De novo expression of circulating biglycan evokes an innate inflammatory tissue response via MyD88/TRIF pathways.
De novo expression of circulating biglycan evokes an innate inflammatory tissue response via MyD88/TRIF pathways.
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DOI：
10.1016/j.matbio.2013.12.003
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发表时间：
2014-04
期刊：
影响因子：
6.9
通讯作者：
Schaefer, Liliana
中科院分区：
文献类型：
--
作者：
Zeng-Brouwers, Jinyang;Beckmann, Janet;Nastase, Madalina-Viviana;Iozzo, Renato V.;Schaefer, Liliana
与基质结合的成分，如富含亮氨酸的小分子蛋白多糖二聚糖，当通过有限的细胞外基质蛋白分解或由循环和体液中的巨噬细胞从头合成时，可以作为强大的信号分子。具体地说，Biglycan通过直接与Toll样受体(TLR)-2和-4结合，作为先天免疫的内源性配体。在这项研究中，我们建立了一个瞬时转基因小鼠模型，在该模型中，由白蛋白启动子驱动的肝细胞从头开始过度生产Biglycan。转基因双聚糖可由肝细胞快速、大量合成并释放到血液中。值得注意的是，我们发现循环中的胆聚糖聚集在肾脏中，导致白细胞重新聚集到肾实质中，同时伴有肾脏化学诱导剂CXCL1、CXCL2、CCL2和CCL5的异常水平。使用缺乏TLR接头蛋白MyD88或TRIF的小鼠，我们发现MyD88缺乏显著减少了中性粒细胞和巨噬细胞在肾脏中的渗透，而TRIF缺乏则减少了T细胞的渗透。CXCL1、CXCL2和CCL2的产生需要MyD88，而T细胞和巨噬细胞诱导剂CCL5的水平需要TRIF。因此，我们提供了强有力的遗传学证据，证明循环中的胆聚糖是一种针对肾实质的强有力的促炎介质。此外，我们的结果提供了第一个证据，证明Biglycan通过两条独立的途径，利用MyD88或TRIF接头蛋白，通过两条独立的途径，都是在TLR2/4的控制下，以不同的方式触发白细胞的化学吸引。由于Biglycan的异常表达存在于多种炎症性疾病中，这种瞬时转基因小鼠模型可以作为一种有价值的研究工具，用于研究Biglycan在体内表达增加的影响，并为制定治疗炎症性疾病的策略提供有价值的研究工具。
Matrix-bound constituents, such as the small leucine-rich proteoglycan biglycan, can act as powerful signaling molecules when released by limited proteolysis of the extracellular matrix or de novo synthesized by macrophages in the circulation and body fluids. Specifically, biglycan acts as an endogenous ligand of innate immunity by directly engaging the Toll-like receptor (TLR)-2 and -4. In this study, we generated a transient transgenic mouse model where biglycan was de novo overproduced by hepatocytes driven by the albumin promoter. Transgenic biglycan was rapidly and abundantly synthesized by hepatocytes and released into the bloodstream. Notably, we found that circulating biglycan accumulated in the kidneys where it caused recruitment of leukocytes infiltrating the renal parenchyma concurrent with abnormal renal levels of chemoattractants CXCL1, CXCL2, CCL2 and CCL5. Using mice deficient in either TLR adapter proteins MyD88 or TRIF we discovered that MyD88 deficiency drastically reduced neutrophil and macrophage infiltration in the kidney, whereas TRIF deficiency decreased T cell infiltrates. Production of CXCL1, CXCL2 and CCL2 required MyD88, whereas the levels of T cell and macrophage attractant CCL5 required TRIF. Thus, we provide robust genetic evidence for circulating biglycan as a powerful pro-inflammatory mediator targeting the renal parenchyma. Furthermore, our results provide the first evidence that biglycan differentially triggers chemoattraction of leukocytes via two independent pathways, both under the control of TLR2/4, utilizing either MyD88 or TRIF adaptor proteins. As aberrant expression of biglycan occurs in several inflammatory diseases, this transient transgenic mouse model could serve as a valuable research tool in investigating the effects of increased biglycan expression in vivo and for the development of therapeutic strategies in the treatment of inflammatory diseases.
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影响因子：
6.2
作者：
Chen, XD;Shi, ST;Young, MF
通讯作者：
Young, MF
影响因子：
6.1
作者：
de Kluijver, J;Schrumpf, JA;Sterk, PJ
通讯作者：
Sterk, PJ
DOI：
10.4049/jimmunol.1003478
发表时间：
2011-12-15
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Popovic ZV;Wang S;Papatriantafyllou M;Kaya Z;Porubsky S;Meisner M;Bonrouhi M;Burgdorf S;Young MF;Schaefer L;Gröne HJ
通讯作者：
Gröne HJ
影响因子：
4.8
作者：
Babelova, Andrea;Moreth, Kristin;Schaefer, Liliana
通讯作者：
Schaefer, Liliana
DOI：
10.1523/jneurosci.4610-11.2012
发表时间：
2012-02-15
期刊：
The Journal of neuroscience : the official journal of the Society for Neuroscience
影响因子：
--
作者：
Amenta AR;Creely HE;Mercado ML;Hagiwara H;McKechnie BA;Lechner BE;Rossi SG;Wang Q;Owens RT;Marrero E;Mei L;Hoch W;Young MF;McQuillan DJ;Rotundo RL;Fallon JR
通讯作者：
Fallon JR