Dysregulation of lysophosphatidic acids in multiple sclerosis and autoimmune encephalomyelitis.
Dysregulation of lysophosphatidic acids in multiple sclerosis and autoimmune encephalomyelitis.
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DOI：
10.1186/s40478-017-0446-4
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发表时间：
2017-06-02
影响因子：
7.1
通讯作者：
Tegeder I
中科院分区：
文献类型：
--
作者：
Schmitz K;Brunkhorst R;de Bruin N;Mayer CA;Häussler A;Ferreiros N;Schiffmann S;Parnham MJ;Tunaru S;Chun J;Offermanns S;Foerch C;Scholich K;Vogt J;Wicker S;Lötsch J;Geisslinger G;Tegeder I
生物活性脂类在多发性硬化症的病理生理学中起作用。在这里，我们表明溶血磷脂酸(LPA)在多发性硬化症(MS)中调节失调，并且与这种疾病的功能相关。对横断面MS患者血清和脑脊液中的LPA和产生细胞外LPA的主要酶--自体趋化因子进行了分析，并与实验性自身免疫性脑脊髓炎(EAE)模型小鼠、TCR1640小鼠的自发性EAE和Lpar2-/-小鼠的EAE进行了比较。在无症状期间，MS和EAE小鼠的血清LPA降低，而TCR1640小鼠的脊髓LPA升高，即在恢复期间炎症消退，因此可能表明脑LPA在重新髓鞘形成期间的积极作用，正如先前的研究所表明的那样。外周LPA在复发时轻度升高，但在难治性复发时进一步下降。外周丢失导致免疫细胞从脾重新分布到脊髓，提示淋巴细胞归巢缺陷。作为支持，LPAR2阳性T细胞在EAE中减少，在Lpar2缺陷小鼠病情加重。此外，LPAR2激动剂的治疗减少了复发-缓解EAE的临床迹象，这表明LPAR2激动剂部分补偿了LPA的内源性丢失，并暗示LPA信号作为一种新的治疗方法。多发性硬化症中溶血磷脂信号的图形概述本文的在线版本(doi：10.1186/s40478-0170446-4)包含补充材料，授权用户可以使用。
Bioactive lipids contribute to the pathophysiology of multiple sclerosis. Here, we show that lysophosphatidic acids (LPAs) are dysregulated in multiple sclerosis (MS) and are functionally relevant in this disease. LPAs and autotaxin, the major enzyme producing extracellular LPAs, were analyzed in serum and cerebrospinal fluid in a cross-sectional population of MS patients and were compared with respective data from mice in the experimental autoimmune encephalomyelitis (EAE) model, spontaneous EAE in TCR1640 mice, and EAE in Lpar2 -/- mice. Serum LPAs were reduced in MS and EAE whereas spinal cord LPAs in TCR1640 mice increased during the ‘symptom-free’ intervals, i.e. on resolution of inflammation during recovery hence possibly pointing to positive effects of brain LPAs during remyelination as suggested in previous studies. Peripheral LPAs mildly re-raised during relapses but further dropped in refractory relapses. The peripheral loss led to a redistribution of immune cells from the spleen to the spinal cord, suggesting defects of lymphocyte homing. In support, LPAR2 positive T-cells were reduced in EAE and the disease was intensified in Lpar2 deficient mice. Further, treatment with an LPAR2 agonist reduced clinical signs of relapsing-remitting EAE suggesting that the LPAR2 agonist partially compensated the endogenous loss of LPAs and implicating LPA signaling as a novel treatment approach. Graphical summary of lysophosphatidic signaling in multiple sclerosis The online version of this article (doi:10.1186/s40478-017-0446-4) contains supplementary material, which is available to authorized users.