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

Authors

  • Lilian O. Moreira,

    1. Department of Infectious Diseases, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA.
    2. Department of Immunology, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA.
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    • Contributed equally to this work.

  • Karim C. El Kasmi,

    1. Department of Infectious Diseases, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA.
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    • Present address: University of Colorado Health Sciences Center, Denver, CO, USA;

    • Contributed equally to this work.

  • Amber M. Smith,

    1. Department of Infectious Diseases, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA.
    2. Department of Immunology, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA.
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  • David Finkelstein,

    1. Hartwell Center for Biotechnology and Bioinformatics, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA.
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  • Sophie Fillon,

    1. Department of Infectious Diseases, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA.
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    • Present address: University of Colorado Health Sciences Center, Denver, CO, USA;

  • Yun-Gi Kim,

    1. Department of Pathology, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA.
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  • Gabriel Núñez,

    1. Department of Pathology, University of Michigan, 1500 East Medical Center Drive, Ann Arbor, MI 48109, USA.
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  • Elaine Tuomanen,

    1. Department of Infectious Diseases, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA.
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  • Peter J. Murray

    Corresponding author
    1. Department of Infectious Diseases, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA.
    2. Department of Immunology, St. Jude Children's Research Hospital, 332 North Lauderdale, Memphis, TN 38105, USA.
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*E-mail peter.murray@stjude.org; Tel. (+1) 901 495 3219; Fax (+1) 901 495 3099.

Summary

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.

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