Intestinal epithelial dopamine receptor signaling drives sex-specific disease exacerbation in a mouse model of multiple sclerosis

Although the gut microbiota can influence central nervous system (CNS) autoimmune diseases, the contribution of the intestinal epithelium to CNS autoimmunity is less clear. Here, we showed that intestinal epithelial dopamine D2 receptors (IEC DRD2) promoted sex-specific disease progression in an ani...

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Published inImmunity (Cambridge, Mass.) Vol. 56; no. 12; pp. 2773 - 2789.e8
Main Authors Peng, Hai-rong, Qiu, Jia-Qian, Zhou, Qin-ming, Zhang, Yu-kai, Chen, Qiao-yu, Yin, Yan-qing, Su, Wen, Yu, Shui, Wang, Ya-ting, Cai, Yuping, Gu, Ming-na, Zhang, Hao-hao, Sun, Qing-qing, Hu, Gang, Wu, Yi-wen, Liu, Jun, Chen, Sheng, Zhu, Zheng-Jiang, Song, Xin-yang, Zhou, Jia-wei
Format Journal Article
LanguageEnglish
Published United States 12.12.2023
Subjects
Animals
Autoimmune Diseases of the Nervous System
Disease Models, Animal
Disease Progression
Female
Male
Mice
Multiple Sclerosis - metabolism
Receptors, Dopamine
Signal Transduction
lysozyme
dopamine D2 receptor
sex difference
multiple sclerosis
intestinal epithelium
CNS autoimmune diseases
phenylethylamine
gut microbiota
N2-acetyl-L-lysine
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Summary:Although the gut microbiota can influence central nervous system (CNS) autoimmune diseases, the contribution of the intestinal epithelium to CNS autoimmunity is less clear. Here, we showed that intestinal epithelial dopamine D2 receptors (IEC DRD2) promoted sex-specific disease progression in an animal model of multiple sclerosis. Female mice lacking Drd2 selectively in intestinal epithelial cells showed a blunted inflammatory response in the CNS and reduced disease progression. In contrast, overexpression or activation of IEC DRD2 by phenylethylamine administration exacerbated disease severity. This was accompanied by altered lysozyme expression and gut microbiota composition, including reduced abundance of Lactobacillus species. Furthermore, treatment with N2-acetyl-L-lysine, a metabolite derived from Lactobacillus, suppressed microglial activation and neurodegeneration. Taken together, our study indicates that IEC DRD2 hyperactivity impacts gut microbial abundances and increases susceptibility to CNS autoimmune diseases in a female-biased manner, opening up future avenues for sex-specific interventions of CNS autoimmune diseases.
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ISSN:1074-7613
1097-4180
1097-4180
DOI:10.1016/j.immuni.2023.10.016