TLR2 signaling depletes IRAK1 and inhibits induction of type I IFN by TLR7/9.
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.
Department of Pathology, Case Western Reserve University/University Hospitals Case Medical Center, Cleveland, OH 44106, USA.
Yi C
YC
Liu
Daimon P
DP
Simmons
Xiaoxia
X
Li
Derek W
DW
Abbott
W Henry
WH
Boom
Clifford V
CV
Harding
D000818:Animals; D054884:Host-Pathogen Interactions / Q000276:immunology; D007109:Immunity; D007370:Interferon Type I / Q000037:antagonists & inhibitors* / Q000235:genetics; D053592:Interleukin-1 Receptor-Associated Kinases / Q000037:antagonists & inhibitors* / Q000172:deficiency; D055666:Lipopeptides / Q000494:pharmacology; D008562:Membrane Glycoproteins / Q000502:physiology*; D051379:Mice; D009169:Mycobacterium tuberculosis / Q000276:immunology; D015398:Signal Transduction / Q000276:immunology*; D051195:Toll-Like Receptor 2 / Q000378:metabolism*; D051199:Toll-Like Receptor 7 / Q000502:physiology*; D051217:Toll-Like Receptor 9 / Q000502:physiology*; D015533:Transcriptional Activation
D007370:Interferon Type I; D055666:Lipopeptides; D008562:Membrane Glycoproteins; C477038:Tlr7 protein, mouse; C495370:Tlr9 protein, mouse; D051195:Toll-Like Receptor 2; D051199:Toll-Like Receptor 7; D051217:Toll-Like Receptor 9; D053592:Interleukin-1 Receptor-Associated Kinases; C507769:Irak1 protein, mouse