HIF-dependent regulation of claudin-1 is central to intestinal epithelial tight junction integrity

Saeedi, Bejan; Kao, Daniel J.; Kitzenberg, David; Dobrinskikh, Evgenia; Schwisow, Kayla; Masterson, Joanne C.; Kendrick, Agnieszka A.; Kelly, Caleb; Bayless, Amanda J.; Kominsky, Douglas J.; Campbell, Eric L.; Kuhn, Kristine A.; Furuta, Glenn T.; Colgan, Sean P.; Glover, Louise

doi:10.1091/mbc.e14-07-1194

Cited by 174 publications

(147 citation statements)

References 43 publications

(67 reference statements)

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“…The NC group had a somewhat higher expression of macrophage migration inhibitory factor, serpin, and interleukin 8; however, these differences were not statistically significant (Figure 3C and 3D). Another miR‐155 target hypoxia‐inducible factor 1α, the mediator of cellular response to hypoxia and regulator of TJ integrity,25, 26 was undetectable in the cell lysates from all analyzed cell groups (neither by ELISA nor Western blot, data not shown).…”

Section: Resultsmentioning

confidence: 93%

Inhibition of MicroRNA‐155 Supports Endothelial Tight Junction Integrity Following Oxygen‐Glucose Deprivation

Peña-Philippides

Gardiner

Caballero-Garrido

et al. 2018

JAHA

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BackgroundBrain microvascular endothelial cells form a highly selective blood brain barrier regulated by the endothelial tight junctions. Cerebral ischemia selectively targets tight junction protein complexes, which leads to significant damage to cerebral microvasculature. Short noncoding molecules called microRNAs are implicated in the regulation of various pathological states, including endothelial barrier dysfunction. In the present study, we investigated the influence of microRNA‐155 (miR‐155) on the barrier characteristics of human primary brain microvascular endothelial cells (HBMECs).Methods and ResultsOxygen‐glucose deprivation was used as an in vitro model of ischemic stroke. HBMECs were subjected to 3 hours of oxygen‐glucose deprivation, followed by transfections with miR‐155 inhibitor, mimic, or appropriate control oligonucleotides. Intact normoxia control HBMECs and 4 oxygen‐glucose deprivation–treated groups of cells transfected with appropriate nucleotide were subjected to endothelial monolayer electrical resistance and permeability assays, cell viability assay, assessment of NO and human cytokine/chemokine release, immunofluorescence microscopy, Western blot, and polymerase chain reaction analyses. Assessment of endothelial resistance and permeability demonstrated that miR‐155 inhibition improved HBMECs monolayer integrity. In addition, miR‐155 inhibition significantly increased the levels of major tight junction proteins claudin‐1 and zonula occludens protein‐1, while its overexpression reduced these levels. Immunoprecipitation and colocalization analyses detected that miR‐155 inhibition supported the association between zonula occludens protein‐1 and claudin‐1 and their stabilization at the HBMEC membrane. Luciferase reporter assay verified that claudin‐1 is directly targeted by miR‐155.ConclusionsBased on these results, we conclude that miR‐155 inhibition–induced strengthening of endothelial tight junctions after oxygen‐glucose deprivation is mediated via its direct target protein claudin‐1.

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Section: Resultsmentioning

confidence: 93%

Inhibition of MicroRNA‐155 Supports Endothelial Tight Junction Integrity Following Oxygen‐Glucose Deprivation

Peña-Philippides

Gardiner

Caballero-Garrido

et al. 2018

JAHA

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“…Moreover, in vivo analysis revealed the importance of HIF-mediated CLDN1 expression during experimental colitis. These results identify a critical link between HIF and specific TJ function, providing important insight into mechanisms of HIF-regulated epithelial homeostasis (13).…”

Section: Molecular Aspects Of Barrier Regulation In the Mucosamentioning

confidence: 81%

“…Claudin-1 (CLDN1) is an important "tight" claudin and has been shown to be dysregulated in a variety of human diseases, including IBD (40). In a recent screen of TJ targets, CLDN1 was identified as a central mediator of aberrant junctional morphology in HIF-1β-deficient intestinal epithelial cell (IEC) lines (13). Using both loss-and gain-of-function approaches, this work showed that HIF maintains CLDN1 expression through binding hypoxia response element (HRE) sequences in the gene promoter.…”

Section: Molecular Aspects Of Barrier Regulation In the Mucosamentioning

confidence: 99%

Oxygen metabolism and barrier regulation in the intestinal mucosa

Glover¹,

Lee²,

Colgan³

2016

Journal of Clinical Investigation

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“…To this end, we exposed Caco-2 and T84 cells to butyrate and profiled the expression of a panel of junctional proteins known to be important in barrier function: Cldn1, Cldn2, Cldn3, Cldn7, occludin, E-cadherin, JAM-A and ZO-1 (30). We have used this approach successfully in the past to define targets for barrier regulation by hypoxia-inducible factor (31). Our studies revealed that butyrate preferentially repressed the expression of Cldn2 relative to control in both Caco2 (0.22 ± 0.14) and T84 cells (0.08 ± 0.07) (Figure 5A and B, p<0.001).…”

Section: Resultsmentioning

confidence: 99%

Microbial-Derived Butyrate Promotes Epithelial Barrier Function through IL-10 Receptor–Dependent Repression of Claudin-2

Zheng

Kelly

Battista

et al. 2017

The Journal of Immunology

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376

260

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Commensal interactions between the enteric microbiota and distal intestine play important roles in regulating human health. Short-chain fatty acids (SCFAs), such as butyrate, produced through anaerobic microbial metabolism represent a major energy source for the host colonic epithelium and enhance epithelial barrier function through unclear mechanisms. Separate studies revealed that the epithelial anti-inflammatory interleukin-10 receptor α-subunit (IL-10RA) is also important for barrier formation. Based on these findings, we examined if SCFAs promote epithelial barrier through IL-10RA-dependent mechanisms. Using human intestinal epithelial cells (IECs), we discovered that SCFAs, particularly butyrate, enhanced IEC barrier formation, induced IL10RA mRNA, IL-10RA protein, and transactivation through activated Stat3 and HDAC inhibition. Loss and gain of IL10RA expression directly correlates with IEC barrier formation and butyrate represses permeability-promoting claudin-2 (Cldn2) tight-junction protein expression through an IL-10RA-dependent mechanism. Our findings provide a novel mechanism by which microbial-derived butyrate promotes barrier through IL-10RA-dependent repression of Cldn2.

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HIF-dependent regulation of claudin-1 is central to intestinal epithelial tight junction integrity

Cited by 174 publications

References 43 publications

Inhibition of MicroRNA‐155 Supports Endothelial Tight Junction Integrity Following Oxygen‐Glucose Deprivation

Inhibition of MicroRNA‐155 Supports Endothelial Tight Junction Integrity Following Oxygen‐Glucose Deprivation

Oxygen metabolism and barrier regulation in the intestinal mucosa

Microbial-Derived Butyrate Promotes Epithelial Barrier Function through IL-10 Receptor–Dependent Repression of Claudin-2

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