Dendritic cell sphingosine 1-phosphate receptor-3 regulates Th1-Th2 polarity in kidney ischemia-reperfusion injury.
Dendritic cell sphingosine 1-phosphate receptor-3 regulates Th1-Th2 polarity in kidney ischemia-reperfusion injury.
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DOI：
10.4049/jimmunol.1200999
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发表时间：
2012-09-01
期刊：
影响因子：
--
通讯作者：
Okusa MD
中科院分区：
文献类型：
--
作者：
Bajwa A;Huang L;Ye H;Dondeti K;Song S;Rosin DL;Lynch KR;Lobo PI;Li L;Okusa MD
树突状细胞（DC）是早期肾脏IRI先天免疫和适应性免疫的核心，改变DC功能的策略可能提供新的治疗机会。鞘氨醇1-磷酸（S1P）通过与其受体（S1P1-5）结合来调节免疫，并在s1p3缺陷小鼠中对肾脏IRI产生保护作用。通过一系列实验，我们确定这种保护作用部分是由于s1p3充足和缺乏dc之间的差异。骨髓细胞缺乏S1P3的小鼠受到IRI的保护，缺乏S1P3的dc表现出不成熟的表型。将WT而非s1p3缺陷dc注射到肾IR重建损伤前dc缺失的小鼠中。将装载糖脂（抗原）的WT而非s1p3缺陷dc过继（即静脉注射）转移到WT小鼠体内会加重IRI，这表明WT而非s1p3缺陷dc激活了NKT细胞。WT DC转移激活Th1-IFN-γ途径，而s1p3缺陷DC激活Th2-IL4途径，IL4阻断抗体逆转IRI保护，支持IL-4介导s1p3缺陷DC保护作用的概念。在IRI前7天或IRI后3小时给药s1p3缺陷dc可保护小鼠免受IRI，并提示其在细胞治疗中的潜在应用。我们得出结论，DC S1P3的缺失阻止DC成熟并促进Th2-IL4反应。这些发现强调了DC - S1P3在调节NKT细胞功能和IRI中的重要性，并支持了选择性S1P3拮抗剂的开发，以耐受DC细胞治疗或全身给药，以预防和治疗IRI和自身免疫性疾病。
Dendritic cells (DCs) are central to innate and adaptive immunity of early kidney IRI and strategies to alter DC function may provide new therapeutic opportunities. Sphingosine 1-phosphate (S1P) modulates immunity through binding to its receptors (S1P1-5) and protection from kidney IRI occurs in S1P3-deficient mice. Through a series of experiments we determined that this protective effect was due in part to differences between S1P3-sufficient and deficient DCs. Mice lacking S1P3 on bone marrow cells were protected from IRI and S1P3-deficient DCs displayed an immature phenotype. WT but not S1P3-deficient DCs injected into mice depleted of DCs prior to kidney IR reconstituted injury. Adoptive transfer (i.e, i.v. injection) of glycolipid (antigen)-loaded WT but not S1P3-deficient DCs into WT mice exacerbated IRI, suggesting that WT but not S1P3-deficient DCs activated NKT cells. Whereas WT DC transfers activated the Th1-IFN-γ pathway, S1P3-deficient DCs activated the Th2-IL4 pathway and an IL4 blocking antibody reversed protection from IRI supporting the concept that IL-4 mediates the protective effect of S1P3-deficient DCs. Administration of S1P3-deficient DCs 7 days prior to or 3 h after IRI protected mice from IRI and suggests their potential use in cell-based therapy. We conclude that absence of DC S1P3 prevents DC maturation and promotes a Th2-IL4 response. These findings highlight the importance of DC S1P3 in modulating NKT cell function and IRI and support development of selective S1P3 antagonists for tolerizing DCs for cell based therapy or for systemic administration for the prevention and treatment of IRI and autoimmune diseases.
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影响因子：
19.6
作者：
Dong, X.;Swaminathan, S.;Griffin, M. D.
通讯作者：
Griffin, M. D.
DOI：
10.1152/ajprenal.00378.2004
发表时间：
2005-04-01
影响因子：
4.2
作者：
Day, YJ;Huang, L;Okusa, MD
通讯作者：
Okusa, MD
影响因子：
15.9
作者：
Burne, MJ;Daniels, F;Rabb, H
通讯作者：
Rabb, H
DOI：
10.1161/atvbaha.108.183319
发表时间：
2009-05-01
影响因子：
8.7
作者：
Ben-Shoshan, Jeremy;Afek, Arnon;George, Jacob
通讯作者：
George, Jacob
影响因子：
32.4
作者：
Green, EA;Eynon, EE;Flavell, RA
通讯作者：
Flavell, RA