Division of Gastroenterology and Hepatology, Department of Medicine, University of Illinois Chicago, Chicago, Illinois, USA.
UIC Cancer Center, University of Illinois Chicago, Chicago, Illinois, USA.
FASEB J. 2023 Jun;37(6):e22957. doi: 10.1096/fj.202202169RR.
Cross talk between immune cells and the intestinal crypt is critical in maintaining intestinal homeostasis. Recent studies highlight the direct impact of vitamin D receptor (VDR) signaling on intestinal and microbial homeostasis. However, the tissue-specific role of immune VDR signaling is not fully understood. Here, we generated a myeloid-specific VDR knockout (VDR ) mouse model and used a macrophage/enteroids coculture system to examine tissue-specific VDR signaling in intestinal homeostasis. VDR mice exhibited small intestine elongation and impaired Paneth cell in maturation and localization. Coculture of enteroids with VDR macrophages increased the delocalization of Paneth cells. VDR mice exhibited significant changes in the microbiota taxonomic and functional files, and susceptibility to Salmonella infection. Interestingly, loss of myeloid VDR impaired Wnt secretion in macrophages, thus inhibiting crypt β-catenin signaling and disrupting Paneth cell differentiation in the epithelium. Taken together, our data have demonstrated that myeloid cells regulate crypt differentiation and the microbiota in a VDR-dependent mechanism. Dysregulation of myeloid VDR led to high risks of colitis-associated diseases. Our study provided insight into the mechanism of immune/Paneth cell cross talk in regulating intestinal homeostasis.
免疫细胞与肠道隐窝之间的串扰对于维持肠道内稳态至关重要。最近的研究强调了维生素 D 受体 (VDR) 信号对肠道和微生物内稳态的直接影响。然而，免疫细胞 VDR 信号的组织特异性作用尚不完全清楚。在这里，我们构建了髓系特异性 VDR 敲除 (VDR ) 小鼠模型，并使用巨噬细胞/肠类器官共培养系统来研究组织特异性 VDR 信号在肠道内稳态中的作用。VDR 小鼠表现出小肠伸长和潘氏细胞成熟和定位受损。与 VDR 巨噬细胞共培养的肠类器官增加了潘氏细胞的定位缺失。VDR 小鼠的微生物群落分类和功能文件发生了显著变化，并且易感染沙门氏菌。有趣的是，髓系 VDR 的缺失会损害巨噬细胞中 Wnt 的分泌，从而抑制隐窝 β-连环蛋白信号转导并破坏上皮细胞中的潘氏细胞分化。总之，我们的数据表明，髓系细胞以 VDR 依赖的机制调节隐窝分化和微生物群。髓系 VDR 的失调导致结肠炎相关疾病的风险增加。我们的研究为免疫细胞/Paneth 细胞相互作用调节肠道内稳态的机制提供了新的见解。
