TLR2 Signaling Depletes IRAK1 and Inhibits Induction of Type I IFN by TLR7/9

J Immunol. 2012 Feb 1;188(3):1019-26. doi: 10.4049/jimmunol.1102181. Epub 2012 Jan 6.

Abstract

Pathogens may signal through multiple TLRs with synergistic or antagonistic effects on the induction of cytokines, including type I IFN (IFN-I). IFN-I is typically induced by TLR9, but not TLR2. Moreover, we previously reported that TLR2 signaling by Mycobacterium tuberculosis or other TLR2 agonists inhibited TLR9 induction of IFN-I and IFN-I-dependent MHC-I Ag cross processing. The current studies revealed that lipopeptide-induced TLR2 signaling inhibited induction of first-wave IFN-α and IFN-β mRNA by TLR9, whereas induction of second-wave IFN-I mRNA was not inhibited. TLR2 also inhibited induction of IFN-I by TLR7, another MyD88-dependent IFN-I-inducing receptor, but did not inhibit IFN-I induction by TLR3 or TLR4 (both Toll/IL-1R domain-containing adapter-inducing IFN-β dependent, MyD88 independent). The inhibitory effect of TLR2 was not dependent on new protein synthesis or intercellular signaling. IL-1R-associated kinase 1 (IRAK1) was depleted rapidly (within 10 min) by TLR2 agonist, but not until later (e.g., 2 h) by TLR9 agonist. Because IRAK1 is required for TLR7/9-induced IFN-I production, we propose that TLR2 signaling induces rapid depletion of IRAK1, which impairs IFN-I induction by TLR7/9. This novel mechanism, whereby TLR2 inhibits IFN-I induction by TLR7/9, may shape immune responses to microbes that express ligands for both TLR2 and TLR7/TLR9, or responses to bacteria/virus coinfection.

Publication types

  • Research Support, N.I.H., Extramural

MeSH terms

  • Animals
  • Host-Pathogen Interactions / immunology
  • Immunity
  • Interferon Type I / antagonists & inhibitors*
  • Interferon Type I / genetics
  • Interleukin-1 Receptor-Associated Kinases / antagonists & inhibitors*
  • Interleukin-1 Receptor-Associated Kinases / deficiency
  • Lipopeptides / pharmacology
  • Membrane Glycoproteins / physiology*
  • Mice
  • Mycobacterium tuberculosis / immunology
  • Signal Transduction / immunology*
  • Toll-Like Receptor 2 / metabolism*
  • Toll-Like Receptor 7 / physiology*
  • Toll-Like Receptor 9 / physiology*
  • Transcriptional Activation

Substances

  • Interferon Type I
  • Lipopeptides
  • Membrane Glycoproteins
  • Tlr7 protein, mouse
  • Tlr9 protein, mouse
  • Toll-Like Receptor 2
  • Toll-Like Receptor 7
  • Toll-Like Receptor 9
  • Interleukin-1 Receptor-Associated Kinases
  • Irak1 protein, mouse