Rossetti Andrea Carlo, Paladini Maria Serena, Trepci Ada, Mallien Anne, Riva Marco Andrea, Gass Peter, Molteni Raffaella
Department of Medical Biotechnology and Translational Medicine, University of Milan, Milan, Italy.
Department of Pharmacological and Biomolecular Sciences, University of Milan, Milan, Italy.
Front Mol Neurosci. 2019 Jul 17;12:166. doi: 10.3389/fnmol.2019.00166. eCollection 2019.
A growing body of evidence supports the close relationship between major depressive disorder (MDD), a severe psychiatric disease more common among women than men, and alterations of the immune/inflammatory system. However, despite the large number of studies aimed at understanding the molecular bases of this association, a lack of information exists on the potential cross-talk between systems known to be involved in depression and components of the inflammatory response, especially with respect to sex differences. Brain-derived neurotrophic factor (BDNF) is a neurotrophin with a well-established role in MDD etiopathology: it is altered in depressed patients as well as in animal models of the disease and its changes are restored by antidepressant drugs. Interestingly, this neurotrophin is also involved in the inflammatory response. Indeed, it can be secreted by microglia, the primary innate immune cells in the central nervous system whose functions may be in turn regulated by BDNF. With these premises, in this study, we investigated the reciprocal impact of BDNF and the immune system by evaluating the neuroinflammatory response in male and female BDNF-heterozygous mutant mice acutely treated with the cytokine-inducer lipopolysaccharide (LPS). Specifically, we assessed the potential onset of an LPS-induced sickness behavior as well as changes of inflammatory mediators in the mouse hippocampus and frontal cortex, with respect to both genotype and sex. We found that the increased inflammatory response induced by LPS in the brain of male mice was independent of the genotype, whereas in the female, it was restricted to the heterozygous mice with no changes in the wild-type group, suggestive of a role for BDNF in the sex-dependent effect of the inflammatory challenge. Considering the involvement of both BDNF and neuroinflammation in several psychiatric diseases and the diverse incidence of such pathologies in males and females, a deeper investigation of the mechanisms underlying their interaction may have a critical translational relevance.
越来越多的证据支持重度抑郁症（MDD）——一种在女性中比男性更常见的严重精神疾病——与免疫/炎症系统改变之间的密切关系。然而，尽管有大量研究旨在了解这种关联的分子基础，但对于已知参与抑郁症的系统与炎症反应成分之间潜在的相互作用，尤其是关于性别差异方面，仍缺乏相关信息。脑源性神经营养因子（BDNF）是一种神经营养因子，在MDD的病因病理学中具有公认的作用：它在抑郁症患者以及该疾病的动物模型中都会发生改变，并且其变化可通过抗抑郁药物恢复。有趣的是，这种神经营养因子也参与炎症反应。事实上，它可由小胶质细胞分泌，小胶质细胞是中枢神经系统中的主要固有免疫细胞，其功能反过来可能受BDNF调节。基于这些前提，在本研究中，我们通过评估用细胞因子诱导剂脂多糖（LPS）急性处理的雄性和雌性BDNF杂合突变小鼠的神经炎症反应，来研究BDNF与免疫系统的相互影响。具体而言，我们评估了LPS诱导的疾病行为的潜在发作以及小鼠海马体和额叶皮质中炎症介质的变化，涉及基因型和性别两个方面。我们发现，LPS在雄性小鼠大脑中诱导的炎症反应增强与基因型无关，而在雌性小鼠中，这种增强仅限于杂合小鼠，野生型组没有变化，这表明BDNF在炎症刺激的性别依赖性效应中发挥作用。鉴于BDNF和神经炎症都参与多种精神疾病，且这些疾病在男性和女性中的发病率不同，对它们相互作用的潜在机制进行更深入的研究可能具有关键的转化意义。
