The TLR2-MyD88-NOD2-RIPK2 signalling axis regulates a balanced pro-inflammatory and IL-10-mediated anti-inflammatory cytokine response to Gram-positive cell walls

Lilian O. Moreira, Karim C. El Kasmi, Amber Smith, David Finkelstein, Sophie Fillon, Yun Gi Kim, Gabriel Núñez, Elaine Tuomanen, Peter J. Murray

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Abstract

Systemic infection with Streptococcus pneumoniae is associated with a vigorous pro-inflammatory response to structurally complex cell wall fragments (PnCW) that are shed during cell growth and antibiotic-induced autolysis. Consistent with previous studies, inflammatory cytokine production induced by PnCW was dependent on TLR2 but independent of NOD2, a cytoplasmic NLR protein. However, in parallel with the pro-inflammatory response, we found that PnCW also induced prodigious secretion of anti-inflammatory IL-10 from macrophages. This response was dependent on TLR2, but also involved NOD2 as absence of NOD2-reduced IL-10 secretion in response to cell wall and translated into diminished downstream effects on IL-10-regulated target gene expression. PnCW-mediated production of IL-10 via TLR2 required RIPK2 a kinase required for NOD2 function, and MyD88 but differed from that known for zymosan in that ERK pathway activation was not detected. As mutations in NOD2 are linked to aberrant immune responses, the temporal and quantitative effects of activation of the TLR2-NOD2-RIPK2 pathway on IL-10 secretion may affect the balance between pro- and anti-inflammatory responses to Gram-positive bacteria.

Original languageEnglish (US)
Pages (from-to)2067-2077
Number of pages11
JournalCellular Microbiology
Volume10
Issue number10
DOIs
StatePublished - Sep 16 2008

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Interleukin-10
Cell Wall
Anti-Inflammatory Agents
Cytokines
Pneumococcal Infections
Autolysis
Zymosan
MAP Kinase Signaling System
Gram-Positive Bacteria
Phosphotransferases
Macrophages
Anti-Bacterial Agents
Gene Expression
Mutation
Growth

All Science Journal Classification (ASJC) codes

  • Microbiology
  • Immunology
  • Virology

Cite this

The TLR2-MyD88-NOD2-RIPK2 signalling axis regulates a balanced pro-inflammatory and IL-10-mediated anti-inflammatory cytokine response to Gram-positive cell walls. / Moreira, Lilian O.; El Kasmi, Karim C.; Smith, Amber; Finkelstein, David; Fillon, Sophie; Kim, Yun Gi; Núñez, Gabriel; Tuomanen, Elaine; Murray, Peter J.

In: Cellular Microbiology, Vol. 10, No. 10, 16.09.2008, p. 2067-2077.

Research output: Contribution to journalArticle

Moreira, Lilian O. ; El Kasmi, Karim C. ; Smith, Amber ; Finkelstein, David ; Fillon, Sophie ; Kim, Yun Gi ; Núñez, Gabriel ; Tuomanen, Elaine ; Murray, Peter J. / The TLR2-MyD88-NOD2-RIPK2 signalling axis regulates a balanced pro-inflammatory and IL-10-mediated anti-inflammatory cytokine response to Gram-positive cell walls. In: Cellular Microbiology. 2008 ; Vol. 10, No. 10. pp. 2067-2077.
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