Secreted Ectodomain of SIGLEC-9 and MCP-1 Synergistically Improve Acute Liver Failure in Rats by Altering Macrophage Polarity.
Secreted Ectodomain of SIGLEC-9 and MCP-1 Synergistically Improve Acute Liver Failure in Rats by Altering Macrophage Polarity.
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DOI：
10.1038/srep44043
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发表时间：
2017-03-08
影响因子：
4.6
通讯作者：
Yamamoto A
中科院分区：
文献类型：
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作者：
Ito T;Ishigami M;Matsushita Y;Hirata M;Matsubara K;Ishikawa T;Hibi H;Ueda M;Hirooka Y;Goto H;Yamamoto A
急性肝功能衰竭（ALF）的有效治疗仍然缺乏。我们最近报道，一个单一的静脉注射无血清条件培养基从干细胞来源于人脱落乳牙（SHED-CM）到D-半乳糖胺（D-Gal）诱导的大鼠ALF模型改善肝损伤。然而，SHED-CM中负责解决ALF的具体因素仍不清楚。在这里，我们发现，消耗两种抗炎M2巨噬细胞诱导剂-单核细胞趋化蛋白-1（MCP-1）和分泌的唾液酸结合Ig样凝集素-9（sSiglec-9）的胞外域-消除了其解决大鼠ALF的能力。此外，单独用MCP-1/sSiglec-9治疗显著改善了ALF大鼠的存活率。该处理诱导抗炎M2，抑制肝细胞凋亡，并促进肝细胞增殖。用M2消耗试剂（甘露糖基化氯膦酸盐脂质体）处理抑制了恢复。此外，MCP-1和sSiglec-9通过CCR 2协同促进骨髓源性巨噬细胞的M2分化，并伴随多种肝再生因子的产生。来自MCP-1/sSiglec-9激活的M2巨噬细胞的条件培养基，而不是来自白细胞介素-4诱导的M2巨噬细胞的条件培养基，抑制D-Gal和LPS诱导的原代肝细胞凋亡，并促进其体外增殖。MCP-1/sSiglec-9的独特组合通过抑制肝细胞凋亡并通过诱导抗炎/组织修复M2巨噬细胞促进肝再生来改善大鼠ALF。
Effective treatments for acute liver failure (ALF) are still lacking. We recently reported that a single intravenous administration of serum-free conditioned medium from stem cells derived from human exfoliated deciduous teeth (SHED-CM) into the D-galactosamine (D-Gal)-induced rat ALF model improves the liver injury. However, the specific factors in SHED-CM that are responsible for resolving ALF remain unclear. Here we found that depleting SHED-CM of two anti-inflammatory M2 macrophage inducers—monocyte chemoattractant protein-1 (MCP-1) and the secreted ectodomain of sialic acid-binding Ig-like lectin-9 (sSiglec-9)—abolished its ability to resolve rat ALF. Furthermore, treatment with MCP-1/sSiglec-9 alone dramatically improved the survival of ALF rats. This treatment induced anti-inflammatory M2, suppressed hepatocyte apoptosis, and promoted hepatocyte proliferation. Treatment with an M2-depletion reagent (mannosylated clodronate liposomes) suppressed the recovery. In addition, MCP-1 and sSiglec-9 synergistically promoted the M2 differentiation of bone marrow-derived macrophages via CCR2, accompanied by the production of multiple liver-regenerating factors. The conditioned medium from MCP-1/sSiglec-9-activated M2 macrophages, but not from interleukin-4-induced ones, suppressed the D-Gal- and LPS-induced apoptosis of primary hepatocytes and promoted their proliferation in vitro. The unique combination of MCP-1/sSiglec-9 ameliorates rat ALF by inhibiting hepatocellular apoptosis and promoting liver regeneration through the induction of anti-inflammatory/tissue-repairing M2 macrophages.