IFN-γ drives inflammatory bowel disease pathogenesis through VE-cadherin–directed vascular barrier disruption

Langer, Victoria; Vivi, Eugenia; Regensburger, Daniela; Winkler, Thomas; Waldner, Maximilian J.; Räth, Timo; Schmid, Benjamin; Skottke, Lisa; Lee, Somin; Jeon, Noo Li; Wohlfahrt, Thomas; Kramer, Viktoria; Tripal, Philipp; Schümann, Michael; Kersting, Stephan; Handtrack, Claudia; Geppert, Carol; Suchowski, Karina; Adams, Ralf H.; Becker, Christoph; Ramming, Andreas; Naschberger, Elisabeth; Britzen-Laurent, Nathalie; Stürzl, Michael

doi:10.1172/jci124884

Cited by 180 publications

(176 citation statements)

References 83 publications

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“…As shown in Figure 3 , YQFM was given in advance to protect the intestinal barrier and reduce the degradation of ZO-1, occludin, and VE-cadherin. Tight junctions and adherens junctions play an important role in maintaining the endothelial barrier, and protecting the endothelial barrier has become a new strategy for treating inflammatory bowel disease [ 39 ]. Connexin protein between endothelial cells (ECs) is the key to maintain endothelial cell function.…”

Section: Discussionmentioning

confidence: 99%

YQFM Alleviates Side Effects Caused by Dasatinib through the ROCK/MLC Pathway in Mice

Liu

Dai

Han

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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Dasatinib, as a second-generation broad-spectrum tyrosine kinase inhibitor, presents an antitumor effect by inhibiting tyrosine kinases. However, dasatinib causes serious side effects, such as gastrointestinal bleeding and liver toxicity, possibly through the activation of ROCK kinase and MLC phosphorylation. At present, there is no effective prevention and treatment method. Previous research studies have shown that YQFM (YiQiFuMai powder injection) protects the blood-brain barrier by inhibiting the ROCK/MLC signaling pathway; whether YQFM can alleviate the side effects of dasatinib is unknown. In this study, dasatinib was injected (i.p. 70 mg/kg) and YQFM (i.p. 0.336 g/kg, 0.672 g/kg, 1.342 g/kg) was given in advance for 3 days to mice, to explore the effect of YQFM on side effects induced by Dasatinib. The results confirmed that YQFM significantly decreased Evans blue leakage in the small intestine and increased intestinal blood flow, increased the expression of ZO-1, Occludin, and VE-cadherin, and reduced the contents of D-lactic acid, s-VE-cadherin, Alanine aminotransferase (ALT), and Aspartate aminotransferase (AST) in serum. Finally, YQFM inhibited the expression of ROCK-1 and phosphorylation of MLC induced by Dasatinib. These findings suggested that YQFM could improve the side effects caused by Dasatinib linked with the ROCK/MLC signaling pathway, as shown in the graphical abstract.

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Section: Discussionmentioning

confidence: 99%

YQFM Alleviates Side Effects Caused by Dasatinib through the ROCK/MLC Pathway in Mice

Liu

Dai

Han

et al. 2020

Evidence-Based Complementary and Alternative Medicine

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“…For further confirmation of the latter, we proceeded with assessment of the functional response of the Colon Intestine-Chip to a well-established barrier disruption cytokine, IFNγ 9 . As has been shown by a number of studies with cell lines and in vivo experimental models, IFNγ modulates the integrity of both the intestinal epithelial 9 and endothelial 49 barrier. The disruption of the epithelial barrier, specifically, is driven by both apoptosis 29 and cytoskeletal remodeling, via upregulation of the MLCK 8, 9 .…”

