Gastroenterology
Abstract
Pancreatic fibrosis is a complication of chronic pancreatitis and is a prominent feature of pancreatic cancer. Pancreatic fibrosis is commonly observed in patients with prolonged pancreatic duct obstruction, which elevates intrapancreatic pressure. We show here that increased pancreatic duct pressure causes fibrosis and describes the mechanism by which pressure increases deposition of extracellular matrix proteins and fibrosis. We found that pancreatic stellate cells (PSCs), the source of the extracellular matrix proteins in fibrosis, express the mechanically activated ion channel Piezo1. By increasing intracellular calcium, mechanical stress or the Piezo1 agonist Yoda1-activated PSCs manifest by loss of perinuclear fat droplets and increased TGF-β1, fibronectin, and type I collagen expression. These effects were blocked by the Piezo1 inhibitor GsMTx4 and absent in PSCs from mice with conditional genetic deletion of Piezo1 in stellate cells, as was pancreatic duct ligation–induced fibrosis. Although TRPV4 has been proposed to have direct mechanosensing properties, we discovered that PSCs from Trpv4-KO mice were protected against Yoda1-triggered activation. Moreover, mice devoid of TRPV4 were protected from pancreatic duct ligation–induced fibrosis. Thus, high pressure within the pancreas stimulates Piezo1 channel opening, and subsequent activation of TRPV4 leads to stellate cell activation and pressure-induced chronic pancreatitis and fibrosis.
Authors
Sandip M. Swain, Joelle M-J Romac, Steven R. Vigna, Rodger A. Liddle
Abstract
Inflammatory bowel disease (IBD) is a chronic illness characterized by dysregulated immune cascades in the intestines, in which the Th17 immune response plays an important role. We demonstrated that mice with intestinal epithelium–specific deletion of Krüppel-like factor 5 (Klf5) developed Th17-dependent colonic inflammation. In the absence of KLF5, there was aberrant cellular localization of phosphorylated STAT3, an essential mediator of the Th17-associated cytokine, IL-22, which is required for epithelial tissue regeneration. In contrast, mitigation of IL-17A with anti–IL-17A neutralizing antibody attenuated colitis in Klf5-deficient mice. There was also a considerable shift in the colonic microbiota of Klf5-deficient mice that phenocopied human IBD. Notably, the inflammatory response due to Klf5 deletion was alleviated by antibiotic treatment, implicating the role of microbiota in pathogenesis. Finally, human colitic tissues had reduced KLF5 levels when compared with healthy tissues. Together, these findings demonstrated the importance of KLF5 in protecting the intestinal epithelium against Th17-mediated immune and inflammatory responses. The mice described herein may serve as a potential model for human IBD.
Authors
Jason Shieh, Timothy H. Chu, Yang Liu, Julie Kim, Ainara Ruiz de Sabando, Soma Kobayashi, Sui Y. Zee, Brian S. Sheridan, Agnieszka B. Bialkowska, Vincent W. Yang
Abstract
Mucosal healing is a key treatment goal for inflammatory bowel disease, and adequate epithelial regeneration is required for an intact gut epithelium. However, the underlying mechanism is unclear. Long non-coding RNAs (lncRNAs) have been reported to be involved in the development of inflammatory bowel disease. Here, we report that a lncRNA named Gm31629, decreases in intestinal epithelial cells in response to inflammatory stimulation. Gm31629 deficiency leads to exacerbated intestinal inflammation and delayed epithelial regeneration in dextran sulfate sodium (DSS) -induced colitis model. Mechanistically, Gm31629 promotes E2F pathways and cell proliferation by stabilizing Y-box protein 1 (YB-1), thus facilitating epithelial regeneration. Genetic overexpression of Gm31629 protects against DSS-induced colitis in vivo. Theaflavin 3-gallate, a natural compound mimicking Gm31629, alleviates DSS-induced epithelial inflammation and mucosal damage. These results demonstrate an essential role of lncRNA Gm31629 in linking intestinal inflammation and epithelial cell proliferation, providing a potential therapeutic approach to inflammatory bowel disease.
