Yersinia V antigen induces both TLR homo- and heterotolerance in an IL-10-involving manner.
The virulence antigen (LcrV) of pathogenic yersiniae "silences" macrophages against stimulation with the TLR2-agonist zymosan A in a CD14/TLR2-dependent fashion via IL-10 induction. This pathogenically important "silencing" resembles TLR tolerance phenomena; in these, pre-exposure to a primary tolerizing TLR-agonist renders macrophages unresponsive to stimulation with a secondary challenging TLR-agonist which may involve either the same (TLR homotolerance) or a different TLR (TLR heterotolerance) as the primary TLR-agonist. Here, we show that rLcrV induces TLR homo- and heterotolerance against TLR2- or TLR4-agonists both in human and murine macrophages, respectively. The underlying mechanism of LcrV-induced tolerance is most likely not due to changes in TLR2- or TLR4 expression, but involves LcrV-mediated IL-10 production, since LcrV-induced TLR homo- and heterotolerance is highly impaired in IL-10(-/-) macrophages. Moreover, the involvement of IL-10 in TLR tolerance induction seems to be a more general phenomenon as shown by experiments using different TLR-agonists in IL-10(-/-) macrophages. Since LcrV acts as a secreted protein upon macrophages without requiring direct cell contact, as shown in transwell assays, we propose that yersiniae exploit IL-10-involving TLR tolerance mechanisms by the virulence factor LcrV.
Reithmeier-Rost
Dagmar
D
Max von Pettenkofer-Institut für Hygiene und Medizinische Mikrobiologie, Ludwig-Maximilians-Universität München, Pettenkoferstrasse 9a, 80336 München, Germany.
Bierschenk
Suse
S
Filippova
Natalia
N
Schröder-Braunstein
Jutta
J
Sing
Andreas
A
D000818:Animals; D000942:Antigens, Bacterial / Q000276:immunology*; D002478:Cells, Cultured; D005260:Female; D006801:Humans; D007108:Immune Tolerance / Q000276:immunology*; D016753:Interleukin-10 / Q000276:immunology* / Q000378:metabolism; D018950:Lipopolysaccharide Receptors / Q000276:immunology / Q000378:metabolism; D008264:Macrophages / Q000276:immunology / Q000378:metabolism / Q000382:microbiology; D008562:Membrane Glycoproteins / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D051379:Mice; D052899:Pore Forming Cytotoxic Proteins; D011956:Receptors, Cell Surface / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D011971:Receptors, Immunologic / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha / Q000276:immunology / Q000378:metabolism; D015007:Yersinia / Q000276:immunology*; D015009:Yersinia Infections / Q000276:immunology* / Q000378:metabolism / Q000382:microbiology
D000942:Antigens, Bacterial; C043908:LcrV protein, Yersinia; D018950:Lipopolysaccharide Receptors; D008562:Membrane Glycoproteins; D052899:Pore Forming Cytotoxic Proteins; D011956:Receptors, Cell Surface; D011971:Receptors, Immunologic; C495342:TLR2 protein, human; C495345:TLR4 protein, human; C493486:Tlr2 protein, mouse; C493487:Tlr4 protein, mouse; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10