Neutrophil-Derived Hyperresistinemia in Severe Acute Streptococcal Infections

Abstract

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.

Functional Genomic Characterization of Virulence Factors from Necrotizing Fasciitis-Causing Strains of Aeromonas hydrophila

“…However, increases in the level of resistin, a proinflammatory peptide derived from neutrophils, have been correlated with disease severity in both NSTIs and septic shock (98). It is known that degranulation events in neutrophils lead to the release of azurophilic and specific granules into the extracellular space, exposing the surrounding tissue to toxic enzymes and antimicrobial peptides (99).…”

Adipocytokines in Severe Sepsis and Septic Shock

“…In a knock-out mouse model it has been demonstrated that the lack of resistin protects against diet-induced insulin resistance and type 2 diabetes mellitus [40]. Elevated resistin serum levels have been found in critically ill patients with significantly higher concentrations in sepsis than in non-sepsis patients and peak values in septic shock [37,41]. Likely, resistin seems to act as an acute-phase protein and might be part of the systemic inflammatory response, as it has been correlated to IL-6, IL-10, TNF-α, C-reactive protein and procalcitonin [42].…”

“…Human resistin is mainly derived from macrophages and neutrophils as recently reported [37] and not from adipocytes (like in mice [38]) and has been implicated in glucose metabolism and insulin sensitivity. It is named for mediating resistance to insulin through the exacerbation of the adipose tissue inflammation in humans [39].…”

Studying the efficacy of resistin as a diagnostic biomarker of neonatal sepsis

“…Besides its direct proinflammatory effects, IL-6 also increases the CRP production by the liver and the expression of resistin on peripheral blood mononuclear cells [14]. As mentioned before, resistin has emerged as a powerful proinflammatory mediator and its role in both acute and chronic inflammatory processes has been described [7,15]. In adult patients with sepsis, resistin was implicated as an effective biomarker of sepsis severity and as a predictor of mortality of critically ill adult patients.…”

“…In rates, resistin is secreted only by adipocytes, whereas in humans, other cells can secret it as muscle cells, and macrophages [5]. Studies in adult patients with sepsis established that resistin is secreted by the macrophages and neutrophils in response to acute bacterial infection [6,7,8]. In addition, it has been reported that resistin levels is correlated with the severity and duration of the disease *Coresponding Author: Heba Mostafa Ahmed, Beni-Suef University, Faculty of Medicine, Depatrement of Pediatrics, Egypt E-mail: heba_most@yahoo.com in patients with sepsis and septic shock [8].…”