Abstract
Activation of the host antibacterial defenses by the toll-like receptors (TLR) also selectively activates energy-sensing and metabolic pathways, but the mechanisms are poorly understood. This includes the metabolic and mitochondrial biogenesis master co-activators, Ppargc1a (PGC-1α) and Ppargc1b (PGC-1β) in Staphylococcus aureus (S. aureus) sepsis. The expression of these genes in the liver is markedly attenuated inTLR2−/− mice and markedly accentuated in TLR4−/− mice compared with wild type (WT) mice. We sought to explain this difference by using specific TLR-pathway knockout mice to test the hypothesis that these co-activator genes are directly regulated through TLR2 signaling. By comparing their responses to S. aureus with WT mice, we found that MyD88-deficient and MAL-deficient mice expressed hepatic Ppargc1a and Ppargc1b normally, but that neither gene was activated in TRAM-deficient mice. Ppargc1a/b activation did not require NF-kβ, but did require an interferon response factor (IRF), because neither gene was activated in IRF-3/7 double-knockout mice in sepsis, but both were activated normally in Unc93b1-deficient (3d) mice. Nuclear IRF-7 levels in TLR2−/− and TLR4−/− mice decreased and increased respectively post-inoculation and IRF-7 DNA-binding at the Ppargc1a promoter was demonstrated by chromatin immunoprecipitation. Also, a TLR2-TLR4-TRAM native hepatic protein complex was detected by immunoprecipitation within 6 h of S. aureus inoculation that could support MyD88-independent signaling to Ppargc1a/b. Overall, these findings disclose a novel MyD88-independent pathway in S. aureus sepsis that links TLR2 and TLR4 signaling in innate immunity to Ppargc1a/b gene regulation in a critical metabolic organ, the liver, by means of TRAM, TRIF, and IRF-7.
Highlights
toll-like receptors (TLR) cell surface receptors that activate innate immunity form specific dimers in response to conserved pathogen-associated molecular patterns (PAMPs) [1]
Studies of Ppargc1 regulation in Unc93b12/2 (3d) mice indicate a lack of involvement of nucleic acid sensing TLRs (TLR3, 7–9), and we identify a post-inoculation interaction of TRAM with TLR2 and TLR4 that may represent a platform for TLR2 signaling to TRAM and interferon response factor (IRF)-3/7
TLR42/2 mice had depressed cytokine up-regulation compared with wild type (WT), but between the two strains only Tnf was statistically different at 6 h PI (TLR42/2 Tnf 6 h PI: 0.6960.28; P,0.01 vs. WT)
Summary
TLR cell surface receptors that activate innate immunity form specific dimers in response to conserved pathogen-associated molecular patterns (PAMPs) [1]. TLR22/2 cells show attenuated cytokine responses to Gram-positive pathogens, such as S. aureus, while MyD882/2 macrophages show no NF-kB-mediated TNF-a and IL-6 production [4]. TLR3 activates TRIF (TICAM-1) and TRAM (TICAM-2) to activate interferon response factors-3 and 7 (IRF-3 and IRF-7) [5,6,7]. Some of these adaptor functions overlap, and TLR2 and TLR4 may signal non-canonically through TRIF [8]. TLR4 is activated by pathogenic S. aureus and Gram-positive cell wall components [10,11,12,13,14,15,16]
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