Carbon monoxide down-modulates Toll-like receptor 4/MD2 expression on innate immune cells and reduces endotoxic shock susceptibility

Authors

  • Sebastián A. Riquelme,

    1. Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
    2. INSERM, UMR 1064, Nantes, France
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  • Susan M. Bueno,

    Corresponding author
    1. Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
    2. INSERM, UMR 1064, Nantes, France
    • Correspondence: Dr Alexis M. Kalergis or Susan M. Bueno, Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Avenida Libertador Bernardo O'Higgins #340, Santiago 8331010, Chile.

      Emails: akalergis@bio.puc.cl, sbueno@bio.puc.cl and akalergis@icloud.com

      Senior author: Alexis M. Kalergis and Susan M. Bueno

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  • Alexis M. Kalergis

    Corresponding author
    1. Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Santiago, Chile
    2. INSERM, UMR 1064, Nantes, France
    3. Departamento de Inmunología y Reumatología, Facultad de Medicina, Pontificia Universidad Católica de Chile, Santiago, Chile
    • Correspondence: Dr Alexis M. Kalergis or Susan M. Bueno, Millennium Institute on Immunology and Immunotherapy, Departamento de Genética Molecular y Microbiología, Facultad de Ciencias Biológicas, Pontificia Universidad Católica de Chile, Avenida Libertador Bernardo O'Higgins #340, Santiago 8331010, Chile.

      Emails: akalergis@bio.puc.cl, sbueno@bio.puc.cl and akalergis@icloud.com

      Senior author: Alexis M. Kalergis and Susan M. Bueno

    Search for more papers by this author

Summary

Carbon monoxide (CO) has been recently reported as the main anti-inflammatory mediator of the haem-degrading enzyme haem-oxygenase 1 (HO-1). It has been shown that either HO-1 induction or CO treatment reduces the ability of monocytes to respond to inflammatory stimuli, such as lipopolysaccharide (LPS), due to an inhibition of the signalling pathways leading to nuclear factor-κB, mitogen-activated protein kinases and interferon regulatory factor 3 activation. Hence, it has been suggested that CO impairs the stimulation of the Toll-like receptor 4 (TLR4)/myeloid differentiation factor-2 (MD2) complex located on the surface of immune cells. However, whether CO can negatively modulate the surface expression of the TLR4/MD2 complex in immune cells remains unknown. Here we report that either HO-1 induction or treatment with CO decreases the surface expression of TLR4/MD2 in dendritic cells (DC) and neutrophils. In addition, in a septic shock model of mice intraperitoneally injected with lipopolysaccharide (LPS), prophylactic treatment with CO protected animals from hypothermia, weight loss, mobility loss and death. Further, mice pre-treated with CO and challenged with LPS showed reduced recruitment of DC and neutrophils to peripheral blood, suggesting that this gas causes a systemic tolerance to endotoxin challenge. No differences in the amount of innate cells in lymphoid tissues were observed in CO-treated mice. Our results suggest that CO treatment reduces the expression of the TLR4/MD2 complex on the surface of myeloid cells, which renders them resistant to LPS priming in vitro, as well as in vivo in a model of endotoxic shock.

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