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Interleukin-33 attenuates sepsis by enhancing neutrophil influx to the site of infection

Nature Medicine volume 16, pages 708–712 (2010)Cite this article

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Abstract

Sepsis is a systemic inflammatory condition following bacterial infection with a high mortality rate and limited therapeutic options1,2. Here we show that interleukin-33 (IL-33) reduces mortality in mice with experimental sepsis from cecal ligation and puncture (CLP). IL-33–treated mice developed increased neutrophil influx into the peritoneal cavity and more efficient bacterial clearance than untreated mice. IL-33 reduced the systemic but not the local proinflammatory response, and it did not induce a T helper type 1 (TH1) to TH2 shift. The chemokine receptor CXCR2 is crucial for recruitment of neutrophils from the circulation to the site of infection3. Activation of Toll-like receptors (TLRs) in neutrophils downregulates CXCR2 expression and impairs neutrophil migration4. We show here that IL-33 prevents the downregulation of CXCR2 and inhibition of chemotaxis induced by the activation of TLR4 in mouse and human neutrophils. Furthermore, we show that IL-33 reverses the TLR4-induced reduction of CXCR2 expression in neutrophils via the inhibition of expression of G protein–coupled receptor kinase-2 (GRK2), a serine-threonine protein kinase that induces internalization of chemokine receptors5,6. Finally, we find that individuals who did not recover from sepsis had significantly more soluble ST2 (sST2, the decoy receptor of IL-33) than those who did recover. Together, our results indicate a previously undescribed mechanism of action of IL-33 and suggest a therapeutic potential of IL-33 in sepsis.

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Figure 1: IL-33 attenuates sepsis and increases neutrophil influx to the site of infection and bacteria clearance.
Figure 2: IL-33 treatment reduces systemic proinflammatory cytokine, chemokine and lung myeloperoixdase (MPO) activity but increases CXCR2 expression on, and chemotaxis of, neutrophils.
Figure 3: IL-33 blocks the downregulation of CXCR2 and chemotaxis mediated by LPS in vitro.
Figure 4: IL-33 blocks the induction of GRK2 by LPS.

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Acknowledgements

This work was supported by the Wellcome Trust, the UK Medical Research Council, the UK and the EU (to F.Y.L.) and the State of São Paulo Research Foundation and National Research Council, Brazil (to F.Q.C.). Tlr4−/− and Myd88−/− mice were from S. Akira (University of Osaka).

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Authors and Affiliations

  1. Division of Immunology, Infection and Inflammation, Glasgow Biomedical Research Centre, University of Glasgow, Glasgow, UK

    Jose C Alves-Filho, Damo Xu & Foo Y Liew

  2. Department of Pharmacology, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil

    Jose C Alves-Filho, Fabiane Sônego, Fabricio O Souto, Andressa Freitas, Waldiceu A Verri Jr & Fernando Q Cunha

  3. Division of Intensive Care, Department of Surgery and Anatomy, School of Medicine of Ribeirão Preto, University of São Paulo, Ribeirão Preto, Brazil

    Maria Auxiliadora-Martins & Anibal Basile-Filho

  4. Medical Research Council Laboratory of Molecular Medicine, Cambridge, UK

    Andrew N McKenzie

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Correspondence to Fernando Q Cunha or Foo Y Liew.

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Alves-Filho, J., Sônego, F., Souto, F. et al. Interleukin-33 attenuates sepsis by enhancing neutrophil influx to the site of infection. Nat Med 16, 708–712 (2010). https://doi.org/10.1038/nm.2156

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