Activation of Macrophages by Lysophosphatidic Acid through the Lysophosphatidic Acid Receptor 1 as a Novel Mechanism in Multiple Sclerosis Pathogenesis
Activation of Macrophages by Lysophosphatidic Acid through the Lysophosphatidic Acid Receptor 1 as a Novel Mechanism in Multiple Sclerosis Pathogenesis
复制标题
DOI：
10.1007/s12035-020-02130-x
复制
发表时间：
2020-09-24
影响因子：
5.1
通讯作者：
Garcia-Diaz, Beatriz
中科院分区：
文献类型：
--
作者：
Fransson, Jennifer;Gomez-Conde, Ana Isabel;Garcia-Diaz, Beatriz
多发性硬化（MS）是一种神经炎症性疾病，其发病机制尚不清楚.溶血磷脂酸（LPA）是一种内源性磷脂，参与多种免疫细胞功能，并在MS中失调。其受体LPA（1）在巨噬细胞中表达，并调节其活化，这是由于MS中巨噬细胞活化在破坏和修复中的作用而引起的。在本研究中，我们研究了LPA（1）在小鼠MS模型，实验性自身免疫性脑脊髓炎（EAE）的基因缺失和药物抑制。在EAE小鼠和MS患者免疫细胞中分析LPA（1）表达。在人单核细胞衍生的巨噬细胞中研究了LPA和LPA（1）对巨噬细胞活化的作用。我们发现LPA（1）活性的缺乏诱导了较轻的临床EAE病程，外周血单核细胞（PBMC）中Lpar1的表达与EAE的复发和严重程度相关。我们在复发期间MS患者的PBMC中观察到与疾病的进行性形式相比相同的过度表达，并且在刺激的单核细胞衍生的巨噬细胞中观察到相同的过度表达。LPA通过LPA（1）在巨噬细胞中诱导促炎样反应，提供了LPA和LPA（1）失调可导致MS炎症的合理方式。这些数据显示了LPA信号传导在MS发病机制中的新机制，促使进一步研究其作为治疗靶生物标志物的用途。
Multiple sclerosis (MS) is a neuroinflammatory disease whose pathogenesis remains unclear. Lysophosphatidic acid (LPA) is an endogenous phospholipid involved in multiple immune cell functions and dysregulated in MS. Its receptor LPA(1)is expressed in macrophages and regulates their activation, which is of interest due to the role of macrophage activation in MS in both destruction and repair. In this study, we studied the genetic deletion and pharmaceutical inhibition of LPA(1)in the mouse MS model, experimental autoimmune encephalomyelitis (EAE). LPA(1)expression was analyzed in EAE mice and MS patient immune cells. The effect of LPA and LPA(1)on macrophage activation was studied in human monocyte-derived macrophages. We show that lack of LPA(1)activity induces milder clinical EAE course and thatLpar1expression in peripheral blood mononuclear cells (PBMC) correlates with onset of relapses and severity in EAE. We see the same over-expression in PBMC from MS patients during relapse compared with progressive forms of the disease and in stimulated monocyte-derived macrophages. LPA induced a proinflammatory-like response in macrophages through LPA(1), providing a plausible way in which LPA and LPA(1)dysregulation can lead to the inflammation in MS. These data show a new mechanism of LPA signaling in the MS pathogenesis, prompting further research into its use as a therapeutic target biomarker.