Authors
Xu Feng, Ye Xiao, Jian He, Mi Yang, Qi Guo, Tian Su, Yan Huang, Jun Yi, Chang-Jun Li, Xiang-Hang Luo, Xiao-Wei Liu, Hai-Yan Zhou
Abstract
Cells recognize both foreign and host-derived double-stranded RNA (dsRNA) via a signaling pathway that is usually studied in the context of viral infection. It has become increasingly clear that the sensing and handling of endogenous dsRNA is also critical for cellular differentiation and development. The adenosine RNA deaminase, ADAR1, has been implicated as a central regulator of the dsRNA response, but how regulation of the dsRNA response might mediate cell fate during injury and whether such signaling is cell intrinsic remain unclear. Here, we show that the ADAR1-mediated response to dsRNA was dramatically induced in 2 distinct injury models of gastric metaplasia. Mouse organoid and in vivo genetic models showed that ADAR1 coordinated a cell-intrinsic, epithelium-autonomous, and interferon signaling–independent dsRNA response. In addition, dsRNA accumulated within a differentiated epithelial population (chief cells) in mouse and human stomachs as these cells reprogrammed to a proliferative, reparative (metaplastic) state. Finally, chief cells required ADAR1 to reenter the cell cycle during metaplasia. Thus, cell-intrinsic ADAR1 signaling is critical for the induction of metaplasia. Because metaplasia increases cancer risk, these findings support roles for ADAR1 and the response to dsRNA in oncogenesis.
Authors
José B. Sáenz, Nancy Vargas, Charles J. Cho, Jason C. Mills
Abstract
Sustained proliferative signaling and resisting cell death are hallmarks of cancer. Zinc finger protein 277 (ZNF277; murine Zfp277), a transcription factor regulating cellular senescence, is overexpressed in colon cancer but its actions in intestinal homeostasis and neoplasia are unclear. Using human and murine intestine, human colon cancer cells, and ApcMin/+ mice with dysregulated β-catenin signaling and exuberant intestinal neoplasia, we explored the actions of ZNF/Zfp277 and defined the underlying mechanisms. In normal human and murine intestine, ZNF/Zfp277 was expressed uniquely in early stem cell progenitors, undifferentiated transit-amplifying cells (TACs). Zfp277 was overexpressed in the ApcMin/+ mouse colon, implicating ZNF/Zfp277 as a transcriptional target of β-catenin signaling. We confirmed this by showing β-catenin knockdown reduced ZNF277 expression and, using chromatin immunoprecipitation, identified two β-catenin binding sites in the ZNF277 promoter. Zfp277 deficiency attenuated intestinal epithelial cell proliferation and tumor formation, and strikingly prolonged ApcMin/+ mouse survival. RNA-Seq and PCR analyses revealed Zfp277 modulates expression of genes in key cancer pathways including β-catenin signaling, the HOXD family that regulates development, and p21WAF1, a cell cycle inhibitor and tumor suppressor. In both human colon cancer cells and the murine colon, ZNF/Zfp277 deficiency induced p21WAF1 expression and promoted senescence. Our findings identify ZNF/Zfp277 as both a TAC marker and colon cancer oncogene that regulates cellular proliferation and senescence, in part by repressing p21WAF1 expression.
