Univ. Lille, Institut National de la Santé Et de la Recherche Médicale (Inserm), Centre de Recherche Hospitalier Universitaire (CHU) Lille, Institut Pasteur de Lille, U1019, Lille, France.
Institut national de la santé et de la recherche médicale (INSERM) U1138, Centre de Recherche des Cordeliers, Paris, France.
Front Immunol. 2023 Oct 9;14:1252979. doi: 10.3389/fimmu.2023.1252979. eCollection 2023.
Crohn's disease (CD) is a complex and poorly understood myeloid-mediated disorder. Genetic variants with loss of function in the gene confer an increased susceptibility to ileal CD. While Nod2 in myeloid cells may confer protection against T-cell mediated ileopathy, it remains unclear whether it may promote resolution of the inflamed colon. In this study, we evaluated the function of Nod2 in myeloid cells in a model of acute colitis and colitis-associated colon cancer (CAC).
To ablate Nod2 specifically within the myeloid compartment, we generated mice. The role of NOD2 was studied in a setting of Dextran Sodium Sulfate (DSS)-induced colitis and in azoxymethane (AOM)/DSS model. Clinical parameters were quantified by colonoscopy, histological, flow cytometry, and qRT-PCR analysis.
Upon DSS colitis model, mice lost less weight than control littermates and had less severe damage to the colonic epithelium. In the AOM/DSS model, endoscopic monitoring of tumor progression revealed a lowered number of adenomas within the colon of mice, associated with less expression of . Mechanistically, lysozyme M was required for the improved disease severity in mice with a defect of NOD2 in myeloid cells.
Our results indicate that loss of Nod2 signaling in myeloid cells aids in the tissue repair of the inflamed large intestine through lysozyme secretion by myeloid cells. These results may pave the way to design new therapeutics to limit the inflammatory and tumorigenic functions of NOD2.
克罗恩病（CD）是一种复杂且尚未被充分理解的骨髓介导疾病。基因变异导致基因功能丧失，使回肠 CD 的易感性增加。虽然髓系细胞中的 Nod2 可能对 T 细胞介导的回肠炎具有保护作用，但尚不清楚它是否可能促进发炎结肠的消退。在这项研究中，我们评估了 Nod2 在髓系细胞中在急性结肠炎和结肠炎相关结肠癌（CAC）模型中的功能。
为了特异性地在髓系细胞中缺失 Nod2，我们生成了 小鼠。在葡聚糖硫酸钠（DSS）诱导的结肠炎和氧化偶氮甲烷（AOM）/DSS 模型中研究了 NOD2 的作用。通过结肠镜检查、组织学、流式细胞术和 qRT-PCR 分析来量化临床参数。
在 DSS 结肠炎模型中，与对照同窝仔相比， 小鼠体重减轻较少，结肠上皮损伤较轻。在 AOM/DSS 模型中，对肿瘤进展的内镜监测显示， 小鼠结肠内的腺瘤数量减少，与 基因的表达减少相关。在机制上，溶菌酶 M 是髓系细胞中 NOD2 缺陷小鼠疾病严重程度改善所必需的。
我们的结果表明，髓系细胞中 Nod2 信号的缺失通过髓系细胞中溶菌酶的分泌有助于发炎大肠的组织修复。这些结果可能为设计新的治疗方法以限制 NOD2 的炎症和肿瘤发生功能铺平道路。
