Abstract
S100A9, a Ca2+-binding protein, is tightly associated to neutrophil pro-inflammatory functions when forming a heterodimer with its S100A8 partner. Upon secretion into the extracellular environment, these proteins behave like damage-associated molecular pattern molecules, which actively participate in the amplification of the inflammation process by recruitment and activation of pro-inflammatory cells. Intracellular functions have also been attributed to the S100A8/A9 complex, notably its ability to regulate nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation. However, the complete functional spectrum of S100A8/A9 at the intracellular level is far from being understood. In this context, we here investigated the possibility that the absence of intracellular S100A8/A9 is involved in cytokine secretion. To overcome the difficulty of genetically modifying neutrophils, we used murine neutrophils derived from wild-type and S100A9−/− Hoxb8 immortalized myeloid progenitors. After confirming that differentiated Hoxb8 neutrophil-like cells are a suitable model to study neutrophil functions, our data show that absence of S100A8/A9 led to a dysregulation of cytokine secretion after lipopolysaccharide (LPS) stimulation. Furthermore, we demonstrate that S100A8/A9-induced cytokine secretion was regulated by the nuclear factor kappa B (NF-κB) pathway. These results were confirmed in human differentiated HL-60 cells, in which S100A9 was inhibited by shRNAs. Finally, our results indicate that the degranulation process could be involved in the regulation of cytokine secretion by S100A8/A9.
Highlights
Using ER-Hoxb8 cells from S100A9 wild-type and knock-out mice as well as human differentiated HL-60 cells infected with lentiviral S100A9-shRNAs, we demonstrated a novel role for S100A8/A9, which is the regulation of cytokine secretion through NF-κB
S100A8, represents one of the most abundant protein complexes found in the cytosol of neutrophils, a knowledge gap remains between its established involvement in the regulation of neutrophil pro-inflammatory functions and its potential contribution to cytokine secretion
Neutrophils being terminally differentiated with a short lifespan, neither expandable in culture nor genetically modifiable, makes them ill-suited for long-term experiments necessary for the characterization of functional roles of S100A8/A9
Summary
Publisher’s Note: MDPI stays neutral with regard to jurisdictional claims in published maps and institutional affiliations. S100A9, together with its partner S100A8, are cytosolic Ca2+ -binding proteins highly expressed in neutrophils, which can operate as homo- or heterodimers [1,2]. An impediment in the formation of tetramers has been associated with a deficiency of intracellular. S100A8/A9 functions highlighting the fact that the heterotetramers, which are formed during an increase of Ca2+ concentration [3], represent the privileged form for the activity of S100A9 [4]. It has later been reported that due to their conformational state after
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