Vagal control of tissue SUMOylation as a novel anti-inflammatory target in IBD

摘要 限制炎症细胞募集是寻找炎症性肠病（IBD）新疗法的关键焦点。我们的工作证明，增强与肠上皮内的小泛素样调节剂（SUMO）的缀合通过调节免疫细胞的组织流入的反应的广泛重编程来有效地减弱肠道炎症。然而，SUMO化是如何生理调节是未知的，限制了我们利用这种内源性保护机制进行实验和治疗的能力。基于我们的初步研究结果，我们假设肠SUMO化是由迷走神经刺激诱导的，确定SUMO化是脑肠轴的潜在关键抗炎效应机制。 迷走神经刺激用于控制炎症，并得到NIH和WHO的认可。我们的目标是将SUMO化定义为这种神经调节干预的关键抗炎效应机制，并在此过程中开发利用SUMO化控制IBD中失调的肠道炎症的特定方法。具体而言： 在目标1中，我们将确定迷走神经刺激增强小鼠SUMO化的能力，并将脾脏定义为该途径的关键中继站。 在目标2中，我们将使用我们的新型条件性敲除和转基因小鼠品系靶向主要SUMO亚型1、2或3，并在两种互补的IBD小鼠模型中建立肠上皮SUMO化对迷走神经抗炎作用的重要性。 这些目标的成功完成将构成我们长期目标的重大进展，即将我们关于SUMO化作为内源性保护性组织反应的基本发现转化为IBD的新型抗炎治疗。通过提供与迷走神经刺激和电针等生物电刺激技术的机制联系，我们不仅将大大提高对脑-肠轴炎症控制机制的理解，而且将为生物电医学在失调性炎症治疗中的更大接受和改进靶向奠定基础。

Abstract Limiting inflammatory cell recruitment is a key focus in the search for new therapies in inflammatory bowel dis-eases (IBD). Our work documents that enhanced conjugation with Small Ubiquitin-like MOdifiers (SUMO) within the intestinal epithelium effectively blunts intestinal inflammation through broad reprogramming of responses regulating the tissue influx of immune cells. However, how SUMOylation is physiologically regulated is unkown, limiting our ability to harness this endogenous, protective mechanism for experimental and therapeutic use. Based on our preliminary findings, we hypothesize that intestinal SUMOylation is induced by stimulation of the vagus nerve identifying SUMOylation as a potentially critical anti-inflammatory effector mechanism of the brain-gut axis. Vagus nerves stimulation is used control inflammation and is endorsed by the NIH and WHO. Our objective is to define SUMOylation as a critical anti-inflammatory effector mechanism of this neuromodulatory intervention and in doing so, to develop specific approaches that harness SUMOylation for control of dysregulated intestinal in-flammation in IBD. Specifically: In Aim 1, we will determine the ability of vagus nerve stimulation to enhance SUMOylation in mice, and define the spleen as a key relay station of this pathway. In Aim 2, we will target major SUMO isoforms 1, 2 or 3, using our novel conditional knockout and transgenic mouse strains and establish the importance of intestinal epithelial SUMOylation for vagal anti-inflammatory ef-fects in two complementary murine models of IBD. Successful completion of these aims will constitute a major advance towards our long-term goal to translate our basic findings on SUMOylation as an endogenous, protective tissue response into novel anti-inflammatory ther-apies in IBD. By providing the mechanistic link to bioelectric stimulation techniques such as vagus nerve stimu-lation and electroacupuncture, we will not only greatly enhance the understanding of inflammatory control mech-anisms of the brain-gut axis, but will lay the foundation to the greater acceptance and improved targeting of bioelectric medicine in the therapy of dysregulated inflammation.