Editors' ChoiceSepsis

Quelling a Shock to the System

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Science Translational Medicine  23 Jun 2010:
Vol. 2, Issue 37, pp. 37ec101
DOI: 10.1126/scitranslmed.3001361

It is an all-too-common occurrence: "It was just an infection, she didn’t seem that sick, it all happened so fast..." When a bacterial infection invades the bloodstream—a condition known as sepsis—it can be deadly, quickly. A systemic inflammatory condition ignited by an uncontrolled bacterial infection, sepsis remains a major cause of mortality in the intensive care unit. Currently, few options exist for the treatment of clinical sepsis, and these therapies have been met with limited success. Now, Alves-Filho et al. demonstrate that the cytokine interleukin-33 (IL-33) may attenuate sepsis by recruiting neutrophils to the source of infection and facilitating bacterial clearance.

The researchers induced sepsis in mice by a common experimental method: puncturing the colon and allowing bacteria to enter the normally sterile peritoneal cavity. Using this model system, Alves-Filho et al. found that animals treated with IL-33 before or shortly after the infectious insult displayed fewer signs of peritonitis and experienced significantly higher survival rates. Treatment with IL-33 was associated with more neutrophils, but fewer bacteria in the peritoneal cavity and reduced amounts of proinflammatory mediators in the bloodstream.

The toll-like receptor 4 (TLR4), which functions as part of the innate immune system by recognizing pathogenic components during infections, down-regulates expression of the chemokine receptor CXCR2 in neutrophils and impairs their influx to the site of infection. The researchers showed that IL-33 promotes neutrophil migration to the infectious source by preventing the TLR4-induced down-regulation of CXCR2. To extend these findings to humans, the authors analyzed peripheral blood cell samples from patients with sepsis. Neutrophils from individuals who did not survive sepsis exhibited lower CXCR2 expression and decreased neutrophil migration ability as compared with that of survivors and healthy individuals.

The results of the study by Alves-Filho et al. show that IL-33 plays an important protective role by mitigating the development of sepsis. The safe and efficient delivery of IL-33 to patients has yet to be explored, and historically even extremely successful treatments for sepsis in animal models have not been translated into the clinic. Nevertheless, IL-33 has the potential of becoming an effective treatment option for clinical sepsis.

J. C. Alves-Filho et al., Interleukin-33 attenuates sepsis by enhancing neutrophil influx to the site of infection. Nat. Med. 13, 708–712 (2010). [Abstract]

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