Mesenchymal Stromal Cells Induce Peculiar Alternatively Activated Macrophages Capable of Dampening Both Innate and Adaptive Immune Responses
Mesenchymal Stromal Cells Induce Peculiar Alternatively Activated Macrophages Capable of Dampening Both Innate and Adaptive Immune Responses
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DOI：
10.1002/stem.2369
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发表时间：
2016-07-01
期刊：
影响因子：
5.2
通讯作者：
Bottino, Cristina
中科院分区：
文献类型：
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作者：
Chiossone, Laura;Conte, Romana;Bottino, Cristina
间充质基质细胞（MSC）支持造血并发挥免疫调节活性。在这里，我们分析了MSC和单核细胞/巨噬细胞之间相互作用的功能结果。我们发现，在巨噬细胞集落刺激因子的存在下，MSC支持经历分化成巨噬细胞的单核细胞的存活。然而，MSC通过前列腺素E2依赖性机制使其极化倾向于特殊的M2样功能表型（M-MSC）。M-MSC的特点是清道夫受体的高表达，增加吞噬能力，白细胞介素（IL）-10和转化生长因子-β的高产量。这些细胞因子有助于M-MSC的免疫调节特性，其不同于典型的IL-4诱导的巨噬细胞（M2）。特别是，与活化的自然杀伤（NK）细胞相互作用，M-MSC抑制活化分子如NKp 44，CD 69和CD 25的表达和IFN的产生，而M2只影响IFN的产生。此外，M-MSC抑制响应同种异体刺激的CD 8（+）T细胞的增殖，并诱导调节性T细胞（Tcells）的扩增。Toll样受体参与将M-MSC的表型和功能特征恢复为M1免疫刺激/促炎巨噬细胞的表型和功能特征。总之，我们的数据表明，MSC诱导产生一种新型的替代活化的巨噬细胞，能够抑制先天性和适应性免疫反应。这些发现可能有助于更好地理解MSC在健康组织和包括癌症在内的炎症性疾病中的作用，并为新的治疗方法提供线索。干细胞2016;34：1909-1921
Mesenchymal stromal cells (MSCs) support hematopoiesis and exert immunoregulatory activities. Here, we analyzed the functional outcome of the interactions between MSCs and monocytes/macrophages. We showed that MSCs supported the survival of monocytes that underwent differentiation into macrophages, in the presence of macrophage colony-stimulating factor. However, MSCs skewed their polarization toward a peculiar M2-like functional phenotype (M-MSC), through a prostaglandin E2-dependent mechanism. M-MSC were characterized by high expression of scavenger receptors, increased phagocytic capacity, and high production of interleukin (IL)-10 and transforming growth factor-. These cytokines contributed to the immunoregulatory properties of M-MSC, which differed from those of typical IL-4-induced macrophages (M2). In particular, interacting with activated natural killer (NK) cells, M-MSC inhibited both the expression of activating molecules such as NKp44, CD69, and CD25 and the production of IFN, while M2 affected only IFN production. Moreover, M-MSC inhibited the proliferation of CD8(+) T cells in response to allogeneic stimuli and induced the expansion of regulatory T cells (Tregs). Toll-like receptor engagement reverted the phenotypic and functional features of M-MSC to those of M1 immunostimulatory/proinflammatory macrophages. Overall our data show that MSCs induce the generation of a novel type of alternatively activated macrophages capable of suppressing both innate and adaptive immune responses. These findings may help to better understand the role of MSCs in healthy tissues and inflammatory diseases including cancer, and provide clues for novel therapeutic approaches. Stem Cells2016;34:1909-1921