Secreted Ectodomain of Sialic Acid-Binding Ig-Like Lectin-9 and Monocyte Chemoattractant Protein-1 Promote Recovery after Rat Spinal Cord Injury by Altering Macrophage Polarity
Secreted Ectodomain of Sialic Acid-Binding Ig-Like Lectin-9 and Monocyte Chemoattractant Protein-1 Promote Recovery after Rat Spinal Cord Injury by Altering Macrophage Polarity
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DOI：
10.1523/jneurosci.4088-14.2015
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发表时间：
2015-02-11
影响因子：
5.3
通讯作者：
Yamamoto, Akihito
中科院分区：
文献类型：
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作者：
Matsubara, Kohki;Matsushita, Yoshihiro;Yamamoto, Akihito
从人乳牙牙髓（SHED）移植的间充质干细胞通过尚不清楚的旁分泌机制支持神经损伤的恢复。在这里，我们表明，条件无血清培养基（CM）从SHEDs，鞘内注射到大鼠损伤的脊髓在急性损伤后的时期，引起显着的功能恢复。SHED-CM诱导恢复的能力与诱导抗炎M2样巨噬细胞的免疫调节活性相关。SHED-CM的分泌组分析揭示了一组先前未识别的抗炎M2样巨噬细胞诱导物：单核细胞趋化蛋白-1（MCP-1）和唾液酸结合Ig样凝集素-9（ED-Siglec-9）的分泌胞外域。从SHED-CM中消耗MCP-1和ED-Siglec-9显著降低了其诱导M2样巨噬细胞和促进脊髓损伤（SCI）后功能恢复的能力。MCP-1和ED-Siglec-9的组合在体外协同促进骨髓源性巨噬细胞的M2样分化，并且这种作用通过CC趋化因子受体2（CCR 2）的选择性拮抗剂或通过CCR 2的基因敲除而消除。此外，MCP-1和ED-Siglec-9给药到损伤的脊髓中诱导了M2样巨噬细胞，并导致SCI后后肢运动功能的显著恢复。通过CCR 2功能的失活抑制这种M2诱导消除了SHED-CM和MCP-1/ED-Siglec-9两者的治疗效果。由MCP-1和ED-Siglec-9激活的巨噬细胞延长神经突并抑制原代小脑颗粒神经元的凋亡以对抗硫酸软骨素蛋白多糖的神经毒性作用。我们的数据表明MCP-1和ED-Siglec-9的独特组合通过抗炎性M2样巨噬细胞诱导修复SCI。
Engrafted mesenchymal stem cells from human deciduous dental pulp (SHEDs) support recovery from neural insults via paracrine mechanisms that are poorly understood. Here we show that the conditioned serum-free medium (CM) from SHEDs, administered intrathecally into rat injured spinal cord during the acute postinjury period, caused remarkable functional recovery. The ability of SHED-CM to induce recovery was associated with an immunoregulatory activity that induced anti-inflammatory M2-like macrophages. Secretome analysis of the SHED-CM revealed a previously unrecognized set of inducers for anti-inflammatory M2-like macrophages: monocyte chemoattractant protein-1 (MCP-1) and the secreted ectodomain of sialic acid-binding Ig-like lectin-9 (ED-Siglec-9). Depleting MCP-1 and ED-Siglec-9 from the SHED-CM prominently reduced its ability to induce M2-like macrophages and to promote functional recovery after spinal cord injury (SCI). The combination of MCP-1 and ED-Siglec-9 synergistically promoted the M2-like differentiation of bone marrow-derived macrophages in vitro, and this effect was abolished by a selective antagonist for CC chemokine receptor 2 (CCR2) or by the genetic knock-out of CCR2. Furthermore, MCP-1 and ED-Siglec-9 administration into the injured spinal cord induced M2-like macrophages and led to a marked recovery of hindlimb locomotor function after SCI. The inhibition of this M2 induction through the inactivation of CCR2 function abolished the therapeutic effects of both SHED-CM and MCP-1/ED-Siglec-9. Macrophages activated by MCP-1 and ED-Siglec-9 extended neurite and suppressed apoptosis of primary cerebellar granule neurons against the neurotoxic effects of chondroitin sulfate proteoglycans. Our data suggest that the unique combination of MCP-1 and ED-Siglec-9 repairs the SCI through anti-inflammatory M2-like macrophage induction.