State Key Laboratory of Membrane Biology, School of Life Sciences, Center for Life Sciences, Peking University, Beijing, 100871, China.
School of Medicine, Tsinghua University, Beijing, 100084, China.
Protein Cell. 2021 Aug;12(8):621-638. doi: 10.1007/s13238-021-00835-w. Epub 2021 Apr 19.
Axonal degeneration is one of the key features of neurodegenerative disorders. In the canonical view, axonal degeneration destructs neural connections and promotes detrimental disease defects. Here, we assessed the enteric nervous system (ENS) of the mouse, non-human primate, and human by advanced 3D imaging. We observed the profound neurodegeneration of catecholaminergic axons in human colons with ulcerative colitis, and similarly, in mouse colons during acute dextran sulfate sodium-induced colitis. However, we unexpectedly revealed that blockage of such axonal degeneration by the Sarm1 deletion in mice exacerbated the colitis condition. In contrast, pharmacologic ablation or chemogenetic inhibition of catecholaminergic axons suppressed the colon inflammation. We further showed that the catecholaminergic neurotransmitter norepinephrine exerted a pro-inflammatory function by enhancing the expression of IL-17 cytokines. Together, this study demonstrated that Sarm1-mediated neurodegeneration within the ENS mitigated local inflammation of the colon, uncovering a previously-unrecognized beneficial role of axonal degeneration in this disease context.
轴突变性是神经退行性疾病的主要特征之一。在经典观点中，轴突变性破坏神经连接并促进有害的疾病缺陷。在这里，我们通过先进的 3D 成像技术评估了小鼠、非人灵长类动物和人类的肠神经系统 (ENS)。我们观察到溃疡性结肠炎患者的人类结肠中儿茶酚胺能轴突发生了深刻的神经退行性变，类似地，在急性葡聚糖硫酸钠诱导的结肠炎期间，小鼠的结肠中也发生了这种变化。然而，我们出人意料地发现，Sarm1 缺失会加剧小鼠的结肠炎病情。相比之下，通过药理学消融或化学遗传抑制儿茶酚胺能轴突可以抑制结肠炎症。我们进一步表明，儿茶酚胺能神经递质去甲肾上腺素通过增强白细胞介素 17（IL-17）细胞因子的表达发挥促炎作用。总之，这项研究表明，ENS 内的 Sarm1 介导的神经退行性变减轻了结肠的局部炎症，揭示了轴突变性在这种疾病背景下的一个以前未被认识的有益作用。
