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

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-κB, AP-1, and Nrf2. Suppression of NF-κB 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 IκB kinase (IKK), NF-κB, 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-κB signaling. Following this induction, increased HO-1 expression in DCs may modulate inflammatory responses in H. pylori infection.

Helicobacter pylori Outer Membrane Vesicles Protect the Pathogen From Reactive Oxygen Species of the Respiratory Burst

“…H. pylori OMVs have been extensively studied with respect to composition, proteome, and virulence functions ( Mullaney et al, 2009 ; Olofsson et al, 2010 ), and play multiple roles in bacterial pathogenesis including biofilm formation, cancer development, and immune evasion ( Parker and Keenan, 2012 ). Furthermore, OMVs display immunomudulatory effects by inducing IL-8 secretion from epithelial cells, activating phagoctyes, and suppressing immune cells of the adaptive immune system ( Mullaney et al, 2009 ; Olofsson et al, 2010 ; Ko et al, 2016 ).…”

PIKKing a way to regulate inflammation

“…Furthermore, rapamycin, despite being used as an anti‐inflammatory, was shown to result in significant upregulation of NF‐κB genes in bone marrow derived macrophages. These studies highlight the conflicting roles of mTOR in both activating and suppressing inflammatory responses which may be important targets for controlling inflammation, especially in the context of cancer, neurodegeneration and infection but further work is required to understand the intricacies of these regulatory networks …”

Helicobacter: Inflammation, immunology and vaccines

“…Helicobacter pylori interactions with dendritic cells (DCs) are important for the differentiation of Th subsets, influence the mucosal immune response, and have an impact on disease outcome. Ko et al . reported that H. pylori outer membrane vesicles (OMVs) are involved in controlling gastric inflammation in vivo.…”