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

摘要 限制炎性细胞募集是寻找炎症性肠病(IBD)新疗法的关键。我们的工作证明，通过对调节免疫细胞组织流入的反应进行广泛的重新编程，加强与肠上皮内小泛素样修饰物(SUMO)的结合，有效地钝化肠道炎症。然而，SUMO化如何在生理上受到调节尚不清楚，这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。根据我们的初步发现，我们假设肠道SUMO化是由刺激迷走神经诱导的，确定SUMO化是脑-肠轴潜在的关键抗炎效应机制。 迷走神经刺激用于控制炎症，并得到美国国立卫生研究院和世界卫生组织的认可。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，并在这样做的同时，开发利用SUMO化来控制IBD失调的肠道炎症的特定方法。具体地说，就是： 在目标1中，我们将确定刺激迷走神经增强小鼠SUMO化的能力，并将脾确定为这一途径的关键中继站。 在目标2中，我们将以主要的相扑亚型1、2或3为靶点，使用我们的新的条件基因敲除和转基因小鼠品系，并在两个互补的IBD小鼠模型中确定肠上皮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是朝着我们的长期目标的重大进步，我们的长期目标是将我们关于SUMO化作为一种内源性保护性组织反应的基本发现转化为治疗IBD的新型抗炎疗法。通过为迷走神经刺激和电针等生物电刺激技术提供机制链接，我们不仅将极大地提高对脑肠轴炎症控制机制的了解，而且将为更广泛地接受和改进生物电药物在治疗调节性炎症中的靶向性奠定基础。

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.