Abstract
Helicobacter pylori is a gram-negative bacterium colonizing the stomach mucosa of half of the world`s population. Persistent infections with H. pylori are linked to gastritis and carriers are predisposed to an elevated gastric cancer risk. However, the host is not able to clear the infection leading to a persistence of H. pylori and a concomitant chronic inflammation. These persistent effects of H. pylori have likely developed as a by-product of more than 60.000 years of co-evolution with the human host. H. pylori has evolved both innate and adaptive immune evasion strategies that allow it to overcome host defenses. Besides its well known negative consequences, chronic H. pylori infections also exert beneficial effects. Epidemiological and animal studies inversely link H. pylori infection to the risk of developing allergic asthma and inflammatory bowel diseases, especially when infection occurs early in life. In previous studies, we have shown that the tolerogenic activity of DCs and the IL-18-dependent expansion of Treg cells are essential for asthma protection driven by H. pylori. However, little was known about the molecular mechanisms promoting tolerogenic responses of dendritic cells and the different contribution of the various myeloid resident populations in the stomach mucosa to tolerance and immunity to H. pylori.
We observed that CX3CR1hi macrophages, monocytes and CD11b+ DCs take up H. pylori and NLRP3 expression is required for the differentiation of CD11b+ DCs. In addition, CD11b+ DCs seem to have a tolerogenic phenotype as the deficiency in these cells leads to an overshooting TH1 response. In contrast, BATF3-dependent CD103+ DCs are necessary for an H. pylori-specific TH1 response in the stomach lamina propria. We could further show that CD103+ DCs and IL-10 expression of CD11c+ cells are essential for allergic asthma protection by regulating allergen-specific TH2 responses. We identified β-catenin signaling in CD11c+ DCs to be required for allergen specific asthma protection. Focusing on the role of bacterial factors, we found the two immunoregulatory factors, GGT and VacA, to be sufficient for asthma protection. The protection conferred by purified VacA from H. pylori culture supernatant is dependent on IL-18, IL-10 and CD103+ DCs. The activation of IL-18 was dependent on H. pylori urease inducing TLR2 to upregulate NLRP3 transcription and the subsequent activation of the NLRP3 inflammasome. Urease-expressing H. pylori, TLR2 and NLRP3 are all essential for asthma protection with live bacteria. Further, we could identify TLR2 and NLRP3 expression to be upregulated in macrophages and CD11b+ DCs take up H. pylori in the stomach lamina propria. This finding supports their importance as immunosuppressive mediators during H. pylori infection.
Overall, our results show a division of labor among different gastric phagocytosing cell subsets. We identified CD103+ DCs, IL-10 production and β-catenin signaling in CD11c+ cells, as well as the urease/TLR2/IL-18 axis as essential mediators of H. pylori-induced immune tolerance. With these findings, we contribute to a better understanding of tolerance induction by this important human pathogen.
Urban, Sabine