Department of Anesthesiology, West China School of Medicine, West China Hospital of Sichuan University, Chengdu, China; The Research Unit of West China (2018RU012), Chinese Academy of Medical Science, Chengdu, China.
Department of Dermatovenereology, West China Hospital of Sichuan University. Chengdu, China.
J Invest Dermatol. 2022 Nov;142(11):2998-3008.e5. doi: 10.1016/j.jid.2022.03.037. Epub 2022 Jun 2.
Mast cell activation and inflammatory mediators play central roles in the pathogenesis of chronic spontaneous urticaria (CSU). The factors that induce mast cell activation in CSU are still largely unknown. Exosomes (EXs) are extracellular vesicles that activate mast cells. In this study, we enriched the EXs derived from the plasma of healthy volunteers and that of patients with CSU without antihistamine sensitivity (i.e., CSU-derived EXs with antihistamine sensitivity) or resistance (i.e., CSU-derived EXs with antihistamine resistance) using ultracentrifugation. We then incubated these EXs with HMC-1 human mast cells. Notably, CSU-derived EXs with antihistamine sensitivity and CSU-derived EXs with antihistamine resistance increased tryptase-1 expression; histamine production; inflammatory mediator production; and toll-like receptor (TLR) 2, TLR4, and phosphorylated MAPK levels in HMC-1 cells. These effects were more significant in the group with CSU-derived EXs with antihistamine resistance than in the group with CSU-derived EXs with antihistamine sensitivity. TLR2, TLR4, and MAPK inhibitors (CC-401, TAK-715, and SCH772984, respectively) reduced CSU-derived EXs-Stimulated production of inflammatory mediators in HMC-1 cells. Overall, EXs in the plasma of patients with CSU were found to activate mast cells and elicit the production of multiple inflammatory mediators, partly through the TLR2, TLR4, and MAPK pathways. In addition, CSU-derived EXs with antihistamine resistance had more powerful mast cell‒activating and histamine-release abilities. Thus, these EXs may be involved in the pathogenesis of CSU with antihistamine resistance.
肥大细胞激活和炎症介质在慢性自发性荨麻疹（CSU）的发病机制中发挥核心作用。CSU 中诱导肥大细胞激活的因素在很大程度上仍不清楚。外泌体（EXs）是激活肥大细胞的细胞外囊泡。在这项研究中，我们使用超速离心法从健康志愿者和对组胺无敏感性（即具有组胺敏感性的 CSU 衍生 EXs）或耐药（即具有组胺耐药性的 CSU 衍生 EXs）的 CSU 患者的血浆中富集 EXs。然后，我们将这些 EXs 与 HMC-1 人肥大细胞孵育。值得注意的是，具有组胺敏感性的 CSU 衍生 EXs 和具有组胺耐药性的 CSU 衍生 EXs 均增加了 HMC-1 细胞中的胰蛋白酶-1 表达、组胺产生、炎症介质产生以及 Toll 样受体（TLR）2、TLR4 和磷酸化 MAPK 水平。在具有组胺耐药性的 CSU 衍生 EXs 组中，这些作用比在具有组胺敏感性的 CSU 衍生 EXs 组中更为显著。TLR2、TLR4 和 MAPK 抑制剂（分别为 CC-401、TAK-715 和 SCH772984）降低了 CSU 衍生 EXs 刺激的 HMC-1 细胞中炎症介质的产生。总体而言，CSU 患者血浆中的 EXs 被发现可激活肥大细胞并引发多种炎症介质的产生，部分通过 TLR2、TLR4 和 MAPK 途径。此外，具有组胺耐药性的 CSU 衍生 EXs 具有更强的激活肥大细胞和释放组胺的能力。因此，这些 EXs 可能参与了具有组胺耐药性的 CSU 的发病机制。
