Department of Medicine A, University Medicine, University of Greifswald, Greifswald, Germany.
Interfaculty Institute for Genetics and Functional Genomics, University Medicine Greifswald, Greifswald, Germany.
Nat Commun. 2022 Aug 3;13(1):4502. doi: 10.1038/s41467-022-32195-2.
Chronic pancreatitis (CP) is characterized by chronic inflammation and the progressive fibrotic replacement of exocrine and endocrine pancreatic tissue. We identify Treg cells as central regulators of the fibroinflammatory reaction by a selective depletion of FOXP3-positive cells in a transgenic mouse model (DEREG-mice) of experimental CP. In Treg-depleted DEREG-mice, the induction of CP results in a significantly increased stroma deposition, the development of exocrine insufficiency and significant weight loss starting from day 14 after disease onset. In CP, FOXP3CD25 Treg cells suppress the type-2 immune response by a repression of GATA3 T helper cells (Th2), GATA3 innate lymphoid cells type 2 (ILC2) and CD206 M2-macrophages. A suspected pathomechanism behind the fibrotic tissue replacement may involve an observed dysbalance of Activin A expression in macrophages and of its counter regulator follistatin. Our study identified Treg cells as key regulators of the type-2 immune response and of organ remodeling during CP. The Treg/Th2 axis could be a therapeutic target to prevent fibrosis and preserve functional pancreatic tissue.
慢性胰腺炎（CP）的特征是慢性炎症和外分泌和内分泌胰腺组织的进行性纤维替代。我们通过在实验性 CP 的转基因小鼠模型（DEREG 小鼠）中选择性耗尽 FOXP3 阳性细胞，将 Treg 细胞鉴定为纤维炎症反应的中心调节剂。在 Treg 耗尽的 DEREG 小鼠中，CP 的诱导导致基质沉积明显增加，从疾病发作后第 14 天开始出现外分泌不足和明显体重减轻。在 CP 中，FOXP3CD25 Treg 细胞通过抑制 GATA3 T 辅助细胞（Th2）、GATA3 先天淋巴样细胞 2（ILC2）和 CD206 M2-巨噬细胞来抑制 2 型免疫反应。巨噬细胞中激活素 A 表达及其拮抗因子 follistatin 的观察到的失衡可能涉及纤维化组织替代的可疑发病机制。我们的研究鉴定了 Treg 细胞作为 CP 期间 2 型免疫反应和器官重塑的关键调节剂。Treg/Th2 轴可能是预防纤维化和保留功能性胰腺组织的治疗靶点。
