Header

UZH-Logo

Maintenance Infos

The role of dendritic cells and macrophages in helicobacter pylori induced immunity and tolerance


Urban, Sabine. The role of dendritic cells and macrophages in helicobacter pylori induced immunity and tolerance. 2017, University of Zurich, Faculty of Science.

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 gas- tritis 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 con- comitant chronic inflammation. These persistent effects of H. pylori have likely de- veloped 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 previ- ous 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 toler- ogenic responses of dendritic cells and the different contribution of the various mye- loid 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 ad- dition, 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 pro- pria. 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 im- munoregulatory factors, GGT and VacA, to be sufficient for asthma protection. The protection conferred by purified VacA from H. pylori culture supernatant is depend- ent on IL-18, IL-10 and CD103+ DCs. The activation of IL-18 was dependent on H. py- lori urease inducing TLR2 to upregulate NLRP3 transcription and the subsequent ac- tivation 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 under- standing of tolerance induction by this important human pathogen.

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 gas- tritis 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 con- comitant chronic inflammation. These persistent effects of H. pylori have likely de- veloped 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 previ- ous 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 toler- ogenic responses of dendritic cells and the different contribution of the various mye- loid 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 ad- dition, 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 pro- pria. 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 im- munoregulatory factors, GGT and VacA, to be sufficient for asthma protection. The protection conferred by purified VacA from H. pylori culture supernatant is depend- ent on IL-18, IL-10 and CD103+ DCs. The activation of IL-18 was dependent on H. py- lori urease inducing TLR2 to upregulate NLRP3 transcription and the subsequent ac- tivation 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 under- standing of tolerance induction by this important human pathogen.

Statistics

Downloads

15 downloads since deposited on 19 Jan 2018
15 downloads since 12 months
Detailed statistics

Additional indexing

Item Type:Dissertation
Referees:Müller Anne, van den Broek Maries, Greter Melanie, Kopf Manfred
Communities & Collections:04 Faculty of Medicine > Institute of Molecular Cancer Research
07 Faculty of Science > Institute of Molecular Cancer Research
Dewey Decimal Classification:570 Life sciences; biology
610 Medicine & health
Language:English
Date:2017
Deposited On:19 Jan 2018 16:14
Last Modified:19 Mar 2018 09:57
OA Status:Green

Download

Download PDF  'The role of dendritic cells and macrophages in helicobacter pylori induced immunity and tolerance'.
Preview
Content: Published Version
Filetype: PDF
Size: 29MB