Abstract
Objectives In Crohn's disease (CD), the mechanisms underlying the regulation by granulocyte-macrophage colony-stimulating factor (GM-CSF) of mucosal barrier function in the ileum are unclear. We analyzed the molecular mechanisms underlying the regulation by GM-CSF of the mucosal barrier function. Methods We examined the role of GM-CSF in the intestinal barrier function in CD at the molecular-, cellular-, and animal-model levels. Results Macrophages directly secreted GM-CSF, promoting intestinal epithelial proliferation and inhibiting apoptosis, which maintained intestinal barrier function. Macrophages were absent in NSAID-induced ileitis, causing GM-CSF deficiency, increasing the apoptosis rate, decreasing the proliferation rate, increasing inter- and paracellular permeabilities, decreasing the TJP levels, and reducing the numbers of mesenteric lymph nodes, memory T cells, and regulatory T cells in Csf1op/op transgenic mice. Conclusions GM-CSF is required for the maintenance of intestinal barrier function. Macrophages directly secrete GM-CSF, promoting intestinal epithelial proliferation and inhibiting apoptosis.
Highlights
Crohn’s disease (CD) is a chronic, recurrent, insidious, and nonspecific transmural inflammation of the digestive tract
We reported that NSAIDassociated intestinal barrier dysfunction may be correlated with granulocyte-macrophage colony-stimulating factor (GM-CSF) autoantibodies, thereby promoting the activation of T cells and development of localized ileal CD [9, 10]
The effects of macrophage deficiency on the apoptosis and proliferation of intestinal epithelial cells in Csf1op/op transgenic mice were determined by terminal deoxynucleotidyl transferase dUTP nick-end labeling (TUNEL) assay and Ki67 staining
Summary
Crohn’s disease (CD) is a chronic, recurrent, insidious, and nonspecific transmural inflammation of the digestive tract. Its symptoms include digestive tract obstruction, perforation, abdominal abscess, fistula, and hemorrhage. Prolonged CD may cause psychiatric symptoms such as anxiety or depression, as well as localized malignancy. CD is a lifelong disease caused by interactions between genetic and environmental factors [1, 2]. The etiology and pathogenesis of CD are unclear. More than 70 genes and loci are related to the occurrence and development of CD according to genome-wide association studies. NOD2/CARD15 was the first CD susceptibility gene to be discovered by genome-wide association studies. Functional deletion of CARD15 increases the susceptibility to CD [3, 4], the explicit rate is low.
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