Induction of neutrophil degranulation by S100A9 via a MAPK-dependent mechanism

Abstract

S100A9 is a proinflammatory protein, expressed abundantly in the cytosol of neutrophils and monocytes. High extracellular S100A9 concentrations have been correlated with chronic inflammatory diseases such as rheumatoid arthritis and Crohn's disease, as well as with phagocyte extravasation. This study tested the hypothesis that S100A9 induces degranulation in human neutrophils. S100A9 was found to up-regulate the surface expression of CD35 and CD66b, proteins contained in secretory vesicles and specific/gelatinase granules, respectively. In addition, gelatinase and albumin, stored, respectively, in specific/gelatinase granules and secretory vesicles, were detected in the supernatants of neutrophils stimulated with S100A9. In contrast, stimulation with S100A9 had no effect on CD63 expression or MPO secretion, two proteins contained in azurophilic granules. S100A9 induced the phosphorylation of the MAPKs, ERK1/2, p38, and JNK. Inhibition of p38 and JNK but not ERK1/2, with specific inhibitors (SB203580, JNKII, and PD98059, respectively), blocked neutrophil degranulation induced by S100A9. Taken together, these results support the hypothesis and clearly indicate that S100A9 induces the degranulation of secretory and specific/gelatinase granules but not of azurophilic granules in a process involving p38 and JNK and further support its classification as a DAMP.

Neutrophils and the S100A9 protein critically regulate granuloma formation

“…Extracellular S100A9 is known to induce the phosphorylation of MAPKs, such as p38, and JNK in human neutrophils, leading to degranulation 41 ; thus, the release of S100A9 from neutrophils and its condensed local accumulation in the central area of granulomas may result in exhaustive degranulation in an autocrine manner. Alternatively, neutrophil degranulation may be facilitated by environmental factors.…”

Use of rapid cytochemical staining to characterize fish blood granulocytes in species of special concern and determine potential for function testing

“…Leukocyte alkaline phosphatase (AP) is present in both tertiary granules of mammalian neutrophils, as well as in some fish species neutrophils and heterophils [4,11]. The use of p-Nitrophenyl Phosphate as substrate for leukocyte AP has been described for mammals [26], and has been adapted in this study for use in sturegon heterophil degranulation assay.…”

Role of the Neutrophil NADPH Oxidase and S100A8/A9 in the Pathophysiology of Chronic Inflammation

“…S100A and S100A9 are known to have antimicrobial effects, transport arachidonic acid to endothelial cells and activate expression of endothelial cell adhesion molecules. Furthermore, the role of S100A8/S100A9 on degranulation (Simard et al, 2010) and on neutrophil migration (Vandal et al, 2003) has been suggested. S100A8 was recently identified as an endogenous ligand of Toll-like receptor 4 (TLR4), amplifying phagocyte activation during inflammation upstream of TNF--dependent effects.…”