IL-1α released from oral epithelial cells upon candidalysin exposure initiates an early innate epithelial response
IL-1α released from oral epithelial cells upon candidalysin exposure initiates an early innate epithelial response
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DOI：
10.1093/intimm/dxaa070
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发表时间：
2021-03-01
影响因子：
4.4
通讯作者：
Domae, Eisuke
中科院分区：
文献类型：
--
作者：
Hanaoka, Mariko;Domae, Eisuke
白色念珠菌是一种共生真菌，主要存在于粘膜表面，当宿主防御受损时，可引起致命的全身感染。念珠菌溶素是一种由白色念珠菌菌丝产生的溶细胞肽毒素，对于粘膜组织损伤至关重要，并且被认为有助于建立全身感染和死亡。念珠菌溶素也是上皮先天反应所必需的，在该反应中产生促炎细胞因子和趋化因子并启动中性粒细胞募集。最近有报道称，表皮生长因子受体（EGFR）对于念珠菌溶菌素触发的上皮反应至关重要。本研究确定 IL-1 α 是念珠菌溶酶介导的初始上皮激活的另一个成分。我们发现，人口腔上皮细胞在接触念珠菌溶素后迅速释放 IL-1 α。在念珠菌溶血素暴露的细胞中阻断 IL-1 α/IL-1 受体 (IL-1R) 信号传导会导致 I kappa B α 磷酸化减少、I kappa B zeta 诱导减少以及粒细胞巨噬细胞集落刺激因子和 IL-8 的产生减少。 c-Fos 的表达是在念珠菌溶酶处理的细胞中 EGFR 信号传导下游诱导的，受 IL-1R 阻断的影响较小。相反，阻断 EGFR 信号传导不会影响念珠菌溶素介导的 I kappa B α 磷酸化和 I kappa B zeta 的诱导，这表明独立的信号传导途径有助于诱导念珠菌溶素孔形成位点下游的 NF-kappa B 和 c-Fos。一致地，EGFR 和 IL-1R 的抗体抑制增强了念珠菌溶素处理的细胞中细胞因子产生的抑制作用。因此，我们确定了 IL-1 α 的立即释放及其与 EGFR 配体在口腔上皮细胞响应念珠菌溶酶的初始激活中的协同作用。
Candida albicans is a commensal fungus that predominantly resides on mucosal surfaces and can cause lethal systemic infection when the host defense is compromised. Candidalysin is a cytolytic peptide toxin produced by C. albicans hyphae that is essential for mucosal tissue damage and is believed to contribute to the establishment of systemic infection and mortality. Candidalysin is also required for the epithelial innate response in which proinflammatory cytokines and chemokines are produced and neutrophil recruitment is initiated. It was recently reported that epidermal growth factor receptor (EGFR) was essential for the candidalysin-triggered epithelial response. The present study identified IL-1 alpha as another component of candidalysin-mediated initial epithelial activation. We found that human oral epithelial cells released IL-1 alpha rapidly after candidalysin exposure. Blockade of IL-1 alpha/IL-1 receptor (IL-1R) signaling in candidalysin-exposed cells resulted in decreased phosphorylation of I kappa B alpha, decreased induction of I kappa B zeta and decreased production of granulocyte-macrophage colony-stimulating factor and IL-8. Expression of c-Fos, which is induced downstream of EGFR signaling in candidalysin-treated cells, is less affected by IL-1R blockade. Inversely, blockade of EGFR signaling does not affect candidalysin-mediated phosphorylation of I kappa B alpha and induction of I kappa B zeta, suggesting that independent signaling pathways contribute to the induction of NF-kappa B and c-Fos downstream of the candidalysin pore formation site. Consistently, antibody inhibition of both EGFR and IL-1R enhanced the suppressive effect of cytokine production in candidalysin-treated cells. Thus, we identified the immediate release of IL-1 alpha and its synergistic role with EGFR ligands on the initial activation of oral epithelial cells in response to candidalysin.