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A toll-like receptor 2 pathway regulates the Ppargc1a/b metabolic co-activators in mice with Staphylococcal aureus sepsis.

Publication ,  Journal Article
Sweeney, TE; Suliman, HB; Hollingsworth, JW; Welty-Wolf, KE; Piantadosi, CA
Published in: PLoS One
2011

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.

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Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2011

Volume

6

Issue

9

Start / End Page

e25249

Location

United States

Related Subject Headings

  • Transcription Factors
  • Trans-Activators
  • Toll-Like Receptor 4
  • Toll-Like Receptor 2
  • Staphylococcus aureus
  • Sepsis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Repressor Proteins
  • Receptors, Interleukin-1
  • Receptors, Interleukin
 

Citation

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Sweeney, T. E., Suliman, H. B., Hollingsworth, J. W., Welty-Wolf, K. E., & Piantadosi, C. A. (2011). A toll-like receptor 2 pathway regulates the Ppargc1a/b metabolic co-activators in mice with Staphylococcal aureus sepsis. PLoS One, 6(9), e25249. https://doi.org/10.1371/journal.pone.0025249
Sweeney, Timothy E., Hagir B. Suliman, John W. Hollingsworth, Karen E. Welty-Wolf, and Claude A. Piantadosi. “A toll-like receptor 2 pathway regulates the Ppargc1a/b metabolic co-activators in mice with Staphylococcal aureus sepsis.PLoS One 6, no. 9 (2011): e25249. https://doi.org/10.1371/journal.pone.0025249.
Sweeney TE, Suliman HB, Hollingsworth JW, Welty-Wolf KE, Piantadosi CA. A toll-like receptor 2 pathway regulates the Ppargc1a/b metabolic co-activators in mice with Staphylococcal aureus sepsis. PLoS One. 2011;6(9):e25249.
Sweeney, Timothy E., et al. “A toll-like receptor 2 pathway regulates the Ppargc1a/b metabolic co-activators in mice with Staphylococcal aureus sepsis.PLoS One, vol. 6, no. 9, 2011, p. e25249. Pubmed, doi:10.1371/journal.pone.0025249.
Sweeney TE, Suliman HB, Hollingsworth JW, Welty-Wolf KE, Piantadosi CA. A toll-like receptor 2 pathway regulates the Ppargc1a/b metabolic co-activators in mice with Staphylococcal aureus sepsis. PLoS One. 2011;6(9):e25249.

Published In

PLoS One

DOI

EISSN

1932-6203

Publication Date

2011

Volume

6

Issue

9

Start / End Page

e25249

Location

United States

Related Subject Headings

  • Transcription Factors
  • Trans-Activators
  • Toll-Like Receptor 4
  • Toll-Like Receptor 2
  • Staphylococcus aureus
  • Sepsis
  • Reverse Transcriptase Polymerase Chain Reaction
  • Repressor Proteins
  • Receptors, Interleukin-1
  • Receptors, Interleukin