S100A9 potentiates the activation of neutrophils by the etiological agent of gout, monosodium urate crystals

Abstract

Gout is one of the most painful types of arthritis that arises when the body mounts an acute inflammatory reaction against a crystallized form of uric acid known as monosodium urate crystals (MSUs). Although MSUs are known to activate neutrophils, the most abundant leukocyte in the synovial fluid of patients with gout, few studies have investigated the effect on neutrophils of the simultaneous stimulation with MSU and proinflammatory mediators in the inflamed joint. Herein, we focused on a protein that is highly expressed in the synovium in gout, S100A9. The predominant expression of S100A9 in and around blood vessels suggests it may prime neutrophils during their migration toward the inflamed joint. Using a combination of functional and signaling assays, we found that S100A9 enhances the production of radical oxygen species as well as IL-1 and IL-8 release by human neutrophils activated with MSU. Moreover, upstream and downstream signaling events activated by MSUs in human neutrophils were also potentiated by S100A9, including the mobilization of intracellular calcium stores, tyrosine phosphorylation, the serine phosphorylation of PKC substrates, Akt, and p38. We also show that S100A9 alone increases glycolysis in human neutrophils, which is suggestive of an additional mechanism through which neutrophils can be primed. Together, our observations indicate a novel way in which S100A9 may contribute to the pathogenesis of gout, by priming neutrophils to respond to MSUs.

Gout and pseudo-gout-related crystals promote GLUT1-mediated glycolysis that governs NLRP3 and interleukin-1β activation on macrophages

“…8-10 12 26 Also reported, MSU crystals increased both OXPHOS and glycolytic activity on human neutrophils. 27 These findings further supported the complexity of cellular metabolic programmes and responses, which varied with the type and concentration of stimuli, cell type and cell species and tissue environment. 13 28-30 For example, LPS stimulated Warburg-like metabolic reprogramming in human monocytes at concentrations between 1 and 100 ng/mL but increased OXPHOS at a low dose of 0.1 ng/ mL.…”

“…14 34 Alternatively, MSU and m-CPPD crystal-induced glucose uptake might stimulate IL-1β production through Akt pathway and ROS production. 27 35 36 PI3K (phosphatidylinositol-3 kinase)/Akt pathway is commonly activated by MSU and m-CPPD crystals. 27 36 37 Akt activation enhanced IL-1β production through induction of ROS and glucose metabolism.…”

“…27 35 36 PI3K (phosphatidylinositol-3 kinase)/Akt pathway is commonly activated by MSU and m-CPPD crystals. 27 36 37 Akt activation enhanced IL-1β production through induction of ROS and glucose metabolism. Akt promoted glycolysis through stimulation of HK-2 and glucose uptake via translocation of GLUT1 to cell surface membrane and activation of its downstream mTORC1.…”

Reversal of Sepsis‐Like Features of Neutrophils by Interleukin‐1 Blockade in Patients With Systemic‐Onset Juvenile Idiopathic Arthritis

“…The discovery of the TLR‐4 ligand LPS as a major regulator of the transcriptome changes in systemic‐onset JIA neutrophils, as well as the observed strong overlap in the transcriptome of neutrophils between systemic‐onset JIA and sepsis or experimental endotoxemia, suggest that in vivo exposure to high levels of TLR‐4–stimulatory S100 proteins could explain the inflammatory gene expression in the neutrophils from patients with active systemic‐onset JIA. Indeed, several studies have demonstrated the priming of neutrophils after stimulation with S100 proteins . However, other inflammatory proteins, such as IL‐1β, might also be responsible for the primed phenotype of neutrophils in systemic‐onset JIA.…”

Bmal1 Regulates Macrophage Polarize Through Glycolytic Pathway in Alcoholic Liver Disease

“…Moreover, mass spectrometry screening showed that S100A9 could act as an intermediate protein for Bmal1 to interact with glycolysis. Reports have pointed out that S100A9 independently induce the increase of ECAR, indicating that it can enhance the rate of glycolysis in neutrophils (Rousseau et al, 2017). The ECAR values and protein expression of glycolytic key enzymes were found to be limited after silencing S100A9.…”