Neutrophil activation and survival are modulated by interaction with NK cells

Abstract

It is increasingly evident that neutrophils are able to cross-talk with other leukocytes to shape ongoing inflammatory and immune responses. In this study, we analyzed whether human NK cells may influence the survival and activation of neutrophils under co-culture conditions. We report that NK cells exposed to either IL-15 or IL-18 alone strongly protect the survival of neutrophils via the release of IFNγ and granulocyte macrophage colony-stimulating factor (GM-CSF) plus IFNγ, respectively, and cause a slight up-regulation of neutrophil CD64 and CD11b expression. In comparison, NK cells exposed to both IL-15 and IL-18 show a lesser ability to increase the survival of neutrophils but can more potently up-regulate CD64 and CD11b expression, as well as induce the de novo surface expression of CD69, in neutrophils. Analysis of the events occurring in neutrophil/NK co-cultures exposed to IL-15 plus IL-18 revealed that (i) neutrophil survival is positively affected by NK-derived GM-CSF but negatively influenced by a CD18-dependent neutrophil/NK contact, (ii) NK-derived IFNγ is almost entirely responsible for the induction of CD64, (iii) both soluble factors (primarily GM-CSF) and direct cell-cell contact up-regulate CD11b and CD69 and (iv) NK-derived GM-CSF induces the expression of biologically active heparin-binding EGF-like growth factor (HB-EGF) in neutrophils. Finally, we demonstrate that NK cells can also express HB-EGF when stimulated with either IL-2 or IL-15, yet independently of endogenous GM-CSF. Altogether, our results define a novel interaction within the innate immune system whereby NK cells, by directly modulating neutrophil functions, might contribute to the pathogenesis of inflammatory diseases.

Natural Killer (NK) Cells in Antibacterial Innate Immunity: Angels or Devils?

“…During L. pneumophila infection, neutrophils immediately produce IL-18, which is indispensable for NK cell activation (165). As mentioned above for macrophages, NK cells can also activate neutrophils and promote their survival; upregulate cell surface expression of CD64, CD11b and CD69; and enhance the production of superoxide anions and heparinbinding epidermal growth factor (166). This property observed when NK cells were exposed to IL-15 and IL-18 partially depended on their production of GM-CSF.…”

A Polysaccharide Virulence Factor of a Human Fungal Pathogen Induces Neutrophil Apoptosis via NK Cells

“…Previous studies have addressed the reciprocal crosstalk of NK cells with PMNs, focusing mainly on the effects of PMNs on NK cell functions and demonstrating that PMNs favor the terminal maturation of NK cells and the acquisition of their full effector functions (6). Furthermore, it has been suggested that soluble factors (IFN-g or GM-CSF) released by cytokine-activated NK cells (i.e., IL-2-treated NK) send survival signals to PMNs and may promote their accumulation for extended time periods at the inflammation site and support their functions there (7,41). In contrast, Thorén et al (26) recently reported that NK cells accelerate spontaneous apoptosis of isolated PMNs.…”

“…Although NK cells can directly recognize some pathogens, it is becoming increasingly clear that NK cell activation requires the presence of such accessory cells as monocytes, macrophages, and dendritic cells (DCs) (2)(3)(4)(5). In addition, previous studies have described the interaction between PMNs and NK cells and its role in the regulation of their separate activities (6,7), but few have addressed the receptors involved in this cross-talk. Moreover, the consequence of this crosstalk during microbial infections has never been investigated.…”

Feedback Amplification of Neutrophil Function

“…IL-18-activated NK cells can prolong neutrophil survival through the production of GM-CSF and IFNγ [92]. For further cooperative amplification loops between neutrophils and T cells or NK cells, we refer to previous review articles [79,93].…”