Bone Morphogenetic Protein 4 Signaling Regulates Epithelial Renewal in the Urinary Tract in Response to Uropathogenic Infection

Mysorekar, Indira U.; Isaacson-Schmid, Megan; Walker, Jennifer N.; Mills, Jason C.; Hultgren, Scott J.

doi:10.1016/j.chom.2009.04.005

Cited by 108 publications

(158 citation statements)

References 41 publications

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“…Recent reports that BMP signalling regulates epithelial regeneration following damage in the adult zebrafish liver and mouse bladder support this hypothesis [9,10]. In the present study, we investigated whether BMP signalling is activated in airway epithelial cells in vivo following acute lung injury and the timing of such activation during regeneration relative to inflammation, epithelial damage and reepithelialisation.…”

Section: Introductionmentioning

confidence: 78%

Bone morphogenetic protein signalling in airway epithelial cells during regeneration

Masterson

Molloy

Gilbert

et al. 2011

Cellular Signalling

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Mechanisms of lung regeneration after injury remain poorly understood. Bone morphogenetic protein 4 (BMP4) is critical for lung morphogenesis and regulates differentiation of the airway epithelium during development, although its mechanism of action is unknown. The role of BMPs in adult lungs is unclear. We hypothesised that BMP signalling is involved in regeneration of damaged adult airways after injury. Our aims were to characterise the regeneration process in 1-nitronaphthalene (1-NN) injured airways, to determine if and when BMP signalling is activated during this process and investigate the effects of BMP4 on normal adult airway epithelial cells (AECs). Rats were injected with 50 mg/kg 1-NN and protein expression in AECs was examined by Western blotting of lung lysis lavage, and by immunofluorescence, at 6, 24, 48 and 96 h post injection. Expression of signalling molecules p-ERK-1, p-ERK-2 and p-Smad1/5/8 in AECs peaked at 6 h post injection, coincident with maximal inflammation and prior to airway denudation which occurred at 24 h. While airways were re-epithelialised by 48 h, AEC proliferation peaked later at 96 h post 1-NN injection. In vitro, BMP4 induced a mesenchymal-like morphology in normal AECs, downregulated E-cadherin expression and increased migration in a wound closure assay. Thus, following acute injury, increased BMP signalling in AECs coincides with inflammation and precedes airway denudation and re-epithelialisation. Our data indicate that, similar to its role in controlling tissue architecture during development, BMP signalling regulates regeneration of the airways following acute injury, involving downregulation of E-cadherin and induction of migration in AECs.

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Section: Introductionmentioning

confidence: 78%

Bone morphogenetic protein signalling in airway epithelial cells during regeneration

Masterson

Molloy

Gilbert

et al. 2011

Cellular Signalling

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“…We have been able to establish MOI conditions in vitro, however, that demonstrate that host cells also proliferate, as they do during clinical infection. 44 Importantly, our assessments of epigenetic responses begin several days following inoculation to allow for bacterial internalization, which characterizes clinical persistence of infection. In this sense, the model is being studied for responses to persistent infection, as the clinical persistent infection phase is characterized by the presence of intracellular bacteria colonies.…”

Section: Discussionmentioning

confidence: 99%

Uropathogenic E. coli infection provokes epigenetic downregulation of CDKN2A (p16INK4A) in uroepithelial cells

