Instituto de Farmacología, Facultad de Medicina, Universidad de Buenos Aires, Paraguay 2155, 9th floor, Buenos Aires 1121, Argentina.
Centro de Investigaciones en Bioquímica Clínica e Inmunología (CIBICI), Consejo Nacional de Investigaciones Científicas y Tecnológicas (CONICET), Departamento de Bioquímica Clínica, Facultad de Ciencias Químicas, Universidad Nacional de Córdoba, Córdoba, Argentina.
EBioMedicine. 2019 Dec;50:290-305. doi: 10.1016/j.ebiom.2019.10.063. Epub 2019 Nov 18.
Depression is a highly prevalent disorder that is one of the leading causes of disability worldwide. Despite an unknown aetiology, evidence suggests that the innate and adaptive immune systems play a significant role in the development and maintenance of major depressive disorder (MDD). The non-competitive glutamatergic N-methyl-D-aspartate receptor (NMDAR) antagonist, (R,S)-ketamine (ketamine), has demonstrated rapid and robust efficacy as an antidepressant when administered at sub-anaesthetic doses.
Our goal was to characterize the pro-inflammatory profile of patients with MDD by measuring pro-inflammatory cytokines in plasma and circulating monocyte subsets and to understand how ketamine induces an anti-inflammatory program in monocyte and macrophages in vitro and vivo.
Our results show that patients with MDD without other comorbidities (N = 33) exhibited significantly higher levels of pro-inflammatory IL-12 and IL-6 in plasma and that these cytokines were associated with increased numbers of non-classical (CD11bCD16CD14) monocytes and increased activation state (CD40CD86) of classical monocytes in circulation. Remarkably, we have demonstrated that sub-anaesthetic doses of ketamine programs human monocytes into M2c-like macrophages by inducing high levels of CD163 and MERTK with intermediate levels of CD64 and stimulating mTOR-associated gene expression in vitro. The NMDAR antagonist MK-801, but not the α-amino-3‑hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) antagonist, NBQX, also polarizes macrophages to an M2c-like phenotype, but this phenotype disappears upon mTOR pathway inhibition. Sub-anaesthetic doses (10 mg/kg) of ketamine administration in mice both promote reduction of circulating classical pro-inflammatory monocytes and increase of alternative M2 macrophage subtypes in the spleen and CNS.
Our results suggest an anti-inflammatory property of ketamine that can skew macrophages to an M2-like phenotype, highlighting potential therapeutic implications not only for patients with MDD but also other inflammatory-based diseases.
This study was supported by grants from the Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) and Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT-FONCYT).
抑郁症是一种高发性疾病，是全球导致残疾的主要原因之一。尽管病因不明，但有证据表明，先天和适应性免疫系统在重度抑郁症（MDD）的发展和维持中起着重要作用。非竞争性谷氨酸 N-甲基-D-天冬氨酸受体（NMDAR）拮抗剂（R，S）-氯胺酮（氯胺酮）以亚麻醉剂量给药时，已被证明具有快速而强大的抗抑郁作用。
我们的目标是通过测量血浆和循环单核细胞亚群中的促炎细胞因子来描述 MDD 患者的促炎特征，并了解氯胺酮如何在体外和体内诱导单核细胞和巨噬细胞的抗炎程序。
我们的结果表明，没有其他合并症的 MDD 患者（N=33）的血浆中促炎细胞因子 IL-12 和 IL-6 水平明显升高，并且这些细胞因子与循环中非经典（CD11bCD16CD14）单核细胞数量增加和经典单核细胞激活状态（CD40CD86）增加有关。值得注意的是，我们已经证明，亚麻醉剂量的氯胺酮通过诱导高水平的 CD163 和 MERTK 以及中等水平的 CD64 并刺激体外 mTOR 相关基因表达，将人单核细胞编程为 M2c 样巨噬细胞。NMDAR 拮抗剂 MK-801，但不是 AMPAR 拮抗剂 NBQX，也将巨噬细胞极化为 M2c 样表型，但这种表型在 mTOR 途径抑制后消失。在小鼠中给予亚麻醉剂量（10mg/kg）的氯胺酮可促进循环中经典促炎单核细胞的减少，并增加脾脏和中枢神经系统中的替代 M2 巨噬细胞亚型。
我们的结果表明氯胺酮具有抗炎特性，可以使巨噬细胞偏向 M2 样表型，这突出了其不仅对 MDD 患者，而且对其他炎症性疾病具有潜在的治疗意义。
这项研究得到了 CONICET 和 ANPCyT-FONCYT 的资助。
