Integrative metabolomics and transcriptomics identifies itaconate as an adjunct therapy to treat ocular bacterial infection.
Integrative metabolomics and transcriptomics identifies itaconate as an adjunct therapy to treat ocular bacterial infection.
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综合代谢组学和转录组学将Itaconate鉴定为治疗眼细菌感染的辅助疗法。
DOI：
10.1016/j.xcrm.2021.100277
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发表时间：
2021-05-18
期刊：
影响因子：
--
通讯作者：
Kumar A
中科院分区：
文献类型：
--
作者：
Singh S;Singh PK;Jha A;Naik P;Joseph J;Giri S;Kumar A
眼睛对细菌感染时引起的炎症介导的组织损伤非常敏感。然而，调节炎症以保护眼睛的机制仍然难以捉摸。在这里，我们使用集成的代谢组学和转录组学来证明免疫调节代谢物衣康酸和免疫反应基因1(IRG1)在细菌(金黄色葡萄球菌)感染的小鼠眼睛、骨髓来源的巨噬细胞(BMDM)和Müller胶质细胞中被诱导。细菌性眼内炎患者的玻璃体中衣康酸水平也升高。IRG1缺陷导致小鼠眼部病理加重。相反，眼内注射衣康酸可通过减少炎症、细菌负荷以及保护视网膜结构和视觉功能来保护irg1−/−和野生型小鼠免受细菌性眼内炎的侵袭。值得注意的是，衣康酸与抗生素具有协同作用。衣康酸的保护和抗炎作用是通过激活NRF2/HO-1信号和抑制NLRP3炎症小体来实现的。总而言之，我们的研究证明IRG1/衣康酸轴是眼内炎症的调节因子，并为联合使用衣康酸和抗生素治疗细菌感染提供了证据。细菌感染增加了眼部IRG1和衣康酸水平，IRG1和NRF2缺乏加剧了眼内细菌感染，衣康酸加强了眼部抗氧化剂NRF2/HO-1信号转导，衣康酸治疗与抗生素在改善眼部感染方面有协同作用，眼部感染仍然是导致失明的主要原因。Singh等人。显示代谢产物衣康酸是在感染的眼睛中产生的，以控制异常的炎症。依他康酸通过增强抗氧化剂NRF2/HO信号而发挥抗炎作用，作为辅助治疗，减少了治疗眼部细菌感染所需的抗生素剂量。
The eye is highly susceptible to inflammation-mediated tissue damage evoked during bacterial infection. However, mechanisms regulating inflammation to protect the eye remain elusive. Here, we used integrated metabolomics and transcriptomics to show that the immunomodulatory metabolite itaconate and immune-responsive gene 1 (Irg1) are induced in bacterial (Staphylococcus aureus)-infected mouse eyes, bone-marrow-derived macrophages (BMDMs), and Müller glia. Itaconate levels are also elevated in the vitreous of patients with bacterial endophthalmitis. Irg1 deficiency in mice led to increased ocular pathology. Conversely, intraocular administration of itaconate protects both Irg1−/− and wild-type mice from bacterial endophthalmitis by reducing inflammation, bacterial burden, and preserving retinal architecture and visual function. Notably, itaconate exerts synergistic effects with antibiotics. The protective, anti-inflammatory effects of itaconate are mediated via activation of NRF2/HO-1 signaling and inhibition of NLRP3 inflammasome. Collectively, our study demonstrates the Irg1/itaconate axis is a regulator of intraocular inflammation and provides evidence for using itaconate, along with antibiotics, to treat bacterial infections. Bacterial infection increases Irg1 and itaconate levels in the eye Irg1 and Nrf2 deficiency exacerbates intraocular bacterial infection Itaconate potentiates antioxidant NRF2/HO-1 signaling in the eye Itaconate treatment synergizes with antibiotics in ameliorating ocular infection Eye infections remain the leading cause of blindness. Singh et al. show that the metabolite itaconate is produced in infected eyes to control aberrant inflammation. Itaconate exerts its anti-inflammatory effect by potentiating antioxidant NRF2/HO signaling and as an adjunct therapy reduces antibiotic dose required to treat ocular bacterial infection.
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Itaconate连接琥珀酸脱氢酶与巨噬细胞代谢重塑和调节炎症的联系。
影响因子：
29
作者：
Lampropoulou V;Sergushichev A;Bambouskova M;Nair S;Vincent EE;Loginicheva E;Cervantes-Barragan L;Ma X;Huang SC;Griss T;Weinheimer CJ;Khader S;Randolph GJ;Pearce EJ;Jones RG;Diwan A;Diamond MS;Artyomov MN
通讯作者：
Artyomov MN
影响因子：
3.4
作者：
Kumar A;Giri S;Kumar A
通讯作者：
Kumar A
影响因子：
44.1
作者：
通讯作者：
--
影响因子：
--
作者：
Cohen, Elisabeth J.
通讯作者：
Cohen, Elisabeth J.
影响因子：
3.8
作者：
de Seymour, Jamie V.;Conlon, Cathryn A.;Baker, Philip N.
通讯作者：
Baker, Philip N.