SARS-CoV-2 spike protein receptor binding domain promotes IL-6 and IL-8 release via ATP/P2Y2 and ERK1/2 signaling pathways in human bronchial epithelia

• Published in: Molecular immunology Vol. 167; pp. 53 - 61
• Main Authors: Zhang, Rui-Gang, Liu, Xing-Jian, Guo, Yu-Ling, Chen, Chun-Ling
• Format: Journal Article
• Language: English
• Published: Elsevier Ltd 01.03.2024
• Subjects: antibodies; ATP; Bronchial epithelia; epithelium; ERK1/2; humans; inflammation; interleukin-6; interleukin-8; monocytes; P2Y2 receptor; phosphorylation; RBD; secretion; Severe acute respiratory syndrome coronavirus 2; Bronchial epithelia; ERK1/2; P2Y2 receptor; RBD; ATP
• ISSN: 0161-5890; 1872-9142; 1872-9142
• DOI: 10.1016/j.molimm.2024.02.005

The spike protein of SARS-CoV-2 as well as its receptor binding domain (RBD) has been demonstrated to be capable of activating the release of pro-inflammatory mediators in endothelial cells and immune cells such as monocytes. However, the effects of spike protein or its RBD on airway epithelial cells and mechanisms underlying these effects have not been adequately characterized. Here, we show that the RBD of spike protein alone can induce bronchial epithelial inflammation in a manner of ATP/P2Y2 dependence. Incubation of human bronchial epithelia with RBD induced IL-6 and IL-8 release, which could be inhibited by antibody. The incubation of RBD also up-regulated the expression of inflammatory indicators such as ho-1 and mkp-1. Furthermore, ATP secretion was observed after RBD treatment, P2Y2 receptor knock down by siRNA significantly suppressed the IL-6 and IL-8 release evoked by RBD. Additionally, S-RBD elevated the phosphorylation level of ERK1/2, and the effect that PD98059 can inhibit the pro-inflammatory cytokine release suggested the participation of ERK1/2. These novel findings provide new evidence of SARS-CoV-2 on airway inflammation and introduce purinergic signaling as promising treatment target. •Two SARS-CoV-2 S-RBD, namely prototypic and delta, promoted IL-6 and IL-8 release.•Delta variant S-RBD induced more ATP release than that of prototypic.•P2Y2 purinergic receptor knockdown abolished S-RBD-provoked IL-6 and IL-8 secretion.•ERK1/2 also participated in S-RBD-induced cytokines release.