Sarm1-mediated neurodegeneration within the enteric nervous system protects against local inflammation of the colon

doi:10.1007/s13238-021-00835-w

Protein Cell

2021, Vol. 12

Issue (8) : 621-638 https://doi.org/10.1007/s13238-021-00835-w

RESEARCH ARTICLE

Sarm1-mediated neurodegeneration within the enteric nervous system protects against local inflammation of the colon

Yue Sun¹, Qi Wang¹, Yi Wang¹, Wenran Ren⁶, Ying Cao¹, Jiali Li^2,⁷, Xin Zhou⁵, Wei Fu⁵, Jing Yang^1,^2,^3,⁴(

)

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

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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

Corresponding Author(s): Jing Yang

Online First Date: 21 May 2021 Issue Date: 28 September 2021

Cite this article:

Yue Sun,Qi Wang,Yi Wang, et al. Sarm1-mediated neurodegeneration within the enteric nervous system protects against local inflammation of the colon[J]. Protein Cell, 2021, 12(8): 621-638.

URL:

https://academic.hep.com.cn/pac/EN/10.1007/s13238-021-00835-w
https://academic.hep.com.cn/pac/EN/Y2021/V12/I8/621

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