▎药明康德团队
作为最为常见的精神疾病之一，抑郁症已经成为笼罩在全球约3亿人头顶的乌云。目前的抗抑郁症药物往往存在起效慢的问题，并且大量抑郁症患者无法从现有药物中得到足够的缓解；同时，对抗抑郁症的新药研发也并不顺利。因此，要真正驱散这朵乌云，我们对抑郁症的背后机制还需要有更深入的了解。
已经有研究证实，
社会心理压力会对包括免疫系统、大脑在内的身体造成深远影响，是抑郁症最主要的危险因素之一。但是，压力导致抑郁症的潜在机制仍未有明确答案。
在一项近期发表于《自然》的研究中，来自西奈山伊坎医学院的研究团队揭开了社会心理压力导致抑郁症的幕后真相。与此前认为的机制不同，
由骨髓释放到血液中的单核细胞才是“罪魁祸首”——这种外周免疫细胞进入大脑的奖赏中心伏隔核后，释放的蛋白酶改变了神经元功能，最终造成行为改变以及抑郁症状。
科学家们已经观察到，在重度抑郁症等与压力相关的神经精神疾病患者里，有一部分会表现出慢性轻度炎症，他们循环系统的促炎细胞因子和白细胞增多；此外在小鼠实验中，压力还会破坏内皮血脑屏障，导致更多循环蛋白进入大脑中负责奖赏的区域，例如伏隔核。
这些发现将免疫系统与抑郁症等应激障碍联系了起来。但在这项研究之前，科学家们关注的往往是大脑中常驻的小胶质细胞，认为是这种免疫细胞释放的白细胞介素控制了神经元的功能与行为。
现在，最新研究提出了不一样的观点。
图片来源：123RF
为了检验慢性压力对不同免疫细胞的影响，研究团队使用了一种社会心理压力小鼠模型，这些小鼠在长期社交挫败压力后对应激敏感，表现出社交回避和对奖赏偏好的下降，并且出现代谢综合征、全身炎症等生理紊乱。
结合质谱流式技术和单细胞RNA测序，研究团队对小鼠循环系统和大脑中的不同免疫细胞亚型进行了高维表型分析。结果，应激敏感小鼠血液和大脑中的促炎性单核细胞均特异性增加；但是相比于正常小鼠，此前重点关注的小胶质细胞却没有明显增加，也没有表现出促炎的特征。
这些发现提醒研究人员，相比于小胶质细胞，
外周单核细胞或许才是抑郁症等应激相关疾病的关键角色。因此，接下来的研究也聚焦于寻找这类细胞影响神经元功能、行为的机制。
▲在压力作用下，单核细胞在大脑的血管中堆积
（图片来源：参考资料[1]）
对于应激敏感小鼠，它们循环系统以及进入大脑的单核细胞中，
Mmp8基因的表达均明显增加，这也是应激敏感小鼠与正常小鼠表达差异最明显的基因。此外对重度抑郁症患者的基因表达分析也显示，
Mmp8是表达上调最多的基因之一。因此，
Mmp8编码的
基质金属蛋白酶8（MMP8）成为通往抑郁机制的新线索。
这里，我们先来简单介绍基质金属蛋白酶（MMP）的作用。在我们的大脑中，神经元与神经胶质细胞分泌的蛋白和聚糖构成了被称为细胞外基质的致密网架。细胞外基质在突触功能等大脑稳态过程中发挥了重要作用，它们的降解与重塑正是受到了MMP的调控。
与其他MMP不同的是，
MMP8并不是由中枢神经系统分泌的，而是来自外周单核细胞和中性粒细胞。
此前，人们对外周MMP在社会心理压力背景下的作用知之甚少。
最新研究证实，慢性压力导致应激敏感小鼠的内皮紧密连接蛋白claudin-5表达下降，血脑屏障通透性增加。由此，
MMP8通过受损的血脑屏障进入大脑，直接浸润伏隔核实质、改变伏隔核的神经生理学，并且调控细胞外间隙的超微结构。MMP8对神经元功能的改变，最终导致社会奖赏行为的损伤，造成抑郁症状。
相反，当应激敏感小鼠的
Mmp8被敲除，压力诱发的社交回避程度下降，同时它们的伏隔核与细胞外间隙也没有出现不利的变化。
▲研究示意图
（图片来源：参考资料[1]）
综上，这些数据揭示了外周免疫因子在压力条件下影响中枢神经系统功能与行为的机制。靶向外周免疫细胞分泌的MMP8，有望为压力相关的神经精神障碍提供全新疗法。
“目前还没有靶向MMP8的药物，虽然尚不清楚此类治疗最终是否能有效治疗抑郁症，但我希望这项研究将促使人们重新开发此类药物，”领导这项研究的Scott Russo教授说，“促进免疫健康的非药物‘生活方式’策略，也可能有助于治疗这些与压力相关的疾病。”
参考资料：
[1] Cathomas, F., Lin, HY., Chan, K.L. et al. Circulating myeloid-derived MMP8 in stress susceptibility and depression. Nature 626, 1108–1115 (2024).
[2]
Mount Sinai study shows that circulating immune cells drawn to the brain during stress can control emotional behaviors. Retrieved Mar. 13, 2024 from https://www.eurekalert.org/news-releases/1033807
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