骨髓间充质干细胞介导IL-10和SOCS3调控自然杀伤细胞治疗脓毒症的机制研究

Sepsis can lead to septic shock, multiple organ failure even death. It is an urgent problem to overcome in critical care medicine. Despite anti-infection, organ support therapy and other therapeutic measures have a certain effect, but its mortality rate is still very high. Scholars have found that sepsis closely related to immune dysfunction and increasing natural killer (NK) cells are a major reason for its deterioration. Our previous studies have confirmed that mesenchymal stem cells (MSCs) have a good effect for the treatment of sepsis, which are connected with (NK) cells. From the perspective of immune cells to explore the mechanism of MSCs treating sepsis become a hot topic, but NK cells in terms of the research has not been reported. Based on this,we will ask two questions : 1.The target cells are NK cells in role of MSCs treatment for sepsis ? 2. If so what is its mechanism? We have confirmed that MSCs inhibit NK cells function by elevating IL-10 in vitro and vivo, therefore, we may assume MSCs act on NK cells by IL-10 and JAK-STAT signaling pathway downstream SOCS3 and further improve sepsis, which will be a new target and theoretical basis for sepsis therapy by MSCs.

脓毒症可导致脓毒性休克甚至多器官功能衰竭而死亡，是重症医学的一个亟待攻克的难题，尽管抗感染和器官功能支持等治疗措施有一定疗效，但死亡率仍极高。现有学者发现脓毒症与免疫功能失调有关，自然杀伤（NK）细胞增多是其恶化的重要原因之一。我们前期研究证实了间充质干细胞（MSCs）对脓毒症有很好治疗作用，而且这种治疗作用与NK细胞密切相关。从免疫细胞角度探讨MSCs治疗脓毒症的机制成为近年来研究热点，但从NK细胞方面的相关研究目前尚未见报道，基于此，我们提出两个问题：1. NK细胞是MSCs对脓毒症的作用靶细胞吗？2. 如果是那么其作用机制又是如何？前期我们通过体内外实验已证实MSCs抑制NK细胞作用且导致IL-10明显增高，所以，我们假设MSCs可能是通过IL-10和JAK-STAT信号通路下游SOCS3作用于NK细胞进而改善脓毒症，这将为MSCs治疗脓毒症提供新的靶点和理论依据。

脓毒症是重症患者常见的致死性疾病，免疫失调在其发生发展过程中发挥了举足轻重的作用，许多基础实验已证明间充质干细胞对脓毒症有一定治疗作用，而具体作用机制仍不明确。我们的研究着重于MSCs通过调节固有免疫细胞NK细胞对脓毒症起到治疗作用。利用盲肠结扎穿孔小鼠模型和体外MSCs与NK细胞共培养系统，发现MSCs可降低脓毒症小鼠病死率和重要脏器炎症反应并抑制NK细胞增殖和成熟。检测血浆和上清液中细胞因子水平，可见MSCs使标本中IL-10增加，并降低IL-6、TNF-α和IFN-γ水平，同时JAK-STAT信号转导通路蛋白表达上升，而在体外实验中，以上改变在加入AG490（JAK抑制剂）、IL-10中和抗体或NK细胞转染SOCS3 siRNA后发生相反变化。盲肠结扎穿刺法（CLP）模型小鼠肺组织免疫组化染色检测也发现MSCs移植后炎症水平受到抑制而IL-10和SOCS3表达增加。我们的研究证实MSCs可以通过上调分泌IL-10激活JAK-STAT信号转导通路及其下游靶蛋白SOCS3调节NK细胞增殖和成熟，从而抑制脓毒症炎症反应和病死率，为脓毒症临床治疗提供了新思路和作用靶点。