Prostaglandin I2 Signaling and Inhibition of Group 2 Innate Lymphoid Cell Responses
Prostaglandin I2 Signaling and Inhibition of Group 2 Innate Lymphoid Cell Responses
复制标题
DOI：
10.1164/rccm.201410-1793oc
复制
发表时间：
2016-01-01
影响因子：
24.7
通讯作者：
Peebles, R. Stokes, Jr.
中科院分区：
文献类型：
--
作者：
Zhou, Weisong;Toki, Shinji;Peebles, R. Stokes, Jr.
理由：2组先天淋巴样细胞（ILC2s）强烈产生IL-5和IL-13，这是哮喘表型的核心细胞毒素；然而，前列腺素（PG） I-2对ILC2功能的影响尚不清楚。目的：研究PGI(2)对小鼠和人体外ILC2细胞因子表达的影响，以及内源性PGI(2)和PGI(2)类似物环卡前列素对体内肺ILC2s的影响。方法：用IL-33培养野生型（WT）和PGI(2)受体缺失（IP-/-）小鼠的骨髓il - c2s，并用PGI(2)类似物cicapprost处理。WT和IP-/-小鼠连续4天鼻内注射互花莲子提取物诱导ILC2反应，并对这些反应进行量化。在给药之前，给攻毒的WT小鼠注射环卡前列素。用IL-33和IL-2培养人流动分选外周血ILC2s，并用PGI(2)类似物cicapprost处理。测量和主要结果：我们证明了PGI(2)通过依赖于PGI(2)受体IP信号传导的方式，通过从小鼠骨髓中纯化的il -33刺激的ILC2s抑制IL-5和IL-13蛋白表达。在一种与严重哮喘发作相关的真菌气致过敏原——交替草提取物连续4天气道刺激的小鼠模型中，内源性PGI(2)信号显著抑制肺IL-5和IL-13蛋白表达，降低肺IL-5和IL-13表达的ILC2s数量，以及IL-5和IL-13染色的平均荧光强度。此外，外源性给药PGI(2)类似物抑制交替孢提取物诱导的肺IL-5和IL-13蛋白表达，减少肺IL-5和IL-13表达的ILC2s数量和IL-5和IL-13染色的平均荧光强度。最后，PGI(2)类似物抑制IL-2和IL-33刺激的人ILC2s表达IL-5和IL-13。结论：这些结果表明PGI(2)可能是一种潜在的治疗方法，可以降低ILC2对含有蛋白酶的空气过敏原（如Alternaria）的反应。
Rationale: Group 2 innate lymphoid cells (ILC2s) robustly produce IL-5 and IL-13, cytolcines central to the asthma phenotype; however, the effect of prostaglandin (PG) I-2 on ILC2 function is unknown.Objectives: To determine the effect of PGI(2) on mouse and human ILC2 cytokine expression in vitro and the effect of endogenous PGI(2) and the PGI(2) analog cicaprost on lung ILC2s in vivo.Methods: Flow-sorted bone marrow ILC2s of wild-type (WT) and PGI(2) receptor-deficient (IP-/-) mice were cultured with IL-33 and treated with the PGI(2) analog cicaprost. WT and IP-/- mice were challenged intranasally with Alternaria alternata extract for 4 consecutive days to induce ILC2 responses, and these were quantified. Prior to A. alternata extract, challenged WT mice were treated with cicaprost. Human flow-sorted peripheral blood ILC2s were cultured with IL-33 and IL-2 and treated with the PGI(2) analog cicaprost.Measurement and Main Results: We demonstrate that PGI(2) inhibits IL-5 and IL-13 protein expression by IL-33-stimulated ILC2s purified from mouse bone marrow in a manner that was dependent on signaling through the PGI(2) receptor IP. In a mouse model of 4 consecutive days of airway challenge with an extract of A. alternata, a fungal aeroallergen associated with severe asthma exacerbations, endogenous PGI(2) signaling significantly inhibited lung IL-5 and IL-13 protein expression, and reduced the number of lung IL-5- and IL-13-expressing ILC2s, as well as the mean fluorescence intensity of IL-5 and IL-13 staining. In addition, exogenous administration of a PGI(2) analog inhibited Alternaria extract-induced lung IL-5 and IL-13 protein expression, and reduced the number of lung IL-5- and IL-13-expressing ILC2s and the mean fluorescence intensity of IL-5 and IL-13 staining. Finally, a PGI(2) analog inhibited IL-5 and IL-13 expression by human ILC2s that were stimulated with IL-2 and IL-33.Conclusions: These results suggest that PGI(2) may be a potential therapy to reduce the ILC2 response to protease-containing aeroallergens, such as Alternaria.