Authors
Guofeng Xie, Zhongsheng Peng, Jinqing Liang, Shannon M. Larabee, Cinthia B. Drachenberg, Harris Yfantis, Jean-Pierre Raufman
Abstract
Maternal obesity affects nearly one-third of pregnancies and is a major risk factor for nonalcoholic fatty liver disease (NAFLD) in adolescent offspring, yet the mechanisms behind NAFLD remain poorly understood. Here, we demonstrate that nonhuman primate fetuses exposed to maternal Western-style diet (WSD) displayed increased fibrillar collagen deposition in the liver periportal region, with increased ACTA2 and TIMP1 staining, indicating localized hepatic stellate cell (HSC) and myofibroblast activation. This collagen deposition pattern persisted in 1-year-old offspring, despite weaning to a control diet (CD). Maternal WSD exposure increased the frequency of DCs and reduced memory CD4+ T cells in fetal liver without affecting systemic or hepatic inflammatory cytokines. Switching obese dams from WSD to CD before conception or supplementation of the WSD with resveratrol decreased fetal hepatic collagen deposition and reduced markers of portal triad fibrosis, oxidative stress, and fetal hypoxemia. These results demonstrate that HSCs and myofibroblasts are sensitive to maternal WSD-associated oxidative stress in the fetal liver, which is accompanied by increased periportal collagen deposition, indicative of early fibrogenesis beginning in utero. Alleviating maternal WSD-driven oxidative stress in the fetal liver holds promise for halting steatosis and fibrosis and preventing developmental programming of NAFLD.
Authors
Michael J. Nash, Evgenia Dobrinskikh, Sean A. Newsom, Ilhem Messaoudi, Rachel C. Janssen, Kjersti M. Aagaard, Carrie E. McCurdy, Maureen Gannon, Paul Kievit, Jacob E. Friedman, Stephanie R. Wesolowski
Abstract
Colorectal cancer (CRC) very severely threatens human health and lifespan. Effective therapeutic strategy has not been established because of without clearly knowing its pathogenesis. Here we report that ceramide and SOAT1 have the roles on both spontaneous and chemical-induced intestine cancers. It was first found by us that miR-148a deficiency dramatically increased mouse gut dysbiosis through upregulating Cers5 expression, which promoted ceramide synthesis afterward. The newly generated ceramide further promoted both AOM/DSS-induced and ApcMin/+ spontaneous intestine tumorigenesis via increasing mouse gut dysbiosis. Meanwhile, increased level of ceramide correlated with the significant enhancements on both β-catenin activity and colorectal tumorigenesis in a fashion of TLR4-dependent. Next, it was found that a direct binding of β-catenin to SOAT1 promoter to activate transcriptional expression of SOAT1, which further induced cholesterol esterification and colorectal tumorigenesis. In human patients of CRC, the same CERS5-TLR4-β-catenin-SOAT1 axis was also found with dysregulation. Finally, the SOAT1 inhibitor (Avasimibe) showed the significant levels of therapeutic effects on both AOM/DSS-induced and ApcMin/+ spontaneous intestine cancer. Our study clarified that ceramide promoted CRC development through increasing gut dysbiosis, further resulting in the increase of cholesterol esterification in a special way of SOAT1-dependent. The treatment through Avasimibe to specifically decrease cholesterol esterification could be considered as a clinical strategy for effective CRC therapy in future study.