Tölg

Sabha

Cortese

et al. 2011

Laboratory Investigation

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Host cell and bacterial factors determine severity and duration of infections. To allow for bacteria pathogenicity and persistence, bacteria have developed mechanisms that modify expression of host genes involved in cell cycle progression, apoptosis, differentiation and the immune response. Recently, Helicobacter pylori infection of the stomach has been correlated with epigenetic changes in the host genome. To identify epigenetic changes during Escherichia coli induced urinary tract infection (UTI), we developed an in vitro model of persistent infection of human uroepithelial cells with uropathogenic E. coli (UPEC), resulting in intracellular bacteria colonies. Cells inoculated with FimH-negative E. coli (N-UPEC) that are not internalized and non-inoculated cells were used as controls. UPEC infection significantly induced de novo methyltransferase (DNMT) activity (12.5-fold P ¼ 0.002 UPEC vs non-inoculated and 250-fold P ¼ 0.001 UPEC vs N-UPEC inoculated cells) and Dnmt1 RNA expression (6-fold P ¼ 0.04 UPEC vs non-inoculated cells) compared with controls. DNMT1 protein levels were significantly increased in three uroepithelial cell lines (5637, J82, HT-1197) in response to UPEC infection as demonstrated by confocal analysis. Real-time PCR analysis of candidate genes previously associated with bacteria infection and/or innate immunity, revealed UPEC-induced downregulation of the tumor suppressor gene CDKN2A (3.3-fold P ¼ 0.007 UPEC vs non-inoculated and 3.3-fold P ¼ 0.001 UPEC vs N-UPEC) and the DNA repair gene MGMT (9-fold P ¼ 0.03 UPEC vs non-inoculated). Expression of CDH1, MLH1, DAPK1 and TLR4 was not affected. Pyrosequencing of CDKN2A and MGMT CpG islands revealed increased methylation in CDKN2A exon 1 (3.8-fold P ¼ 0.04 UPEC vs N-UPEC and UPEC vs non-inoculated). Methylation of MGMT was not affected. UPEC-induced methylation of CDKN2A exon 1 may increase bladder cancer and presage UTI risk, and be useful as a biological marker for UTI susceptibility or recurrence.

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“…Urothelial tissue regeneration is an important step in the resolution of UTIs (37). We analyzed bladder tissue sections from control and Atg16L1 HM mice at 6 and 14 dpi and found that, relative to uninfected bladders from control and Atg16L1 HM mice (Fig.…”

Section: Atg16l1 Deficiency Leads To Rapid Clearance Of Bacteriuria Andmentioning

confidence: 99%

“…UTI89, a pathogenic UPEC strain (27,37), was used for all studies. Adult female mice (8-10 wk old) were anesthetized and inoculated transurethrally with 10 7 cfu UTI89 in PBS.…”

mentioning

confidence: 99%

Atg16L1 deficiency confers protection from uropathogenic Escherichia coli infection in vivo

Wang¹,

Mendonsa²,

Symington³

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

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104

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Urinary tract infection (UTI), a frequent and important disease in humans, is primarily caused by uropathogenic Escherichia coli (UPEC). UPEC forms acute cytoplasmic biofilms within superficial urothelial cells and can persist by establishing membrane-enclosed latent reservoirs to seed recurrent UTI. The host responds with an influx of innate immune cells and shedding of infected epithelial cells. The autophagy gene ATG16L1 has a commonly occurring mutation that is associated with inflammatory disease and intestinal cell abnormalities in mice and humans. Here, we show that Atg16L1-deficient mice (Atg16L1 HM ) cleared bacteriuria more rapidly and thoroughly than controls and showed rapid epithelial recovery. Atg16L1 deficiency was associated with a potent proinflammatory cytokine response with increased recruitment of monocytes and neutrophils to infected bladders. Chimeric and genetic studies showed that Atg16L1 HM hematopoietic cells alone could increase clearance and that Atg16L1-deficient innate immune cells were required and sufficient for enhanced bacteriuric clearance. We also show that Atg16L1-deficient mice exhibit cell-autonomous architectural aberrations of superficial urothelial cells, including increases in multivesicular bodies, lysosomes, and expression of the UPEC receptor Up1a. Finally, we show that Atg16L1 HM epithelial cells contained a significantly reduced number of latent reservoirs. Together, our results show that Atg16L1 deficiency confers protection in vivo to the host against both acute and latent UPEC infection, suggest that deficiency in a key autophagy protein can be protective against infection in an animal model of one of the most common diseases of women worldwide, and may have significant clinical implications for understanding the etiology of recurrent UTIs.Atg5 | Lyz-Cre | Rag1

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Bone Morphogenetic Protein 4 Signaling Regulates Epithelial Renewal in the Urinary Tract in Response to Uropathogenic Infection

Cited by 108 publications

References 41 publications

Bone morphogenetic protein signalling in airway epithelial cells during regeneration

Bone morphogenetic protein signalling in airway epithelial cells during regeneration

Uropathogenic E. coli infection provokes epigenetic downregulation of CDKN2A (p16INK4A) in uroepithelial cells

Atg16L1 deficiency confers protection from uropathogenic Escherichia coli infection in vivo

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