Dataset Information

Disruption of Epithelium Integrity by Inflammation-Associated Fibroblasts through Prostaglandin Signaling: IAFs disrupt colon epithelium via PGE2-EP4.

ABSTRACT: Inflammation-associated fibroblasts (IAFs) are associated with the progression and drug resistance of chronic inflammatory diseases such as inflammatory bowel disease (IBD), but their direct impact on epithelial function and architecture is unknown. In this study, we developed an in vitro model whereby human colon fibroblasts are induced to become IAFs by specific cytokines and recapitulate key features of IAFs in vivo. When co-cultured with patient-derived colon organoids (colonoids), IAFs induced rapid colonoid swelling and barrier disruption due to swelling and rupture of individual epithelial cells. Epithelial cells co-cultured with IAFs also exhibit increased DNA damage, mitotic errors, and proliferation arrest. These IAF-induced epithelial defects are mediated through a paracrine pathway involving prostaglandin E2 (PGE2) and the PGE2 receptor EP4, leading to PKA-dependent activation of the CFTR chloride channel. Importantly, EP4-specific chemical inhibitors effectively prevented colonoid swelling and restored normal proliferation and genome stability of IAF-exposed epithelial cells. These findings reveal a mechanism by which IAFs could promote and perpetuate IBD and suggest a potential treatment to mitigate inflammation-associated epithelial injury.

SUBMITTER: Dong Y

PROVIDER: S-EPMC10557697 | biostudies-literature | 2023 Sep

REPOSITORIES: biostudies-literature

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Disruption of Epithelium Integrity by Inflammation-Associated Fibroblasts through Prostaglandin Signaling: IAFs disrupt colon epithelium via PGE2-EP4.

Dong Yi Y Johnson Blake A BA Ruan Linhao L Zeineldin Maged M Liu Albert Z AZ Raychaudhuri Sumana S Chiu Ian I Zhu Jin J Smith Barbara B Zhao Nan N Searson Peter P Watanabe Shigeki S Donowitz Mark M Larman Tatianna C TC Li Rong R

bioRxiv : the preprint server for biology 20230928

Inflammation-associated fibroblasts (IAFs) are associated with the progression and drug resistance of chronic inflammatory diseases such as inflammatory bowel disease (IBD), but their direct impact on epithelial function and architecture is unknown. In this study, we developed an <i>in vitro</i> model whereby human colon fibroblasts are induced to become IAFs by specific cytokines and recapitulate key features of IAFs <i>in vivo</i>. When co-cultured with patient-derived colon organoids (colonoi ...[more]

PMID: 37808771

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Project description:With increasing body weight, macrophages accumulate in adipose tissue. There, activated macrophages secrete numerous proinflammatory cytokines and chemokines, giving rise to chronic inflammation and insulin resistance. Prostaglandin E2 suppresses macrophage activation via EP4; however, the role of EP4 signaling in insulin resistance and type 2 diabetes mellitus remains unknown. In this study, we treated db/db mice with an EP4-selective agonist, ONO-AE1-329, for 4 weeks to explore the role of EP4 signaling in obesity-related inflammation in vivo. Administration of the EP4 agonist did not affect body weight gain or food intake; however, in the EP4 agonist-treated group, glucose tolerance and insulin resistance were significantly improved over that of the vehicle-treated group. Additionally, administration of the EP4 agonist inhibited the accumulation of F4/80-positive macrophages and the formation of crown-like structures in white adipose tissue, and the adipocytes were significantly smaller. The treatment of the EP4 agonist increased the number of anti-inflammatory M2 macrophages, and in the stromal vascular fraction of white adipose tissue, which includes macrophages, it markedly decreased the levels of proinflammatory cytokines and chemokines. Further, EP4 activation increased the expression of adiponectin and peroxidase proliferator-activated receptors in white adipose tissue. Next, we examined in vitro M1/M2 polarization assay to investigate the impact of EP4 signaling on determining the functional phenotypes of macrophages. Treatment with EP4 agonist enhanced M2 polarization in wild-type peritoneal macrophages, whereas EP4-deficient macrophages were less susceptible to M2 polarization. Notably, antagonizing peroxidase proliferator-activated receptor δ activity suppressed EP4 signaling-mediated shift toward M2 macrophage polarization. Thus, our results demonstrate that EP4 signaling plays a critical role in obesity-related adipose tissue inflammation and insulin resistance by regulating macrophage recruitment and polarization. The activation of EP4 signaling holds promise for treating obesity and type 2 diabetes mellitus.

Dataset Information

Disruption of Epithelium Integrity by Inflammation-Associated Fibroblasts through Prostaglandin Signaling: IAFs disrupt colon epithelium via PGE2-EP4.

Publications

Disruption of Epithelium Integrity by Inflammation-Associated Fibroblasts through Prostaglandin Signaling: IAFs disrupt colon epithelium via PGE2-EP4.

Similar Datasets

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