Cooperation of Gastric Mononuclear Phagocytes with Helicobacter pylori during Colonization

Abstract

Helicobacter pylori, the dominant member of the human gastric microbiota, elicits immunoregulatory responses implicated in protective versus pathological outcomes. To evaluate the role of macrophages during infection, we employed a system with a shifted pro-inflammatory macrophage phenotype by deleting PPARγ in myeloid cells, and found a 5 to 10-fold decrease in gastric bacterial loads. Higher levels of colonization in wild-type (WT) mice were associated with increased presence of mononuclear phagocytes (MNPs) and in particular with the accumulation of CD11b+F4/80hiCD64+CX3CR1+ macrophages in the gastric lamina propria. Depletion of phagocytic cells by clodronate liposomes in WT resulted in a reduction of gastric H. pylori colonization compared to non-treated mice. PPARγ-deficient and macrophage-depleted mice presented decreased IL-10-mediated myeloid and T cell regulatory responses early post-infection. IL-10 neutralization during H. pylori infection led to increased IL-17-mediated responses and increased neutrophil accumulation at the gastric mucosa. In conclusion, we report the induction of IL-10-driven regulatory responses mediated by CD11b+F4/80hiCD64+CX3CR1+ MNPs that contribute to maintaining high levels of H pylori loads in the stomach by modulating effector T cell responses at the gastric mucosa.

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

“…To explore the dynamics of the selected genes in vivo, WT and LysCre+ mice were infected with H. pylori. In a previous study, we demonstrated that H. pylori infection in vivo induces strong regulatory mechanisms driven by IL-10-expressing myeloid cells starting at day 14 post-infection and reaching maximum levels at day 28 post-infection (Viladomiu et al, 2017). To evaluate whether induction of regulatory responses in vivo alters the kinetics of targeted genes, stomachs were collected at day 28 from infected and non-infected mice.…”

“…The in vivo interplay between H. pylori and the myeloid cell compartment revealed that macrophages are highly responsive to H. pylori-induced regulatory responses (Viladomiu et al, 2017). Here, we sought to explore H. pylori interactions with macrophages employing a synchronized gentamycin protection co-culture system comparing cells obtained from WT and PPARγ fl/fl;LysCre+ (LysCre+) mice.…”

“…Macrophages have been described as key immune cells in H. pylori-induced regulatory mechanisms (Leber et al, 2016). Particularly, H. pylori interacts with a specific subset of mononuclear phagocytes that generate IL-10-driven regulatory responses facilitating optimal colonization of the gastric mucosa (Viladomiu et al, 2017). We demonstrated that macrophage peroxisome proliferator-activated receptor gamma (PPARγ), an anti-inflammatory transcription factor, was needed for the induction of the full spectrum regulatory response (Viladomiu et al, 2017).…”

“…Particularly, H. pylori interacts with a specific subset of mononuclear phagocytes that generate IL-10-driven regulatory responses facilitating optimal colonization of the gastric mucosa (Viladomiu et al, 2017). We demonstrated that macrophage peroxisome proliferator-activated receptor gamma (PPARγ), an anti-inflammatory transcription factor, was needed for the induction of the full spectrum regulatory response (Viladomiu et al, 2017). Additional macrophage-expressed genes (Par1, HO-1) have been shown to play a similar role to PPARγ and contribute to keeping high levels of colonization while reducing pathology and disease (Chionh et al, 2015; Gobert et al, 2014).…”

“…Indeed, suppression or inactivation of a single regulatory protein, for instance PPARγ, results in stronger inflammation, while activation or enhanced expression leads to a balanced response, maintained by induction of immunoregulation (Hontecillas et al, 2011 ? Odegaard et al, 2007; Viladomiu et al, 2017; Viladomiu et al, 2012).…”