MyD88 drives the IFN-ß response to Lactobacillus acidophilus in dendritic cells through a mechanism involving IRF1, IRF3, and IRF7

TY - JOUR

T1 - MyD88 drives the IFN-ß response to Lactobacillus acidophilus in dendritic cells through a mechanism involving IRF1, IRF3, and IRF7

AU - Weiss, Gudrun Margarethe

AU - Maaetoft-Udsen, Kristina

AU - Stifter, Sebastian A.

AU - Hertzog, Paul

AU - Goriely, Stanislas

AU - Thomsen, Allan Randrup

AU - Paludan, Søren Riis

AU - Frøkiær, Hanne

PY - 2012/9/15

Y1 - 2012/9/15

N2 - 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.

AB - 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.

KW - Animals

KW - Cells, Cultured

KW - Dendritic Cells

KW - Endosomes

KW - Interferon Regulatory Factor-1

KW - Interferon Regulatory Factor-3

KW - Interferon Regulatory Factor-7

KW - Interferon-beta

KW - Lactobacillus acidophilus

KW - Mice

KW - Mice, Inbred C57BL

KW - Mice, Knockout

KW - Myeloid Differentiation Factor 88

KW - Phagosomes

KW - Protein Processing, Post-Translational

KW - Signal Transduction

U2 - 10.4049/jimmunol.1103491

DO - 10.4049/jimmunol.1103491

M3 - Journal article

C2 - 22896628

SN - 0022-1767

VL - 189

SP - 2860

EP - 2868

JO - Journal of Immunology

JF - Journal of Immunology

IS - 6

ER -