RESUMEN
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.
Asunto(s)
Proteínas del Dominio Armadillo/genética , Colitis Ulcerosa/genética , Proteínas del Citoesqueleto/genética , Sistema Nervioso Entérico/metabolismo , Enfermedades Neurodegenerativas/genética , Animales , Proteínas del Dominio Armadillo/deficiencia , Catecolaminas/metabolismo , Colitis Ulcerosa/inducido químicamente , Colitis Ulcerosa/diagnóstico por imagen , Colitis Ulcerosa/metabolismo , Colon/diagnóstico por imagen , Colon/metabolismo , Colon/patología , Proteínas del Citoesqueleto/deficiencia , Sulfato de Dextran/administración & dosificación , Modelos Animales de Enfermedad , Sistema Nervioso Entérico/diagnóstico por imagen , Sistema Nervioso Entérico/patología , Regulación de la Expresión Génica , Humanos , Imagenología Tridimensional , Interleucina-17/genética , Interleucina-17/metabolismo , Macaca mulatta , Masculino , Ratones , Ratones Noqueados , Enfermedades Neurodegenerativas/inducido químicamente , Enfermedades Neurodegenerativas/diagnóstico por imagen , Enfermedades Neurodegenerativas/metabolismo , Neuronas/metabolismo , Neuronas/patología , Norepinefrina/metabolismo , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/genética , Miembro 3 del Grupo F de la Subfamilia 1 de Receptores Nucleares/metabolismo , Transducción de Señal , Factor de Necrosis Tumoral alfa/genética , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
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.