Induction of neutrophil degranulation by S100A9 via a MAPK-dependent mechanism
Jean-Christophe Simard1, Denis Girard, Philippe A Tessier
1Laboratoire de Recherche en Inflammation et Physiologie des Granulocytes, Université du Québec, INRS-Institut Armand-Frappier, Laval, Quebec, Canada.
Insights
S100A9 protein triggers degranulation in human neutrophils by activating specific cellular pathways. This finding clarifies S100A9
Area of Science:
- Immunology
- Cell Biology
- Biochemistry
Background:
- S100A9 is a pro-inflammatory protein found in neutrophils and monocytes.
- Elevated extracellular S100A9 levels are linked to chronic inflammatory conditions and phagocyte migration.
Purpose of the Study:
- To investigate whether S100A9 induces degranulation in human neutrophils.
- To elucidate the molecular mechanisms underlying S100A9-mediated neutrophil activation.
Main Methods:
- Human neutrophils were stimulated with S100A9.
- Surface expression of degranulation markers (CD35, CD66b, CD63) was analyzed.
- Secretion of granule contents (gelatinase, albumin, MPO) was measured.
- Mitogen-activated protein kinase (MAPK) phosphorylation (ERK1/2, p38, JNK) was assessed.
- Specific MAPK inhibitors were used to block degranulation.
Main Results:
- S100A9 increased surface expression of CD35 and CD66b, indicating secretory and specific/gelatinase granule release.
- Gelatinase and albumin were detected in supernatants, confirming granule content release.
- S100A9 did not affect CD63 expression or MPO secretion (azurophilic granules).
- S100A9 induced phosphorylation of ERK1/2, p38, and JNK.
- Inhibition of p38 and JNK, but not ERK1/2, blocked S100A9-induced degranulation.
Conclusions:
- S100A9 induces degranulation of secretory and specific/gelatinase granules in human neutrophils.
- This process involves the activation of p38 and JNK MAPKs.
- The findings support S100A9's role as a damage-associated molecular pattern (DAMP) in inflammation.
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.
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