TLR2 mediates Helicobacter pylori-induced tolerogenic immune response in mice.
We have shown that Helicobacter pylori induces tolerogenic programming of dendritic cells and inhibits the host immune response. Toll-like receptors (TLRs) represent a class of transmembrane pattern recognition receptors essential for microbial recognition and control of the innate immune response. In this study, we examined the role of TLRs in mediating H. pylori tolerogenic programming of dendritic cells and their impact on anti-H. pylori immunity using C57BL/6 wild-type and TLR2-knockout (TLR2KO) mice. We analyzed the response of TLR2KO bone marrow-derived dendritic cells (BMDCs) to H. pylori SS1 stimulation and the outcome of chronic H. pylori infection in TLR2KO mice. We showed that H. pylori-stimulated BMDCs upregulated the expression of TLR2, but not TLR4, TLR5, or TLR9. H. pylori-stimulated BMDCs from TLRKO mice induced lower Treg and Th17 responses, but a higher IFN-γ response compared to H. pylori-stimulated BMDCs from wild-type mice. In vivo analyses following an H. pylori infection of 2 months duration showed a lower degree of gastric H. pylori colonization in TLR2KO mice and more severe gastric immunopathology compared to WT mice. The gastric mucosa of the infected TLR2KO mice showed a lower mRNA expression of Foxp3, IL-10, and IL-17A, but higher expression of IFN-γ compared to the gastric mRNA expression in infected wild-type mice. Moreover, the H. pylori-specific Th1 response was higher and the Treg and Th17 responses were lower in the spleens of infected TLR2KO mice compared to infected WT mice. Our data indicate that H. pylori mediates immune tolerance through TLR2-derived signals and inhibits Th1 immunity, thus evading host defense. TLR2 may be an important target in the modulation of the host response to H. pylori.
Department of Pharmacology, School of Medicine, Shandong University, Jinan, Shandong, China ; Division of Gastroenterology, Department of Internal Medicine, University of Michigan Health System, Ann Arbor, Michigan, United States of America.
Xia
X
Sun
Min
M
Zhang
Mohamad
M
El-Zataari
Stephanie Y
SY
Owyang
Kathryn A
KA
Eaton
Maochang
M
Liu
Yu-Ming
YM
Chang
Weiping
W
Zou
John Y
JY
Kao
D000818:Animals; D018845:CD11 Antigens / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis; D003713:Dendritic Cells / Q000276:immunology; D005260:Female; D005756:Gastritis / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D016481:Helicobacter Infections / Q000276:immunology* / Q000382:microbiology* / Q000473:pathology; D016480:Helicobacter pylori / Q000254:growth & development / Q000502:physiology*; D000949:Histocompatibility Antigens Class II / Q000378:metabolism; D007108:Immune Tolerance / Q000276:immunology*; D018836:Inflammation Mediators / Q000378:metabolism; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D013045:Species Specificity; D013270:Stomach / Q000276:immunology / Q000382:microbiology / Q000473:pathology; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D018417:Th1 Cells / Q000276:immunology; D058504:Th17 Cells / Q000276:immunology; D051195:Toll-Like Receptor 2 / Q000378:metabolism*
D018845:CD11 Antigens; D016207:Cytokines; D000949:Histocompatibility Antigens Class II; D018836:Inflammation Mediators; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2