Authors
Yahui Zhu, Li Gu, Xi Lin, Jinmiao Zhang, Yi Tang, Xinyi Zhou, Bingjun Lu, Xingrong Lin, Cheng Liu, Edward V. Prochownik, Youjun Li
Abstract
Despite decades of research there is no specific therapy for Acute Pancreatitis (AP). In the current study, we have evaluated the efficacy of pirfenidone, an anti-inflammatory and anti-fibrotic agent which is FDA-approved for treatment of idiopathic pulmonary fibrosis (IPF), in ameliorating local and systemic injury in AP. Our results suggest that treatment with pirfenidone in therapeutic settings (i.e. after initiation of injury), even when administered at the peak of injury, reduces severity of local and systemic injury and inflammation in multiple models of AP. In-vitro evaluation suggests that pirfenidone decreases cytokine release from acini and macrophages and disrupts acinar-macrophage crosstalk. Therapeutic pirfenidone treatment increases IL-10 secretion from macrophages preceding changes in histology and modulates the immune phenotype of inflammatory cells with decreased levels of inflammatory cytokines. Antibody-mediated IL-10 depletion, use of IL-10 Knock Out mice, and macrophage depletion experiments confirmed the role of IL-10 and macrophages in its mechanism of action, as pirfenidone was unable to reduce severity of AP in these scenarios. Since pirfenidone is FDA approved for IPF, a trial evaluating the efficacy of pirfenidone in patients with moderate to severe AP can be initiated expeditiously. Key Words: Acute Pancreatitis, Pirfenidone, Interleukin-10, L-arginine pancreatitis, Systemic inflammation, lung injury
Authors
Ejas Palathingal Bava, John George, Mohammad Tarique, Srikanth Iyer, Preeti Sahay, Beatriz Gomez Aguilar, Dujon B. Edwards, Bhuwan Giri, Vrishketan Sethi, Tejeshwar Jain, Prateek Sharma, Utpreksha Vaish, Harrys K. C. Jacob, Anthony Ferrantella, Craig L. Maynard, Ashok K. Saluja, Rajinder K. Dawra, Vikas Dudeja
Abstract
Colorectal cancers (CRCs) exhibit differences in incidence, pathogenesis, molecular pathways and outcome depending on the location of the tumor. The transcriptomes of 27,927 single human CRC cells, from three left-sided and three right-sided CRC patients were profiled by scRNA-seq. Right-sided CRC harbors a significant proportion of exhausted CD8 T cells of a highly migratory nature. One cluster of cells from left-sided CRC exhibiting states preceding exhaustion and a high ratio of “pre-exhausted” to exhausted T cells were favorable prognostic markers. Notably, we identified a novel RBP4+ NTS+ subpopulation of cancer cells that exclusively expands in left-sided CRC. Tregs from left-sided CRC showed higher levels of immunotherapy-related genes than those from right-sided CRC, indicating that left-sided CRC may have increased responsiveness to immunotherapy. Antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC) induced by M2-like macrophages were more pronounced in left-sided CRC and correlated with a good prognosis in CRC.
Authors
Wei Guo, Cuiyu Zhang, Xia Wang, Dandan Dou, Dawei Chen, Jingxin Li
Abstract
Synthetic immunosuppressive glucocorticoids (GCs) are widely used to control inflammatory bowel disease (IBD). However, the impact of GC signaling on intestinal tumorigenesis remains controversial. Here, we report that intestinal epithelial glucocorticoid receptor (GR), but not whole intestinal tissue GR, promotes chronic intestinal inflammation-associated colorectal cancer in both humans and mice. In colorectal cancer patients, GR is enriched in intestinal epithelial cells and high epithelial GR is associated with poor prognosis. Consistently, intestinal epithelium-specific deletion of GR (GR iKO) in mice increases macrophage infiltration, improves tissue recovery, and enhances anti-tumor response in a chronic inflammation-associated colorectal cancer model. Consequently, GR iKO mice develop fewer and less advanced tumors than control mice. Furthermore, oral GC administration in the early-phase of tissue injury delays recovery and accelerates the formation of aggressive colorectal cancers. Our study reveals that intestinal epithelial GR signaling represses acute colitis but promotes chronic inflammation-associated colorectal cancer, and suggests that colorectal epithelial GR could serve as a predictive marker for colorectal cancer risk and prognosis. Our findings further suggest that although synthetic glucocorticoid treatment for IBD should be used with caution, there is a therapeutic window for glucocorticoid therapy during colorectal cancer development in immunocompetent patients.
Authors
Shuang Tang, Zhan Zhang, Robert H. Oakley, Wenling Li, Weijing He, Xiaojiang Xu, Ming Ji, Qing Xu, Liang Chen, Alicia S. Wellman, Qingguo Li, Leping Li, Jian-Liang Li, Xinxiang Li, John A. Cidlowski, Xiaoling Li
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