S100A4 Induces Neutrophilic Inflammation in Chronic Rhinosinusitis with Nasal Polyps via TLR4 Pathway

Treating neutrophilic inflammation in chronic rhinosinusitis with nasal polyps (CRSwNP) remains a challenge. Managing excessive infiltration and activation of neutrophils in tissues is important for improving CRSwNP outcomes. S100A4, a calcium-binding protein, regulates cell migration, chemotaxis and tissue fibrosis. In this study, we sought to examine the role of S100A4 in neutrophilic inflammation in CRSwNP and its involvement in TLR4 signaling.

Quantitative RT-PCR and immunofluorescence were used to analyze the expression and cellular distribution of S100A4 in sinonasal mucosa. Primary human nasal epithelial cells (hNECs) were cultured and treated with S100A4 to assess cytokine and chemokine production. Additionally, we employed TLR4 inhibitor (TAK-242) to investigate whether S100A4 exert this effect via TLR4 pathway.

We found increased levels of S100A4 mRNA and S100A4⁺ cell number in CRSwNP patients compared with control, with the highest levels in uncontrolled and mixed eosinophilic-neutrophilic CRSwNP. Compared to eosinophils, S100A4 exhibits a stronger correlation with neutrophils. S100A4 was primarily located in inflammatory cells in lamina propria, with neutrophils forming the majority of S100A4⁺ cells. S100A4 treatment led to upregulation of neutrophil chemokines and pro-inflammatory cytokine IL-36γ, in nasal epithelia cells. S100A4 induced effect through TLR4 pathway, and can be inhibited by clarithromycin and dexamethasone.

S100A4 is elevated in neutrophilic CRSwNP and exerts its pro-inflammatory effect on nasal epithelial cells via TLR4 signaling cascade.