Dovrolis Nikolas, Valatas Vassilis, Drygiannakis Ioannis, Filidou Eirini, Spathakis Michail, Kandilogiannakis Leonidas, Tarapatzi Gesthimani, Arvanitidis Konstantinos, Bamias Giorgos, Vradelis Stergios, Manolopoulos Vangelis G, Paspaliaris Vasilis, Kolios George
Laboratory of Pharmacology, Department of Medicine, Democritus University of Thrace, 68100 Alexandroupolis, Greece.
Individualised Medicine & Pharmacological Research Solutions Center (IMPReS), 68100 Alexandroupolis, Greece.
Biomedicines. 2024 Jul 26;12(8):1674. doi: 10.3390/biomedicines12081674.
Monocyte recruitment in the lamina propria and inflammatory phenotype driven by the mucosal microenvironment is critical for the pathogenesis of inflammatory bowel disease. However, the stimuli responsible remain largely unknown. Recent works have focused on stromal cells, the main steady-state cellular component in tissue, as they produce pro-inflammatory chemokines that contribute to the treatment-resistant nature of IBD.
We studied the regulation of these processes by examining the communication patterns between stromal and myeloid cells in ileal Crohn's disease (CD) using a complete single-cell whole tissue sequencing analysis pipeline and in vitro experimentation in mesenchymal cells.
We report expansion of S4 stromal cells and monocyte-like inflammatory macrophages in the inflamed mucosa and describe interactions that may establish sustained local inflammation. These include expression of CCL2 by S1 fibroblasts to recruit and retain monocytes and macrophages in the mucosa, where they receive signals for proliferation, survival, and differentiation to inflammatory macrophages from S4 stromal cells through molecules such as MIF, IFNγ, and FN1. The overexpression of CCL2 in ileal CD and its stromal origin was further demonstrated in vitro by cultured mesenchymal cells and intestinal organoids in the context of an inflammatory milieu.
Our findings outline an extensive cross-talk between stromal and myeloid cells, which may contribute to the onset and progression of inflammation in ileal Crohn's disease. Understanding the mechanisms underlying monocyte recruitment and polarization, as well as the role of stromal cells in sustaining inflammation, can provide new avenues for developing targeted therapies to treat IBD.
固有层中的单核细胞募集以及由黏膜微环境驱动的炎症表型对于炎症性肠病的发病机制至关重要。然而，引发这些反应的刺激因素在很大程度上仍不清楚。近期的研究聚焦于基质细胞，它是组织中主要的稳态细胞成分，因为它们会产生促炎趋化因子，这促成了炎症性肠病难治的特性。
我们通过使用完整的单细胞全组织测序分析流程研究回肠克罗恩病（CD）中基质细胞与髓样细胞之间的通讯模式，并在间充质细胞中进行体外实验，来探究这些过程的调控机制。
我们报告了在炎症黏膜中S4基质细胞和单核细胞样炎性巨噬细胞的扩增，并描述了可能导致持续性局部炎症的相互作用。这些相互作用包括S1成纤维细胞表达CCL2以在黏膜中募集和保留单核细胞和巨噬细胞，在黏膜中它们通过MIF、IFNγ和FN1等分子从S4基质细胞接收增殖、存活和分化为炎性巨噬细胞的信号。在炎性环境中，培养的间充质细胞和肠类器官在体外进一步证实了回肠CD中CCL2的过表达及其基质来源。
我们的研究结果概述了基质细胞与髓样细胞之间广泛的相互作用，这可能促成回肠克罗恩病炎症的发生和进展。了解单核细胞募集和极化的潜在机制，以及基质细胞在维持炎症中的作用，可为开发治疗炎症性肠病的靶向疗法提供新途径。
