The defensive alliance between neutrophils and NK cells as a novel arm of innate immunity

Abstract

The immune system is equipped with a plethora of mechanisms that protect the host from the harmful effects of environmental insults. However, the traditional "hierarchical" view of the immune response, in which innate, "nonspecific" cells are first recruited to the site of damage, before the highly "specific", adaptive immune response develops, has been questioned recently. First, the innate response is much more specific than recognized previously: indeed, each cell of the innate system is not only endowed with an ever-expanding array of germ-line-encoded receptors, which differentiate between distinct insults, but also is modulated continuously by other leukocytes that concomitantly interact with and respond to that particular insult. The other reason is that the cells of the innate system are instrumental for the adaptive system to accomplish its function, as they can also modulate the activity of lymphocytes reciprocally during the entire course of the immune response. This complex pattern of interactions is illustrated by recent advances on the functions of PMNs, clearly showing that unexpectedly, these cells also contribute to the regulation of the host immune response by crosstalk with innate and adaptive leukocytes, including NK cells. Herein, given the peculiar role of neutrophils and NK cells in inflammation, clearance of pathogens/viral-infected cells, and cancer immunosurveillance, we summarize the current knowledge about the mechanisms whereby neutrophils and NK cells interact and regulate the activities of one another, as well as discuss their potential implications involved in the pathogenesis of chronic, inflammatory pathologies, infections, and tumors.

Proinflammatory Proteins S100A8/S100A9 Activate NK Cells via Interaction with RAGE

“…In addition, numerous other functions are currently attributed to neutrophils, such as the capacity to regulate various aspects of the inflammatory, immune, angiogenic, hematopoietic, wound-healing, antiviral, and antitumoral responses (24,25). Recent evidence indicated that there is crosstalk between neutrophils and NK cells as follows: NK cellderived IFN-g modulates the survival, migration into inflammatory sites, and functional responses of neutrophils, and conversely, neutrophil-derived IL-15 and IL-18 are essential for NK cell activation and proliferation (4). Based on recent observation, it is possible to speculate that additional neutrophil-derived factors affect the activity of NK cells (26).…”

“…NK cells need to be primed with cytokines such as IL-12, IL-15, and IL-18, and by crosstalk with accessory cells to achieve their effector potential (3). Although multiple mechanisms have been clarified for the acquisition of their effector functions (4), it is believed that there are still unknown major mediators for modulating the maturation, activation, and survival of NK cells (4). S100A8 and S100A9, which belong to a family of 25 homologous low-m.w.…”

Activation of TAK1 by Chemotactic and Growth Factors, and Its Impact on Human Neutrophil Signaling and Functional Responses

“…Activation of TAK1 by chemoattractants and GM-CSF in human neutrophils. (A) Cells were stimulated for the indicated times with 1 nM GM-CSF, 30 nM fMLF, or 30 nM LTB 4 . After cell disruption, TAK1 was immunoprecipitated from the lysates; immunoprecipitates were split in two parts, which were either immediately analyzed in kinase assays using MBP as a substrate or processed for SDS-PAGE and subsequent immunoblot analysis of their TAK1 content.…”

“…Diisopropyl fluorophosphate, fMLF, myelin basic protein (MBP), PMSF, and propidium iodide were from Sigma-Aldrich (St. Louis, MO). LTB 4 and PAF were from Cayman Chemical (Ann Arbor, MI). The protease inhibitors, aprotinin, 4-(2-aminomethyl)benzenesulfonyl fluoride, leupeptin, and pepstatin A, were all from Roche (Laval, QC, Canada).…”

On the potential involvement of CD11d in co-stimulating the production of interferon- by natural killer cells upon interaction with neutrophils via intercellular adhesion molecule-3

“…While performing their specific activities, innate immune cells continuously interact to modulate each others' activities and adapt their response to the specific characteristics of the insult. The role of neutrophils in shaping the developing immune response is increasingly being recognized, not only for their cross-talks with components of the innate immune system, such as monocytes and macrophages, 1 dendritic cells (DC) 2 and natural killer (NK) cells, 3 but also with unpolarized/polarized T lymphocytes. 4 Recently, we have discovered and have started characterizing a novel network within the innate immune response in which human neutrophils can directly cooperate with both NK cells and one of the major DC subsets present in the blood and tissues, known as 6-sulfo LacNAc + DC (slanDC), to ultimately amplify the production of IFNγ by NK cells upon activation with LPS plus the IL-15/IL-18 combination.…”