Reprogramming of a subpopulation of human blood neutrophils by prolonged exposure to cytokines

Abstract

Essential cells of innate immunity, neutrophils are often considered to be a homogenous population of terminally differentiated cells. During inflammation, neutrophils are extravasated cells exposed to local factors that prolong their survival and activate their production of mediators implicated in disease progression. In this study, a phenotypically distinct subset of human neutrophils that appear after prolonged exposure to cytokines was characterized. Freshly isolated neutrophils from healthy donors were incubated with granulocyte-macrophage colony-stimulating factor, tumor necrosis factor-a and interleukin (IL)-4, three cytokines that are locally present in various inflammatory conditions. Eight to 17% of neutrophils survived beyond 72 h. This subset of non-apoptotic neutrophils, as evaluated by three different markers, was enriched by discontinuous Percoll gradient centrifugation before studying their phenotype. These viable neutrophils showed neoexpression of HLA-DR, CD80 and CD49d. Compared with freshly isolated neutrophils, they responded differentially to second signals similar to formyl-methionyl-leucyl-phenylalanine with three-to four-fold increases in production of superoxide anions and leukotrienes. These cells augmented their phagocytic index by 141%, increased their adhesion to human primary fibroblasts, but reduced their migration in response to chemotactic stimuli and decreased exocytosis of primary and secondary granules. In addition, they produced substantial amounts of IL-8, IL-1Ra and IL-1b. This neutrophil subset had a unique profile of phosphorylation of intracellular signaling molecules. In conclusion, the present identification of a novel neutrophil phenotype highlights the reprogammable character of the neutrophil. This aspect is crucial for our understanding of its contribution to disease pathogenesis and host defense.

Sepsis lethality via exacerbated tissue infiltration and TLR-induced cytokine production by neutrophils is integrin α3β1-dependent

“…36 Moreover, subsets of neutrophils with distinct cytokine and chemokine production profiles, different effects on macrophage activation, and unique surface antigen expression have been identified in mice 37 and humans. 38 Our findings therefore further extend the current understanding of neutrophil characteristics in the mammalian immune system.…”

Neonatal Neutrophils with Prolonged Survival Secrete Mediators Associated with Chronic Inflammation

“…Exposure of neutrophils to bacterial components or cytokines can prolong their longevity, and these surviving neutrophils retain inflammatory and cytotoxic functions, including the secretion of critical mediators [22][23][24] . However, less information exists regarding neutrophils that survive spontaneous apoptosis in the absence of survival factors, which may also represent the subpopulation of neutrophils with the capacity for very prolonged survival with intact inflammatory function [24] .…”

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