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Indoleamine 2,3-dioxygenase 1 activation in mature cDC1 promotes tolerogenic education of inflammatory cDC2 via metabolic communication
Immunity ( IF 32.4 ) Pub Date : 2022-06-14 , DOI: 10.1016/j.immuni.2022.05.013
Marco Gargaro 1 , Giulia Scalisi 2 , Giorgia Manni 2 , Carlos G Briseño 3 , Prachi Bagadia 3 , Vivek Durai 3 , Derek J Theisen 3 , Sunkyung Kim 3 , Marilena Castelli 2 , Chenling A Xu 4 , Gerd Meyer Zu Hörste 5 , Giuseppe Servillo 6 , Maria A Della Fazia 2 , Giulia Mencarelli 2 , Doriana Ricciuti 2 , Eleonora Padiglioni 2 , Nicola Giacchè 7 , Carolina Colliva 7 , Roberto Pellicciari 7 , Mario Calvitti 2 , Teresa Zelante 2 , Dietmar Fuchs 8 , Ciriana Orabona 2 , Louis Boon 9 , Alban Bessede 10 , Marco Colonna 3 , Paolo Puccetti 6 , Theresa L Murphy 3 , Kenneth M Murphy 11 , Francesca Fallarino 6
Affiliation  

Conventional dendritic cells (cDCs), cDC1 and cDC2, act both to initiate immunity and maintain self-tolerance. The tryptophan metabolic enzyme indoleamine 2,3-dioxygenase 1 (IDO1) is used by cDCs in maintaining tolerance, but its role in different subsets remains unclear. At homeostasis, only mature CCR7+ cDC1 expressed IDO1 that was dependent on IRF8. Lipopolysaccharide treatment induced maturation and IDO1-dependent tolerogenic activity in isolated immature cDC1, but not isolated cDC2. However, both human and mouse cDC2 could induce IDO1 and acquire tolerogenic function when co-cultured with mature cDC1 through the action of cDC1-derived l-kynurenine. Accordingly, cDC1-specific inactivation of IDO1 in vivo exacerbated disease in experimental autoimmune encephalomyelitis. This study identifies a previously unrecognized metabolic communication in which IDO1-expressing cDC1 cells extend their immunoregulatory capacity to the cDC2 subset through their production of tryptophan metabolite l-kynurenine. This metabolic axis represents a potential therapeutic target in treating autoimmune demyelinating diseases.



中文翻译:

成熟 cDC1 中的吲哚胺 2,3-双加氧酶 1 激活通过代谢通讯促进炎症性 cDC2 的致耐受性教育

传统的树突状细胞 (cDC)、cDC1 和 cDC2 既可以启动免疫力又可以维持自我耐受。色氨酸代谢酶吲哚胺 2,3-双加氧酶 1 (IDO1) 被 cDC 用于维持耐受性,但其在不同亚群中的作用仍不清楚。在体内平衡时,只有成熟的 CCR7 + cDC1 表达依赖于 IRF8 的 IDO1。脂多糖处理在分离的未成熟 cDC1 中诱导成熟和 IDO1 依赖性致耐受性活性,但在分离的 cDC2 中没有。然而,当通过 cDC1 衍生的l -犬尿氨酸的作用与成熟的 cDC1 共培养时,人和小鼠 cDC2 都可以诱导 IDO1 并获得致耐受性功能。因此,IDO1在体内的 cDC1 特异性失活加重实验性自身免疫性脑脊髓炎的疾病。这项研究确定了一种以前未被识别的代谢通讯,其中表达 IDO1 的 cDC1 细胞通过产生色氨酸代谢物l-犬尿氨酸将其免疫调节能力扩展到 cDC2 亚群。该代谢轴代表了治疗自身免疫性脱髓鞘疾病的潜在治疗靶点。

更新日期:2022-06-14
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