Deletion of astroglial CXCL10 delays clinical onset but does not affect progressive axon loss in a murine autoimmune multiple sclerosis model.
Deletion of astroglial CXCL10 delays clinical onset but does not affect progressive axon loss in a murine autoimmune multiple sclerosis model.
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DOI：
10.1186/1742-2094-11-105
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发表时间：
2014-06-12
影响因子：
9.3
通讯作者：
Pleasure D
中科院分区：
文献类型：
--
作者：
Mills Ko E;Ma JH;Guo F;Miers L;Lee E;Bannerman P;Burns T;Ko D;Sohn J;Soulika AM;Pleasure D
多发性硬化症(MS)的特征是中枢神经系统(CNS)炎症、脱髓鞘和轴突变性。CXCL10(IP-10)是一种针对CXCR3+T细胞的趋化因子，可调节T细胞在外周的分化和迁移，但在中枢神经系统内源性产生的CXCL10对免疫细胞转运的影响尚不清楚。我们创造了cxcl10小鼠，并将它们与携带星形胶质细胞特异性Cre转基因(MGFAPcre)的小鼠杂交，以阻断星形胶质细胞CXCL10的合成。用髓鞘少突胶质细胞糖蛋白35-55(MOG多肽)免疫小鼠和仔鼠，诱导实验性自身免疫性脑脊髓炎(EAE)。与对照组相比，mGFAPcre/CXCL10fl/fl EAE组小鼠脊髓CXCL10的mRNA和蛋白表达显著降低，证实星形胶质细胞是EAE诱导的中枢神经系统CXCL10合成的主要来源。星形胶质细胞CXCL10缺失并未显著改变急性炎症中枢神经系统中CD4+淋巴细胞和CD11b+细胞的总体组成，但减少了脊髓血管周围间隙中CD4+淋巴细胞的积聚。此外，CXCL10缺失不影响IBA1+小胶质细胞/巨噬细胞在病变内的聚集。在星形胶质细胞CXCL10缺失的EAE小鼠中，临床症状较轻，急性脱髓鞘显著减少，但两组的长期轴突丢失同样严重。我们的结论是，星形胶质细胞CXCL10促进了MOG多肽EAE的脊髓血管周围CD4+淋巴细胞聚集和急性脊髓脱髓鞘，但在该MS模型中并不在进行性轴突丢失中起重要作用。
Multiple sclerosis (MS) is characterized by central nervous system (CNS) inflammation, demyelination, and axonal degeneration. CXCL10 (IP-10), a chemokine for CXCR3+ T cells, is known to regulate T cell differentiation and migration in the periphery, but effects of CXCL10 produced endogenously in the CNS on immune cell trafficking are unknown. We created floxed cxcl10 mice and crossed them with mice carrying an astrocyte-specific Cre transgene (mGFAPcre) to ablate astroglial CXCL10 synthesis. These mice, and littermate controls, were immunized with myelin oligodendrocyte glycoprotein peptide 35-55 (MOG peptide) to induce experimental autoimmune encephalomyelitis (EAE). In comparison to the control mice, spinal cord CXCL10 mRNA and protein were sharply diminished in the mGFAPcre/CXCL10fl/fl EAE mice, confirming that astroglia are chiefly responsible for EAE-induced CNS CXCL10 synthesis. Astroglial CXCL10 deletion did not significantly alter the overall composition of CD4+ lymphocytes and CD11b+ cells in the acutely inflamed CNS, but did diminish accumulation of CD4+ lymphocytes in the spinal cord perivascular spaces. Furthermore, IBA1+ microglia/macrophage accumulation within the lesions was not affected by CXCL10 deletion. Clinical deficits were milder and acute demyelination was substantially reduced in the astroglial CXCL10-deleted EAE mice, but long-term axon loss was equally severe in the two groups. We concluded that astroglial CXCL10 enhances spinal cord perivascular CD4+ lymphocyte accumulation and acute spinal cord demyelination in MOG peptide EAE, but does not play an important role in progressive axon loss in this MS model.
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