PACAP is a pathogen-inducible resident antimicrobial neuropeptide affording rapid and contextual molecular host defense of the brain
PACAP is a pathogen-inducible resident antimicrobial neuropeptide affording rapid and contextual molecular host defense of the brain
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DOI：
10.1073/pnas.1917623117
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发表时间：
2021-01-05
影响因子：
11.1
通讯作者：
Wong, Gerard C. L.
中科院分区：
文献类型：
--
作者：
Lee, Ernest Y.;Chan, Liana C.;Wong, Gerard C. L.
中枢神经系统（CNS）抵御感染的防御必须在不产生潜在有害的免疫细胞介导的或可能损害关键功能的脱靶炎症的情况下完成。由于中枢神经系统是一个免疫特权区室，中枢神经系统内源性的诱导型先天防御机制可能在这方面发挥重要作用。垂体腺苷酸环化酶激活多肽 (PACAP) 是一种神经肽，已知可调节神经发育、情绪和某些应激反应。虽然已知 PACAP 与免疫系统相互作用，但其在直接防御大脑或其他组织方面的重要性尚未确定。在这里，我们展示了我们的机器学习分类器可以筛选神经肽中的免疫活性，并正确地将 PACAP 识别为抗菌神经肽，与之前的实验工作一致。此外，同步加速器 X 射线散射、抗菌测定和机械指纹分析提供了关于 PACAP 如何通过多种协同机制（包括膜完整性和能量失调以及细胞死亡途径激活）对病原体发挥抗菌活性的精确见解。重要的是，在体内金黄色葡萄球菌或白色念珠菌感染的小鼠模型中，常驻 PACAP 在大脑中被选择性诱导高达 50 倍，而不诱导免疫细胞浸润。我们展示了即使在 CNS 以外的各种组织中 PACAP 诱导也存在差异，以及这些观察到的诱导模式如何与在模拟这些组织的特定生理环境的条件下测量的 PACAP 抗菌功效一致。 PACAP 的系统发育分析揭示了从原始无脊椎动物到现代哺乳动物的预测抗菌特性的密切保守性。总之，这些发现证实了我们的假设，即 PACAP 是一种古老的神经内分泌免疫效应器，可以保护中枢神经系统免受感染，同时最大限度地减少潜在的有害神经炎症。
Defense of the central nervous system (CNS) against infection must be accomplished without generation of potentially injurious immune cell-mediated or off-target inflammation which could impair key functions. As the CNS is an immune-privileged compartment, inducible innate defense mechanisms endogenous to the CNS likely play an essential role in this regard. Pituitary adenylate cyclase-activating polypeptide (PACAP) is a neuropeptide known to regulate neurodevelopment, emotion, and certain stress responses. While PACAP is known to interact with the immune system, its significance in direct defense of brain or other tissues is not established. Here, we show that our machine-learning classifier can screen for immune activity in neuropeptides, and correctly identified PACAP as an antimicrobial neuropeptide in agreement with previous experimental work. Furthermore, synchrotron X-ray scattering, antimicrobial assays, and mechanistic fingerprinting provided precise insights into how PACAP exerts antimicrobial activities vs. pathogens via multiple and synergistic mechanisms, including dysregulation of membrane integrity and energetics and activation of cell death pathways. Importantly, resident PACAP is selectively induced up to 50-fold in the brain in mouse models of Staphylococcus aureus or Candida albicans infection in vivo, without inducing immune cell infiltration. We show differential PACAP induction even in various tissues outside the CNS, and how these observed patterns of induction are consistent with the antimicrobial efficacy of PACAP measured in conditions simulating specific physiologic contexts of those tissues. Phylogenetic analysis of PACAP revealed close conservation of predicted antimicrobial properties spanning primitive invertebrates to modern mammals. Together, these findings substantiate our hypothesis that PACAP is an ancient neuro-endocrine-immune effector that defends the CNS against infection while minimizing potentially injurious neuroinflammation.