Gender differences in circulating levels of neutrophil extracellular traps in serum of multiple sclerosis patients

Abstract

Neutrophil extracellular traps (NETs) trap and kill pathogens very efficiently but also activate dendritic cells and prime T cells. Previously, we demonstrated that neutrophils are primed and circulating NETs are elevated in relapsing remitting multiple sclerosis (RRMS), a T cell-mediated autoimmune disease. Here, we demonstrate gender specific differences in circulating NETs but not in neutrophil priming in RRMS patients. Although the results from our systematic and in depth characterization of these patients argue against a major role of circulating NETs in this disease, they suggest that NETs may underlie gender-specific differences in MS pathogenesis. Abstract (100 words)Neutrophil extracellular traps (NETs) trap and kill pathogens very efficiently but also activate dendritic cells and prime T cells. Previously, we demonstrated that neutrophils are primed and circulating NETs are elevated in relapsing remitting multiple sclerosis (RRMS), a T cell-mediated autoimmune disease. Here, we demonstrate gender specific differences in circulating NETs but not in neutrophil priming in RRMS patients. Although the results from our systematic and in depth characterization of these patients argue against a major role of circulating NETs in this disease, they suggest that NETs may underlie gender-specific differences in MS pathogenesis.Key words: Neutrophil, neutrophil extracellular traps (NETs), multiple sclerosis, genderCirculating NETs in MS patients 3 1-IntroductionThe main function of the innate immune system during infection is to eliminate the pathogen, and neutrophils are key players in innate immune responses.Women of reproductive age are more resistant to sepsis and subsequent morbidity and mortality than men (Schroder et al., 1998), and the incidence of sepsis in postmenopausal women increases to levels almost equal to those seen in age-matched men (Martin et al., 2003). Women also have a higher systemic neutrophil count compared with men (Bain and England, 1975a), and neutrophil counts correlate with estradiol levels during menstruation (Bain and England, 1975b) and pregnancy (Efrati et al., 1964) suggesting that sex hormones influence neutrophilia and overall resistance to sepsis most likely by delaying apoptosis in neutrophils (Molloy et al., 2003). In order to eliminate pathogens during infections, neutrophils are armed with a variety of weapons including engulfment and intracellular degradation of microbes (Hampton et al., 1998;Segal, 2005), release of oxygen species and granule proteins (Lehrer and Ganz, 1999) and release of extracellular chromatin fibers bound to granular, nuclear and cytoplasmic proteins called neutrophil extracellular traps (NETs) (Brinkmann et al., 2004). NETs not only trap and kill pathogens very efficiently but also minimize collateral tissue damage by containing proteases to the DNA fibers and act as physical barriers preventing microbial spread. Despite the well documented importance of NETs as an effective antimicrobial first line defense mechanism, there is increasing ...

Granulocyte colony-stimulating factor (G-CSF) increases histone-complexed DNA plasma levels in healthy volunteers

“…Interestingly, there was a significant difference in the levels of hc-DNA between male and female healthy volunteers, which is in contrast to the results of Tillack et al [23]. In their work, Tillack et al detected gender differences in patients diagnosed with remittent-relapsing multiple sclerosis, but not in healthy volunteers or any other patient group under investigation.…”

The contribution of neutrophils to CNS autoimmunity

“…NETs are extracellular matrices composed of fibers containing DNA, decondensed chromatin, histones, and antimicrobial proteins that immobilize and kill microbes [33, 34]. Although beneficial during infection, NETs have been associated with pathophysiological conditions, including MS. A subset of RRMS patients have higher circulating levels of NETs in their sera, although higher levels of NETs did not correlate with disease activity [18, 35]. Interestingly, in vitro studies demonstrated that transendothelial migration of neutrophils across brain endothelium triggered the release of NETs that contributed to neuronal cell death [36].…”

Gestational bisphenol-A exposure lowers the threshold for autoimmunity in a model of multiple sclerosis

“…In mice, G-CSF is important for the mobilization and maturation of neutrophils (27), and neutrophil recruitment to the CNS is critical for EAE development (3-5) through proposed effector mechanisms such as the disruption of the blood-brain barrier and the maturation of antigen-presenting cells (3). In parallel, neutrophils in patients with MS are found to be more numerous and in a primed state (28) with elevated levels of the CD11b integrin (29), and greater propensity to form neutrophil extracellular traps particularly in male compared with female patients with MS (30). In addition, levels of systemic neutrophil chemokines correlate with indices of brain lesion formation in MS (5), and neutrophils have been observed in areas of blood-brain barrier disruption in early lesions of MS (31).…”