Adipose-derived mesenchymal stromal cells induce immunomodulatory macrophages which protect from experimental colitis and sepsis
Adipose-derived mesenchymal stromal cells induce immunomodulatory macrophages which protect from experimental colitis and sepsis
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DOI：
10.1136/gutjnl-2012-302152
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发表时间：
2013-08-01
期刊：
影响因子：
24.5
通讯作者：
Delgado, Mario
中科院分区：
文献类型：
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作者：
Anderson, Per;Souza-Moreira, Luciana;Delgado, Mario
目的探讨脂肪间充质基质细胞（adipose-derivedmesenchymalstromalcells，ASCs）对体外培养的巨噬细胞（macrophages，M phi）活化状态的影响，以及ASCs对实验性结肠炎和脓毒症的治疗作用（ASC-M phi），并表征了几种调节性巨噬细胞标志物的表达，包括酶和细胞因子，以及它们的体外免疫调节能力。研究了ASC-M phi在由三硝基苯磺酸和葡聚糖硫酸钠诱导的两种实验性炎症性结肠炎模型和由盲肠结扎和穿刺诱导的多微生物脓毒症模型中的治疗效果。结果ASC-M phi表现出明显不同于经典活化的巨噬细胞或由白细胞介素（IL）-4诱导的交替活化的巨噬细胞的表型，其特征在于高的凝血酶活性，在再刺激时IL-10的产生增加以及对T细胞和巨噬细胞的有效免疫抑制活性。ASCs上环氧合酶-2的激活似乎是诱导这种表型的关键。全身输注ASC-M phi可抑制小鼠结肠炎，降低死亡率和体重减轻，同时降低结肠和全身炎性细胞因子水平。重要的是，在已建立的慢性结肠炎中治疗性注射ASC-M phi缓解了其进展并避免了疾病复发。此外，ASC-M phi保护严重的脓毒症，通过减少炎症细胞浸润到各种器官，并通过下调生产的几种炎症介质，ASC-M phi衍生的IL-10发挥了关键作用.ConclusionASCs诱导一个独特的调节激活状态的巨噬细胞，具有强大的免疫调节能力和治疗潜力，在炎症性肠病和脓毒症。
ObjectiveTo investigate the effect of adipose-derived mesenchymal stromal cells (ASCs) on the activation state of macrophages (M phi) in vitro, and the potential therapeutic effect of these cells in experimental colitis and sepsis.DesignMurine bone marrow-derived macrophages were cultured with ASCs or with ASC conditioned media (ASC-M phi) and characterised for the expression of several regulatory macrophage markers, including enzymes and cytokines, and for their immunomodulatory capacity in vitro. The therapeutic effect was investigated of ASC-M phi in two models of experimental inflammatory colitis induced by trinitrobenzene sulphonic acid and dextran sodium sulphate, and in polymicrobial sepsis induced by caecal ligation and puncture.ResultsASC-M phi showed a phenotype that clearly differed from the classically activated macrophages or the alternatively activated macrophages induced by interleukin (IL)-4, characterised by high arginase activity, increased production of IL-10 upon restimulation and potent immunosuppressive activity on T cells and macrophages. Activation of cyclo-oxygenase-2 on ASCs seems to be critically involved in inducing this phenotype. Systemic infusion of ASC-M phi inhibited colitis in mice, reducing mortality and weight loss while lowering the colonic and systemic levels of inflammatory cytokines. Importantly, therapeutic injection of ASC-M phi in established chronic colitis alleviated its progression and avoided disease recurrence. Moreover, ASC-M phi protected from severe sepsis by reducing the infiltration of inflammatory cells into various organs and by downregulating the production of several inflammatory mediators, where ASC-M phi-derived IL-10 played a critical role.ConclusionASCs induce a distinct regulatory activation state of macrophages which possess potent immunomodulatory ability and therapeutic potential in inflammatory bowel diseases and sepsis.