Rab27-Dependent Exosome Production Inhibits Chronic Inflammation and Enables Acute Responses to Inflammatory Stimuli.
Rab27-Dependent Exosome Production Inhibits Chronic Inflammation and Enables Acute Responses to Inflammatory Stimuli.
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DOI：
10.4049/jimmunol.1700904
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发表时间：
2017-11-15
期刊：
影响因子：
--
通讯作者：
O'Connell RM
中科院分区：
文献类型：
--
作者：
Alexander M;Ramstead AG;Bauer KM;Lee SH;Runtsch MC;Wallace J;Huffaker TB;Larsen DK;Tolmachova T;Seabra MC;Round JL;Ward DM;O'Connell RM
细胞外囊泡，包括外泌体，最近被认为是哺乳动物免疫细胞通讯的新介质。然而，内源性外泌体在体内调节免疫细胞功能中的作用才刚刚开始被确定。在这里，我们证明Rab27a和Rab27b双敲除（Rab27DKO）外泌体分泌不足的小鼠具有慢性、低级别炎症表型，其特征是炎症细胞因子升高和骨髓增生。经过进一步研究，我们发现其中一些表型可以通过WT造血细胞或GM-CSF扩增的骨髓细胞产生的外泌体进行补充。此外，慢性炎症的Rab27DKO小鼠对细菌LPS的反应迟钝，类似于内毒素耐受。这一缺陷是由WT细胞的骨髓外泌体修复的，而不是miR-155−/−细胞，这表明摄取含有miR-155的外泌体对于适当的LPS反应是重要的。此外，我们发现miR-155的直接靶点SHIP1和IRAK-M是已知的LPS反应的负调节因子，在Rab27DKO小鼠中升高，并且在WT处理后降低，但miR-155−/−外泌体没有。总之，我们的研究发现rab27依赖性外泌体的产生有助于造血系统内的稳态和对炎症刺激的适当反应。
Extracellular vesicles, including exosomes, have recently been implicated as novel mediators of immune cell communication in mammals. However, roles for endogenously produced exosomes in regulating immune cell functions in vivo are just beginning to be identified. Here, we demonstrate that Rab27a and Rab27b double knockout (Rab27DKO) mice that are deficient in exosome secretion have a chronic, low-grade inflammatory phenotype characterized by elevated inflammatory cytokines and myeloproliferation. Upon further investigation, we found that some of these phenotypes could be complemented by WT hematopoietic cells or administration of exosomes produced by GM-CSF expanded bone marrow cells. Additionally, chronically inflamed Rab27DKO mice had a blunted response to bacterial LPS, resembling endotoxin tolerance. This defect was rescued by bone marrow exosomes from WT but not miR-155−/− cells suggesting that uptake of miR-155-containing exosomes is important for a proper LPS response. Further, we found that SHIP1 and IRAK-M, direct targets of miR-155 that are known negative regulators of the LPS response, were elevated in Rab27DKO mice and decreased following treatment with WT but not miR-155−/− exosomes. Together, our study finds that Rab27-dependent exosome production contributes to homeostasis within the hematopoietic system and appropriate responsiveness to inflammatory stimuli.
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DOI：
10.1111/j.1600-0854.2009.01029.x
发表时间：
2010-04
期刊：
Traffic (Copenhagen, Denmark)
影响因子：
--
作者：
Johnson JL;Brzezinska AA;Tolmachova T;Munafo DB;Ellis BA;Seabra MC;Hong H;Catz SD
通讯作者：
Catz SD
DOI：
10.1038/nri3622
发表时间：
2014-03
期刊：
Nature reviews. Immunology
影响因子：
--
作者：
通讯作者：
--
影响因子：
4.8
作者：
Bala, Shashi;Marcos, Miguel;Szabo, Gyongyi
通讯作者：
Szabo, Gyongyi
影响因子：
7.3
作者：
Hornick, Noah I.;Doron, Ben;Kurre, Peter
通讯作者：
Kurre, Peter
影响因子：
4
作者：
Alexander, Margaret;O'Connell, Ryan M.
通讯作者：
O'Connell, Ryan M.