Department of Neurobiology and Anatomy, The University of Texas McGovern Medical School, P.O. Box 20708, Houston, TX, 77225, USA.
J Neuroinflammation. 2023 Jul 4;20(1):158. doi: 10.1186/s12974-023-02838-2.
Inflammation is a fundamental biological response to injury and infection, which if unregulated can contribute to the pathophysiology of many diseases. The vagus nerve, which primarily originates from the dorsal motor nucleus (DMN), plays an important role in rapidly dampening inflammation by regulating splenic function. However, direct vagal innervation of the spleen, which houses the majority of immune and inflammatory cells, has not been established. As an alternative to direct innervation, an anti-inflammatory reflex pathway has been proposed which involves the vagus nerve, the sympathetic celiac ganglion, and the neurotransmitter norepinephrine. Although sympathetic regulation of inflammation has been shown, the interaction of the vagus nerve and the celiac ganglia requires a unique interaction of parasympathetic and sympathetic inputs, making this putative mechanism of brain-spleen interaction controversial. BODY: As neuropeptides can be expressed at relatively high levels in neurons, we reasoned that DMN neuropeptide immunoreactivity could be used to determine their target innervation. Employing immunohistochemistry, subdiaphragmatic vagotomy, viral tract tracing, CRISPR-mediated knock-down, and functional assays, we show that cocaine and amphetamine-regulated transcript (CART) peptide-expressing projection neurons in the caudal DMN directly innervate the spleen. In response to lipopolysaccharide (LPS) stimulation, CART acts to reduce inflammation, an effect that can be augmented by intrasplenic administration of a synthetic CART peptide. These in vivo effects could be recapitulated in cultured splenocytes, suggesting that these cells express the as yet unidentified CART receptor(s).
Our results provide evidence for direct connections between the caudal DMN and spleen. In addition to acetylcholine, these neurons express the neuropeptide CART that, once released, acts to suppress inflammation by acting directly upon splenocytes.
炎症是机体对损伤和感染的基本生物学反应，如果不受调控，可能会导致许多疾病的病理生理学改变。迷走神经主要起源于背侧运动核（DMN），通过调节脾脏功能，在迅速抑制炎症方面发挥着重要作用。然而，脾脏中存在大量免疫和炎症细胞，迷走神经对其的直接支配尚未得到证实。作为直接支配的替代方案，已经提出了一种抗炎反射途径，该途径涉及迷走神经、交感腹腔神经节和神经递质去甲肾上腺素。尽管已经证明了交感神经对炎症的调节作用，但迷走神经和腹腔神经节的相互作用需要副交感神经和交感神经输入的独特相互作用，这使得这种大脑-脾脏相互作用的假设机制存在争议。
由于神经肽在神经元中可以表达出相对较高的水平，我们推断 DMN 神经肽免疫反应性可用于确定其靶支配。通过免疫组织化学、膈下迷走神经切断术、病毒追踪、CRISPR 介导的敲低和功能测定，我们发现尾侧 DMN 中的可卡因和安非他命调节转录物（CART）肽表达投射神经元直接支配脾脏。在脂多糖（LPS）刺激下，CART 作用于减少炎症，这种作用可以通过脾内给予合成 CART 肽来增强。这些体内效应可以在培养的脾细胞中重现，这表明这些细胞表达了尚未鉴定的 CART 受体。
我们的结果为尾侧 DMN 和脾脏之间的直接连接提供了证据。除了乙酰胆碱外，这些神经元还表达神经肽 CART，一旦释放，它就会通过直接作用于脾细胞来抑制炎症。
