Editors' ChoiceInflammation

Could Interleukin-33 Be the Stopgap Against Sepsis?

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Science Translational Medicine  26 May 2010:
Vol. 2, Issue 33, pp. 33ec83
DOI: 10.1126/scitranslmed.3001296

A whole-body inflammatory response to infection, sepsis is a deadly disease with a high mortality rate and limited therapeutic options. Sepsis often leads to cardiovascular shock, and the insufficient blood flow to organs and the direct damage caused by the plethora of inflammatory mediators spewed in response to bacterial infection often lead to irreversible multiple-organ failure and death. While our bodies try to fight the infection, our immune system goes haywire and causes so much damage that critically ill patients succumb more to sepsis than to the actual infection, which we can fight quite effectively with antibiotics. There is surprisingly little we can do to inhibit or reverse organ damage and increase survival in septic patients, except for supportive care such as administering drugs that raise the patient’s blood pressure or reduce blood glucose, which is frequently elevated in sepsis. Alves-Filho et al. now show that interleukin-33 (IL-33) reduces death in mice with experimental sepsis.

IL-33 is a member of the IL-1 family and binds a membrane-associated heterodimeric receptor complex consisting of the IL-1 receptor accessory protein and ST2, which is part of a superfamily of proteins that includes the IL-1 and Toll-like receptors (TLRs). ST2 is known to negatively regulate the activation of TLRs—which ignite a key inflammatory signaling pathway—via sequestration of TLR signaling components. In a mouse model of sepsis, the authors show that IL-33 reduced the systemic proinflammatory response but left intact the local response, which is important for clearing the infection. Activation of TLRs in neutrophils is known to inhibit neutrophil migration to the site of infection (chemotaxis). But IL-33 prevented the inhibition of chemotaxis induced by activation of TLR4 in septic mice and in human neutrophils in culture. Furthermore, the authors found that humans who did not recover from sepsis had significantly more soluble ST2, which binds and neutralizes IL-33, than those who did recover. Although these results are exciting because they suggest therapeutic potential for IL-33 in sepsis, a big caveat remains. Thus far, therapeutic strategies that have targeted a single cytokine as a treatment for sepsis have universally failed in clinical trials. Researchers hope that the promise of IL-33 as a treatment for sepsis will not also wane.

J. C. Alves-Filho et al., Interleukin-33 attenuates sepsis by enhancing neutrophil influx to the site of infection. Nat. Med. 16 May 2010 (10.1038/nm.2156) [Abstract]

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