IL-17 Producing Lymphocytes Cause Dry Eye and Corneal Disease With Aging in RXRα Mutant Mouse.
IL-17 Producing Lymphocytes Cause Dry Eye and Corneal Disease With Aging in RXRα Mutant Mouse.
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DOI：
10.3389/fmed.2022.849990
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发表时间：
2022
影响因子：
3.9
通讯作者：
Pflugfelder SC
中科院分区：
文献类型：
--
作者：
Alam J;Yazdanpanah G;Ratnapriya R;Borcherding N;de Paiva CS;Li D;Guimaraes de Souza R;Yu Z;Pflugfelder SC
研究IL-17在功能缺失的Pinkie小鼠品系RXRα突变中发生干眼病的相关机制。在角膜和结膜中评估干眼病的指标。通过单细胞RNA测序（scRNA-seq）进行表达谱分析，比较结膜免疫细胞中的基因表达。用流式细胞术和共聚焦显微镜对结膜免疫细胞进行免疫分型。研究了RXRα配体9-顺式维甲酸（RA）在培养单核细胞和γδ T细胞中的活性。与野生型（WT） C57BL/6相比，Pinkie有更多干眼病的迹象，包括泪液体积减少、角膜屏障破坏、角膜/结膜角化和杯状细胞丢失、角膜血管化、混浊和溃疡。结膜免疫细胞scrna测序结果显示，两株小鼠结膜中IL-17的主要表达群体为γδ T细胞，Pinkie小鼠结膜中IL-17的表达比例增加了4倍。与WT相比，IL-17a和IL-17f在Pinkie中显著升高，以常规T细胞和γδ T细胞为主要产生者。流式细胞术显示，小指组织中IL-17+ γδ T细胞数量增加。9-顺式RA治疗可抑制γδ T诱导IL-17的产生和单核细胞上清对γδ T细胞IL-17产生的刺激活性。与WT骨髓嵌合体相比，干燥应激后，Pinkie嵌合体结膜中IL-17+ γδ T细胞增加，抗IL-17处理抑制干眼症诱导的角膜MMP-9产生/活性和结膜杯状细胞损失。这些发现表明RXRα抑制结膜中产生干眼病诱导IL-17的淋巴细胞，并确定RXRα是干眼病的潜在治疗靶点。
To investigate IL-17 related mechanisms for developing dry eye disease in the Pinkie mouse strain with a loss of function RXRα mutation. Measures of dry eye disease were assessed in the cornea and conjunctiva. Expression profiling was performed by single-cell RNA sequencing (scRNA-seq) to compare gene expression in conjunctival immune cells. Conjunctival immune cells were immunophenotyped by flow cytometry and confocal microscopy. The activity of RXRα ligand 9-cis retinoic acid (RA) was evaluated in cultured monocytes and γδ T cells. Compared to wild type (WT) C57BL/6, Pinkie has increased signs of dry eye disease, including decreased tear volume, corneal barrier disruption, corneal/conjunctival cornification and goblet cell loss, and corneal vascularization, opacification, and ulceration with aging. ScRNA-seq of conjunctival immune cells identified γδ T cells as the predominant IL-17 expressing population in both strains and there is a 4-fold increased percentage of γδ T cells in Pinkie. Compared to WT, IL-17a, and IL-17f significantly increased in Pinkie with conventional T cells and γδ T cells as the major producers. Flow cytometry revealed an increased number of IL-17+ γδ T cells in Pinkie. Tear concentration of the IL-17 inducer IL-23 is significantly higher in Pinkie. 9-cis RA treatment suppresses stimulated IL-17 production by γδ T and stimulatory activity of monocyte supernatant on γδ T cell IL-17 production. Compared to WT bone marrow chimeras, Pinkie chimeras have increased IL-17+ γδ T cells in the conjunctiva after desiccating stress and anti-IL-17 treatment suppresses dry eye induced corneal MMP-9 production/activity and conjunctival goblet cell loss. These findings indicate that RXRα suppresses generation of dry eye disease-inducing IL-17 producing lymphocytes s in the conjunctiva and identifies RXRα as a potential therapeutic target in dry eye.
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影响因子：
4.4
作者：
Chotikavanich S;de Paiva CS;Li de Q;Chen JJ;Bian F;Farley WJ;Pflugfelder SC
通讯作者：
Pflugfelder SC
影响因子：
3.4
作者：
De Paiva, Cintia S.;Corrales, Rosa M.;Pfiugfelder, Stephen C.
通讯作者：
Pfiugfelder, Stephen C.
DOI：
10.1006/bbrc.2000.2371
发表时间：
2000-04-02
影响因子：
3.1
作者：
Fritsche, J;Stonehouse, TJ;Kreutz, M
通讯作者：
Kreutz, M
DOI：
10.1016/j.jid.2016.12.032
发表时间：
2017-07
期刊：
The Journal of investigative dermatology
影响因子：
--
作者：
Lambert S;Swindell WR;Tsoi LC;Stoll SW;Elder JT
通讯作者：
Elder JT
影响因子：
4.4
作者：
Butcher, Matthew J.;Wu, Chih-I;Galkina, Elena V.
通讯作者：
Galkina, Elena V.