Peptidoglycan induces bradykinin receptor 1 expression through Toll-like receptor 2 and NF-κB signaling pathway in human nasal mucosa-derived fibroblasts of chronic rhinosinusitis patients.

Numerous studies have demonstrated that Gram-positive microbiomes play an important role in the pathogenesis and in the way of treatment of chronic rhinosinusitis (CRS). Kinins are inflammatory mediators and one of their receptors, namely bradykinin receptor 1 (BKR1 or B1R), is believed to be induced and involved in inflammation in pathophysiological conditions. In the present study, we investigated the effect of peptidoglycan (PGN), a major cell wall component of G(+) bacteria, on BKR expression and its signaling pathway in nasal fibroblasts from CRS without nasal polyp (CRSsNP). The PGN induced increases in B1R mRNA and protein production. The induction was abolished by the NF-κB and protein kinase A inhibitor. In parallel, the PGN treatment directly activated IκB/NF-κB signaling and CREB phosphorylation. Interestingly, a further analysis suggested no involvement of cAMP/PKA/CREB pathway in this induction. The B1R expression and IκB/NF-κB signaling pathway could be attenuated by Toll-like receptor-2 (TLR2) blocking/neutralizing Ab. In a functional assay, the addition of B1R selective agonist (Des-Arg10 -kallidin) to the fibroblasts after PGN stimulation led to an increase in CXCL8 release and p38 MAPK and ERK1/2 phosphorylation, which could be inhibited by the B1R antagonist. Taken together, our results revealed for the first time that PGN can increase B1R expression in human nasal mucosa-derived fibroblasts through TLR2 activation and NF-κB signaling pathway. This induction functionally leads to MAPKs activation and CXCL8 release upon B1R stimulation. Our results also suggest that a major component of G(+) bacteria can participate in B1R upregulation in nasal mucosa during CRSsNP progression.