Dataset Information

Crude Preparations of Helicobacter pylori Outer Membrane Vesicles Induce Upregulation of Heme Oxygenase-1 via Activating Akt-Nrf2 and mTOR-I?B Kinase-NF-?B Pathways in Dendritic Cells.

ABSTRACT: Helicobacter pylori sheds outer membrane vesicles (OMVs) that contain many surface elements of bacteria. Dendritic cells (DCs) play a major role in directing the nature of adaptive immune responses against H. pylori, and heme oxygenase-1 (HO-1) has been implicated in regulating function of DCs. In addition, HO-1 is important for adaptive immunity and the stress response. Although H. pylori-derived OMVs may contribute to the pathogenesis of H. pylori infection, responses of DCs to OMVs have not been elucidated. In the present study, we investigated the role of H. pylori-derived crude OMVs in modulating the expression of HO-1 in DCs. Exposure of DCs to crude H. pylori OMVs upregulated HO-1 expression. Crude OMVs obtained from a cagA-negative isogenic mutant strain induced less HO-1 expression than OMVs obtained from a wild-type strain. Crude H. pylori OMVs activated signals of transcription factors such as NF-?B, AP-1, and Nrf2. Suppression of NF-?B or Nrf2 resulted in significant attenuation of crude OMV-induced HO-1 expression. Crude OMVs increased the phosphorylation of Akt and downstream target molecules of mammalian target of rapamycin (mTOR), such as S6 kinase 1 (S6K1). Suppression of Akt resulted in inhibition of crude OMV-induced Nrf2-dependent HO-1 expression. Furthermore, suppression of mTOR was associated with inhibition of I?B kinase (IKK), NF-?B, and HO-1 expression in crude OMV-exposed DCs. These results suggest that H. pylori-derived OMVs regulate HO-1 expression through two different pathways in DCs, Akt-Nrf2 and mTOR-IKK-NF-?B signaling. Following this induction, increased HO-1 expression in DCs may modulate inflammatory responses in H. pylori infection.

SUBMITTER: Ko SH

PROVIDER: S-EPMC4962631 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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Crude Preparations of Helicobacter pylori Outer Membrane Vesicles Induce Upregulation of Heme Oxygenase-1 via Activating Akt-Nrf2 and mTOR-IκB Kinase-NF-κB Pathways in Dendritic Cells.

Ko Su Hyuk SH Rho Da Jeong DJ Jeon Jong Ik JI Kim Young-Jeon YJ Woo Hyun Ae HA Kim Nayoung N Kim Jung Mogg JM

Infection and immunity 20160721 8

Helicobacter pylori sheds outer membrane vesicles (OMVs) that contain many surface elements of bacteria. Dendritic cells (DCs) play a major role in directing the nature of adaptive immune responses against H. pylori, and heme oxygenase-1 (HO-1) has been implicated in regulating function of DCs. In addition, HO-1 is important for adaptive immunity and the stress response. Although H. pylori-derived OMVs may contribute to the pathogenesis of H. pylori infection, responses of DCs to OMVs have not b ...[more]

PMID: 27185786

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Project description:AimsTo examine the pro-resolving effects of taurine chloramine (TauCl).ResultsTauCl injected into the peritoneum of mice enhanced the resolution of zymosan A-induced peritonitis. Furthermore, when the macrophages obtained from peritoneal exudates were treated with TauCl, their efferocytic ability was elevated. In the murine macrophage-like RAW264.7 cells exposed to TauCl, the proportion of macrophages engulfing the apoptotic neutrophils was also increased. In these macrophages treated with TauCl, expression of heme oxygenase-1 (HO-1) was elevated along with increased nuclear translocation of the nuclear factor E2-related factor 2 (Nrf2). TauCl binds directly to Kelch-like ECH association protein 1 (Keap1), which appears to retard the Keap1-driven degradation of Nrf2. This results in stabilization and enhanced nuclear translocation of Nrf2 and upregulation of HO-1 expression. TauCl, when treated to peritoneal macrophages isolated from either Nrf2 or HO-1 wild-type mice, stimulated efferocytosis (phagocytic engulfment of apoptotic neutrophils by macrophages), but not in the macrophages from Nrf2 or HO-1 knockout mice. Furthermore, transcriptional expression of some scavenger receptors recognizing the phosphatidylserines exposed on the surface of apoptotic cells was increased in RAW264.7 cells treated with TauCl. Pharmacologic inhibition of HO-1 activity or knockdown of HO-1 gene in RAW264.7 cells abolished the TauCl-induced efferocytosis, whereas both overexpression of HO-1 and treatment with carbon monoxide (CO), the product of HO, potentiated the efferocytic activity of macrophages.InnovationThis work provides the first evidence that TauCl stimulates efferocytosis by macrophages. The results of this study suggest the therapeutic potential of TauCl in the management of inflammatory disorders.ConclusionTauCl can facilitate resolution of inflammation by increasing the efferocytic activity of macrophages through Nrf2-mediated HO-1 upregulation and subsequent production of CO.

Project description:Atypical hemolytic uremic syndrome (aHUS) is a severe disease characterized by microvascular endothelial cell (EC) lesions leading to thrombi formation, mechanical hemolysis and organ failure, predominantly renal. Complement system overactivation is a hallmark of aHUS. To investigate this selective susceptibility of the microvascular renal endothelium to complement attack and thrombotic microangiopathic lesions, we compared complement and cyto-protection markers on EC, from different vascular beds, in in vitro and in vivo models as well as in patients. No difference was observed for complement deposits or expression of complement and coagulation regulators between macrovascular and microvascular EC, either at resting state or after inflammatory challenge. After prolonged exposure to hemolysis-derived heme, higher C3 deposits were found on glomerular EC, in vitro and in vivo, compared with other EC in culture and in mice organs (liver, skin, brain, lungs and heart). This could be explained by a reduced complement regulation capacity due to weaker binding of Factor H and inefficient upregulation of thrombomodulin (TM). Microvascular EC also failed to upregulate the cytoprotective heme-degrading enzyme heme-oxygenase 1 (HO-1), normally induced by hemolysis products. Only HUVEC (Human Umbilical Vein EC) developed adaptation to heme, which was lost after inhibition of HO-1 activity. Interestingly, the expression of KLF2 and KLF4-known transcription factors of TM, also described as possible transcription modulators of HO-1- was weaker in micro than macrovascular EC under hemolytic conditions. Our results show that the microvascular EC, and especially glomerular EC, fail to adapt to the stress imposed by hemolysis and acquire a pro-coagulant and complement-activating phenotype. Together, these findings indicate that the vulnerability of glomerular EC to hemolysis is a key factor in aHUS, amplifying complement overactivation and thrombotic microangiopathic lesions.

Dataset Information

Crude Preparations of Helicobacter pylori Outer Membrane Vesicles Induce Upregulation of Heme Oxygenase-1 via Activating Akt-Nrf2 and mTOR-I?B Kinase-NF-?B Pathways in Dendritic Cells.

Publications

Crude Preparations of Helicobacter pylori Outer Membrane Vesicles Induce Upregulation of Heme Oxygenase-1 via Activating Akt-Nrf2 and mTOR-IκB Kinase-NF-κB Pathways in Dendritic Cells.

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