MyD88 drives the IFN-β response to Lactobacillus acidophilus in dendritic cells through a mechanism involving IRF1, IRF3, and IRF7.
Type I IFNs are induced by pathogens to protect the host from infection and boost the immune response. We have recently demonstrated that this IFN response is not restricted to pathogens, as the Gram-positive bacterium Lactobacillus acidophilus, a natural inhabitant of the intestine, induces high levels of IFN-β in dendritic cells. In the current study, we investigate the intracellular pathways involved in IFN-β upon stimulation of dendritic cells with L. acidophilus and reveal that this IFN-β induction requires phagosomal uptake and processing but bypasses the endosomal receptors TLR7 and TLR9. The IFN-β production is fully dependent on the TIR adapter molecule MyD88, partly dependent on IFN regulatory factor (IRF)1, but independent of the TIR domain-containing adapter inducing IFN-β MyD88 adapter-like, IRF and IRF7. However, our results suggest that IRF3 and IRF7 have complementary roles in IFN-β signaling. The IFN-β production is strongly impaired by inhibitors of spleen tyrosine kinase (Syk) and PI3K. Our results indicate that L. acidophilus induces IFN-β independently of the receptors typically used by bacteria, as it requires MyD88, Syk, and PI3K signaling and phagosomal processing to activate IRF1 and IRF3/IRF7 and thereby the release of IFN-β.
Department of Basic Sciences and Environment, Molecular Immunology, Faculty of Life Sciences, University of Copenhagen, 1871 Frederiksberg, Denmark. gudrun.weiss@imperial.ac.uk
Gudrun
G
Weiss
Kristina
K
Maaetoft-Udsen
Sebastian A
SA
Stifter
Paul
P
Hertzog
Stanislas
S
Goriely
Allan R
AR
Thomsen
Søren R
SR
Paludan
Hanne
H
Frøkiær
D000818:Animals; D002478:Cells, Cultured; D003713:Dendritic Cells / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology*; D011992:Endosomes / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D050856:Interferon Regulatory Factor-1 / Q000172:deficiency / Q000502:physiology*; D050838:Interferon Regulatory Factor-3 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D050839:Interferon Regulatory Factor-7 / Q000037:antagonists & inhibitors / Q000172:deficiency / Q000502:physiology*; D016899:Interferon-beta / Q000378:metabolism*; D007779:Lactobacillus acidophilus / Q000276:immunology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D053594:Myeloid Differentiation Factor 88 / Q000172:deficiency / Q000502:physiology*; D010588:Phagosomes / Q000276:immunology / Q000378:metabolism; D011499:Protein Processing, Post-Translational / Q000276:immunology; D015398:Signal Transduction / Q000235:genetics / Q000276:immunology
D050856:Interferon Regulatory Factor-1; D050838:Interferon Regulatory Factor-3; D050839:Interferon Regulatory Factor-7; C494258:Irf1 protein, mouse; C494233:Irf3 protein, mouse; C494235:Irf7 protein, mouse; C507780:Myd88 protein, mouse; D053594:Myeloid Differentiation Factor 88; D016899:Interferon-beta