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* Center for Infectious Medicine, Karolinska Institutet, Department of Medicine F59, Karolinska University Hospital, Stockholm, Sweden; and
Department of Clinical Sciences, Lund University, Lund, Sweden
The concept of neutrophil activation and degranulation as important contributors to disease pathology in invasive group A streptococcal infections has recently been emphasized. This study focuses on two of the most severe streptococcal manifestations, toxic shock syndrome and necrotizing fasciitis, and the newly described proinflammatory molecule resistin, known to derive from adipocytes and monocytes. We demonstrate for the first time that these conditions are characterized by hyperresistinemia in circulation as well as at the local site of infection. Importantly, analyses of patient tissue biopsies and whole blood revealed that neutrophils represent a novel and dominant source of resistin in bacterial septic shock. This was confirmed by the identification of resistin within neutrophil azurophilic granules. In vitro assays using primary neutrophils showed that resistin release was readily triggered by streptococcal cell wall components and by the streptococcal M1 protein, but not by the potent streptococcal superantigens. This is the first report demonstrating that resistin is released from neutrophils in response to microbial stimuli, which adds resistin to the neutrophil granule proteins that are likely to contribute to the pathologic inflammatory responses associated with severe streptococcal infections.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was financially supported by grants from the European Union’s Sixth Framework Program (ASSIST), the Swedish Foundation for Strategic Research, the Torsten and Ragnar Söderberg Foundation, the Swedish Research Council, Svenska Sällskapet för Medicinsk Forskning, the Magnus Bergvall Foundation, the Åke Wiberg Foundation, the Anders Otto Swärd Foundation, the Lars Hierta Foundation, Stiftelsen Clas Groschinsky Minnesfond, Stiftelsen Längmanska Kulturfonden and the Swedish Society of Medicine (12610 and 13413), Karolinska University Hospital, and the Karolinska Institutet.
2 A.L., J.S.-C., and A.H. contributed equally to this study.
3 Address correspondence and reprint requests to Dr. Anna Norrby-Teglund, Karolinska Institutet, Karolinska University Hospital Huddinge F59, Stockholm, S-141 86, Sweden. E-mail address: Anna.Norrby-Teglund{at}ki.se
4 Abbreviations used in this paper: STSS, streptococcal toxic shock syndrome; ACIA, acquired computerized image analysis; MOI, multiplicity of infection; MPO, myeloperoxidase; PPAR
, peroxisome proliferator-activated receptor .
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