Helicobacter pylori γ-Glutamyltranspeptidase Induces Tolerogenic Human Dendritic Cells by Activation of Glutamate Receptors

Abstract

Helicobacter pylori infection is characterized by chronic persistence of the bacterium. Different virulence factors, including H. pylori γ-glutamyltranspeptidase (gGT), have been reported to induce tolerogenicity by reprogramming dendritic cells (DCs). gGT is present in all bacterial isolates, indicating an important role for gGT in the course of infection. In the current study, we have analyzed the effect of H. pylori gGT on human DCs and the subsequent adaptive immune response. We show that glutamate produced due to H. pylori gGT enzymatic activity tolerizes DCs by inhibiting cAMP signaling and dampening IL-6 secretion in response to the infection. Together, our results provide a novel molecular mechanism by which H. pylori manipulates the host’s immune response to persist within its host.

Transmaternal Helicobacter pylori exposure reduces allergic airway inflammation in offspring through regulatory T cells

“…16,17,19,22 Interestingly, the immunomodulatory activity of H pylori depends on 2 determinants, the vacuolating cytotoxin (VacA) and g-glutamyl-transpeptidase (GGT), which are on the one hand required for the protective effects of the live infection and on the other hand recapitulate many of the benefits associated with live infection when administered in purified form. 18,22,23 Here we hypothesized that the perinatal transmaternal exposure (ie, exclusively through the mother) to immunomodulatory molecules of H pylori that occurs in utero or during lactation can recapitulate the benefits of H pylori infection early in life. To test this idea, we perinatally exposed animals to H pylori extract or purified VacA and evaluated their response to allergens in 2 models of allergen-induced airway inflammation.…”

Identification of regulatory genes through global gene expression analysis of aHelicobacter pylorico-culture system

“…In addition to the effector mechanisms dominated by Th1 and Th17 cells (Bhuiyan et al, 2014; Carbo et al, 2013; Caruso et al, 2008; D’Elios et al, 1997; Shi et al, 2010; Smythies et al, 2000), H. pylori induces strong regulatory responses that suppress mucosal inflammation, contribute to tissue integrity maintenance and prevent effective bacterial clearance (Lundgren, Suri-Payer, Enarsson, Svennerholm, & Lundin, 2003; Raghavan, Fredriksson, Svennerholm, Holmgren, & Suri-Payer, 2003; Raghavan & Quiding-Jarbrink, 2012). Historically, H. pylori-associated regulatory responses have been mainly attributed to dendritic cells by inhibition of effector T cells and promotion of regulatory T cells (Kabisch et al, 2016; Kaebisch, Mejias-Luque, Prinz, & Gerhard, 2014; Tanaka et al, 2010). Recently, macrophages have been identified as an integral component in the generation of a regulatory gastric microenvironment during this bacterial infection (Leber et al, 2016; Viladomiu et al, 2017).…”

“…Interestingly, H. pylori infection may be an important driver of systemic tolerance in asymptomatic individuals with an inverse correlation between the presence of this bacterium and the development of autoimmune diseases, asthma, esophageal adenocarcinoma and type-2-diabetes (Bassaganya-Riera et al, 2012; de Martel et al, 2005; Reibman et al, 2008; van Wijck et al, 2018; Xie et al, 2013). These conflicting implications may stem from the relative predominance of antagonistic immune responses that encompass both effector and regulatory components elicited by H. pylori (Bhuiyan et al, 2014; Kabisch, Semper, Wustner, Gerhard, & Mejias-Luque, 2016; Raghavan & Quiding-Jarbrink, 2012; Smythies et al, 2000). However, long-term colonization by the bacterium, due to the failure of the immune system to clear the infection, suggests that the strong H. pylori-induced regulatory responses can shift inflammatory/effector responses leading to chronicity of the infection.…”

Impact of nitric oxide's bidirectional role on glaucoma: focus onHelicobacter pylori–related nitrosative stress

“…Glutamate appears to be an essential immunomodulator during Hp ‐I, and expression of Hp ‐related γ‐glutamyltranspeptidase is important for its colonization. It induces a tolerogenic effect via activation of glutamate receptors . Justino et al .…”