Functional heterogeneity and differential priming of circulating neutrophils in human experimental endotoxemia

Abstract

Neutrophils play an important role in host defense. However, deregulation of neutrophils contributes to tissue damage in severe systemic inflammation. In contrast to complications mediated by an overactive neutrophil compartment, severe systemic inflammation is a risk factor for development of immune suppression and as a result, infectious complications. The role of neutrophils in this clinical paradox is poorly understood, and in this study, we tested whether this paradox could be explained by distinct neutrophil subsets and their functionality. We studied the circulating neutrophil compartment immediately after induction of systemic inflammation by administering 2 ng/kg Escherichia coli LPS i.v. to healthy volunteers. Neutrophils were phenotyped by expression of membrane receptors visualized by flow cytometry, capacity to interact with fluorescently labeled microbes, and activation of the NADPH-oxidase by oxidation of Amplex Red and dihydrorhodamine. After induction of systemic inflammation, expression of membrane receptors on neutrophils, such as CXCR1 and -2 (IL-8Rs), C5aR, FcgammaRII, and TLR4, was decreased. Neutrophils were also refractory to fMLF-induced up-regulation of membrane receptors, and suppression of antimicrobial function was shown by decreased interaction with Staphylococcus epidermis. Simultaneously, activation of circulating neutrophils was demonstrated by a threefold increase in release of ROS. The paradoxical phenotype can be explained by the selective priming of the respiratory burst. In contrast, newly released, CD16(dim) banded neutrophils display decreased antimicrobial function. We conclude that systemic inflammation leads to a functionally heterogeneous neutrophil compartment, in which newly released refractory neutrophils can cause susceptibility to infections, and activated, differentiated neutrophils can mediate tissue damage.

Comparative proteome analysis of peripheral neutrophils from sulfur mustard-exposed and COPD patients

“…Recent genomic and proteomic studies showed that PMN isolated from COPD patients displayed altered protein profiles and mRNA expression patterns (Langereis et al, 2011;Oudijk et al, 2005;Pillay et al, 2010). The main finding in the present study's noncontrol subjects was that the proteomes of their PMN had overexpression of S100A8, S100A12, PDI, GAPDH, and SOD, and under-expression of serpin B1, cronin 1A, actin isoforms, coactosin, and Rho GDPDI.…”

“…resting, primed, or activated); these changes are induced by cytokines and chemokines and are likely characterized by epigenetic changes (Oudijk et al, 2005). Phenotype changes not only alter the PMN shape and permit infiltration of injured tissues, but also make the cells functionally hyper-active in response to stimuli (Pillay et al, 2010;Sheppard et al, 2005). Neutrophil serine proteases (NSP), i.e.…”

Neutrophils in cancer: neutral no more

“…However, the consequence of immature neutrophils in the bloodstream of tumor-bearing hosts is not entirely understood. Interestingly, immature neutrophils and neutrophil progenitor cellssome of which express KIT -are found in mouse models and patients with inflammation [69][70][71][72][73] .…”

Immune Cell Dysfunction as a Consequence of Severe Sepsis

“…Ward et al, 2010). The increase in peripheral banded neutrophils appears to be a response of the bone marrow to the widespread apoptosis of mature neutrophils in response to the cytokine storm of sepsis -however, while the newly released neutrophils are rapidly produced, they lack many of the functional aspects of fully differentiated neutrophils (Pillay et al, 2010). The increased number of banded neutrophils therefore may arise at the loss of fully differentiated and functional neutrophils.…”