生物
先天免疫系统
细胞生物学
神经酰胺
内质网
鞘氨醇
未折叠蛋白反应
脂质信号
类胡萝卜素
塔普斯加尔金
抗菌肽
下调和上调
第二信使系统
信号转导
细胞凋亡
免疫系统
微生物学
免疫学
生物化学
炎症
受体
抗菌剂
基因
作者
Kyungho Park,Peter M. Elias,Kyoung-Oh Shin,Yong-Moon Lee,Melanie Hupe,Andrew W. Borkowski,Richard L. Gallo,Julie D. Saba,Walter M. Holleran,Yoshikazu Uchida
摘要
A variety of external perturbations can induce endoplasmic reticulum (ER) stress, followed by stimulation of epithelial cells to produce an innate immune element, the cathelicidin antimicrobial peptide (CAMP). ER stress also increases production of the proapoptotic lipid ceramide and its antiapoptotic metabolite, sphingosine-1-phosphate (S1P). We demonstrate here that S1P mediates ER stress-induced CAMP generation. Cellular ceramide and S1P levels rose in parallel with CAMP levels following addition of either exogenous cell-permeating ceramide (C2Cer), which increases S1P production, or thapsigargin (an ER stressor), applied to cultured human skin keratinocytes or topically to mouse skin. Knockdown of S1P lyase, which catabolizes S1P, enhanced ER stress-induced CAMP production in cultured cells and mouse skin. These and additional inhibitor studies show that S1P is responsible for ER stress-induced upregulation of CAMP expression. Increased CAMP expression is likely mediated via S1P-dependent NF-κB–C/EBPα activation. Finally, lysates of both ER-stressed and S1P-stimulated cells blocked growth of virulent Staphylococcus aureus in vitro, and topical C2Cer and LL-37 inhibited invasion of Staphylococcus aureus into murine skin. These studies suggest that S1P generation resulting in increased CAMP production comprises a novel regulatory mechanism of epithelial innate immune responses to external perturbations, pointing to a new therapeutic approach to enhance antimicrobial defense.
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