经丛炎和结肠炎发展中的作用。
与对照组（0.36 ± 0.08，P =.0007）相比，复发克罗恩病患者的肌间神经节中靠近胶质细胞而不是神经元的 T 细胞数量明显更高（2.42 ± 0.5）。共培养实验表明，促炎细胞因子的暴露增强了 T 细胞与胶质细胞的黏附，并增加了胶质细胞中细胞间黏附分子-1（ICAM-1）的表达。接下来，我们证明 T 细胞与胶质细胞的黏附可被抗 ICAM-1 抗体抑制。最后，使用 Winnie 结肠炎小鼠模型，我们发现用 lifitegrast 阻断 ICAM-1/淋巴细胞功能相关抗原-1（LFA-1）可减轻结肠炎的严重程度并减少肌间神经丛中的 T 细胞浸润。
我们目前的工作认为，通过黏附分子 ICAM-1/LFA-1，胶质细胞与 T 细胞的相互作用在肌间神经丛炎的发展中起作用，并表明阐明胶质细胞与 T 细胞相互作用的功能后果对于理解克罗恩病发展和复发所涉及的机制很重要。