Section: Discussionmentioning

confidence: 81%

A Micro-engineered Human Colon Intestine-Chip Platform to Study Leaky Barrier

Αποστόλου

Panchakshari

Banerjee

et al. 2020

Preprint

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The intestinal epithelial barrier supports the symbiotic relationship between the microbiota colonizing the intestinal epithelium and the host immune system to maintain homeostasis. Leaky barrier is increasingly recognized as part of the pathogenesis of a number of chronic conditions in addition to inflammatory and infectious diseases. As our understanding on the regulation of the barrier remains limited, effective therapeutic targeting for the compromised barrier is still an unmet need. Here we combined advancements on the organoids and Organ-on-Chip technologies to establish a micro-engineered Colon Intestine-Chip for studying development and regulation of the human intestinal barrier. Our data demonstrate the significance of the endothelium in co-culture with the epithelial cells within a tissue-relevant microenvironment for the establishment of a tight epithelial barrier of polarized cells. Pathway analysis of the RNA sequencing (RNA-Seq), revealed significant upregulation of mechanisms relevant to the maturation of the intestinal epithelium in organoid-derived epithelial cells in co-culture with endothelium as compared to organoids maintained in suspension. We provide evidence that the Colon Intestine-Chip platform responds to interferon gamma (IFNγ), a prototype cytokine utilized to model inflammation-induced barrier disruption, by induction of apoptosis and reorganization of the apical junctional complexes as shown with other systems. We also describe the mechanism of action of interleukin 22 (IL-22) on mature, organoid-derived intestinal epithelial cells that is consistent with barrier disruption. Overall we propose the Colon Intestine-Chip as a promising human organoid-derived platform to decipher mechanisms driving the development of leaky gut in patients and enable their translation for this unmet medical need.

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“…Considering the extensive downstream signalling linked to VE-cadherin and, because miR-27 is also present in normal ECs, disturbing the equilibrium of miR-27a and VE-cadherin expression could lead to increases of VE-cadherin in normal ECs. Although lack of VE-cadherin has been shown to be harmful and has close links with diseases [25,27,78], little evidence suggests that small levels of overexpression of VE-cadherin causes any side effect. In addition, EC junctional molecules, including VE-cadherin, are tightly regulated by many factors, including phosphorylation, dephosphorylation, and association with other proteins [70].…”

Section: Plos Biologymentioning

confidence: 99%

Targeting miR-27a/VE-cadherin interactions rescues cerebral cavernous malformations in mice

Zhao

Choi

et al. 2020

PLoS Biol

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Cerebral cavernous malformations (CCMs) are vascular lesions predominantly developing in the central nervous system (CNS), with no effective treatments other than surgery. Lossof-function mutation in CCM1/krev interaction trapped 1 (KRIT1), CCM2, or CCM3/programmed cell death 10 (PDCD10) causes lesions that are characterized by abnormal vascular integrity. Vascular endothelial cadherin (VE-cadherin), a major regulator of endothelial cell (EC) junctional integrity is strongly disorganized in ECs lining the CCM lesions. We report here that microRNA-27a (miR-27a), a negative regulator of VE-cadherin, is elevated in ECs isolated from mouse brains developing early CCM lesions and in cultured ECs with CCM1 or CCM2 depletion. Furthermore, we show miR-27a acts downstream of kruppel-like factor (KLF)2 and KLF4, two known key transcription factors involved in CCM lesion development. Using CD5-2 (a target site blocker [TSB]) to prevent the miR-27a/VE-cadherin mRNA interaction, we present a potential therapy to increase VE-cadherin expression and thus rescue the abnormal vascular integrity. In CCM1-or CCM2-depleted ECs, CD5-2 reduces monolayer permeability, and in Ccm1 heterozygous mice, it restores dermal vessel barrier function. In a neonatal mouse model of CCM disease, CD5-2 normalizes vasculature and reduces vascular leakage in the lesions, inhibits the development of large lesions, and significantly reduces the size of established lesions in the hindbrain. Furthermore, CD5-2 limits the accumulation of inflammatory cells in the lesion area. Our work has established that VE-cadherin is a potential therapeutic target for normalization of the vasculature and highlights that targeting miR-27a/VE-cadherin interaction by CD5-2 is a potential novel therapy for the devastating disease, CCM.

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IFN-γ drives inflammatory bowel disease pathogenesis through VE-cadherin–directed vascular barrier disruption

Cited by 180 publications

References 83 publications

YQFM Alleviates Side Effects Caused by Dasatinib through the ROCK/MLC Pathway in Mice

YQFM Alleviates Side Effects Caused by Dasatinib through the ROCK/MLC Pathway in Mice

A Micro-engineered Human Colon Intestine-Chip Platform to Study Leaky Barrier

Targeting miR-27a/VE-cadherin interactions rescues cerebral cavernous malformations in mice

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