Qi Wang
Yi Wang
Wenran Ren
Ying Cao
Jiali Li
Xin Zhou
Wei Fu
Jing Yang
1 State Key Laboratory of Membrane Biology, School of Life Sciences, Center for Life Sciences, Peking University, Beijing 100871, China;
2 IDG/McGovern Institute for Brain Research, Peking University, Beijing 100871, China;
3 Chinese Institute for Brain Research, Beijing 102206, China;
4 Shenzhen Bay Laboratory, Institute of Molecular Physiology, Shenzhen 518055, China;
5 Department of General Surgery, Peking University Third Hospital, Beijing 100191, China;
6 School of Medicine, Tsinghua University, Beijing 100084, China;
7 Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming 650223, China
Received Date: 2021-01-07
Rev Recd Date:2021-03-01
Abstract
Abstract
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, nonhuman 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.Keywords: 3D imaging,
enteric nervous system,
axonal degeneration,
neurodegeneration,
catecholaminergic axons,
Sarm1,
colitis
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