Zuo Muqiu, Fang Jiankai, Huang Peiqing, Liu Shisong, Hou Pengbo, Wang Shiqing, Liu Zhanhong, Feng Chao, Cao Lijuan, Li Peishan, Shi Yufang, Shao Changshun
The Third Affiliated Hospital of Soochow University, Institutes for Translational Medicine, State Key Laboratory of Radiation Medicine and Protection, Suzhou Medical College of Soochow University, Suzhou, Jiangsu, 215123, China.
Department of Experimental Medicine and Biochemical Sciences, TOR, University of Rome "Tor Vergata", Rome, 00133, Italy.
Cell Death Discov. 2023 Jul 28;9(1):269. doi: 10.1038/s41420-023-01568-x.
Muscle stem cells (MuSCs) have been demonstrated to exert impressive therapeutic efficacy in disease settings through orchestrating inflammatory microenvironments. Nevertheless, the mechanisms underlying the immunoregulatory property of MuSCs remain largely uncharacterized. Here, we showed that interleukin-4-induced-1 (IL4I1), an essential enzyme that catalyzes indole metabolism in humans, was highly expressed in human MuSCs exposed to IFN-γ and TNF-α. Functionally, the MuSCs were found to inhibit the infiltration of neutrophils into sites of inflammation in a IL4I1-dependent manner and thus ameliorate acute lung injury in mice. Mechanistically, the indole metabolites, including indole-3-pyruvic acid (I3P) and indole-3-aldehyde (I3A), produced by IL4I1, acted as ligands to activate aryl hydrocarbon receptor (AHR), leading to augmented expression of TNF-stimulated gene 6 (TSG-6) in inflammatory cytokine-primed MuSCs. Furthermore, I3P administration alone suppressed neutrophil infiltration into damaged lungs. I3P could also reduce the level of reactive oxygen species in neutrophils. Therefore, our study has uncovered a novel mechanism by which MuSCs acquire their immunoregulatory property and may help to develop or optimize MuSC-based therapies for inflammatory diseases.
肌肉干细胞（MuSCs）已被证明通过协调炎症微环境在疾病环境中发挥令人印象深刻的治疗效果。然而，MuSCs免疫调节特性的潜在机制在很大程度上仍未得到充分表征。在这里，我们发现白细胞介素-4诱导因子1（IL4I1），一种催化人类吲哚代谢的必需酶，在暴露于IFN-γ和TNF-α的人MuSCs中高度表达。在功能上，发现MuSCs以IL4I1依赖的方式抑制中性粒细胞向炎症部位的浸润，从而改善小鼠的急性肺损伤。从机制上讲，IL4I1产生的吲哚代谢产物，包括吲哚-3-丙酮酸（I3P）和吲哚-3-醛（I3A），作为配体激活芳烃受体（AHR），导致炎症细胞因子预处理的MuSCs中TNF刺激基因6（TSG-6）的表达增加。此外，单独给予I3P可抑制中性粒细胞浸润到受损肺中。I3P还可以降低中性粒细胞中的活性氧水平。因此，我们的研究揭示了一种新的机制，通过该机制MuSCs获得其免疫调节特性，并可能有助于开发或优化基于MuSC的炎症性疾病治疗方法。
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