美国哈佛医学院Roni Nowarski团队取得一项新突破。他们提出了由IL-18和环二核苷酸cGAMP调控的代谢开关控制了肠道耐受性。相关论文于2024年6月20日发表于国际顶尖学术期刊《免疫学》杂志上。

该课题组人员描述了一种先天免疫代谢开关，该开关可编程长期肠道耐受性。肠道白细胞介素-18 (IL-18)刺激通过代谢重编程为脂肪酸氧化来阻止巨噬细胞的促炎糖酵解极化，从而引起耐受原性巨噬细胞。通过IL-18激活SLC12A3 (NCC)触发脂肪酸氧化重编程，导致钠内流、线粒体DNA释放和干扰素刺激因子基因(STING)的激活。

巨噬细胞通过编码IL-18刺激记忆的双稳态开关和维持巨噬细胞衍生的2' 3'-环GMP-AMP (cGAMP)，和上皮衍生的IL-18产生的细胞间正反馈来维持脂肪酸氧化。因此，组织强化的代谢开关在肠道中编码持久的免疫耐受，并可能在慢性炎症中重建受损的免疫耐受。

据悉，组织暴露于不同的炎症挑战，形成未来的炎症反应。虽然细胞代谢调节免疫功能，但代谢如何规划和稳定组织内的免疫状态并调节对炎症的易感性却知之甚少。

附：英文原文

Title: A metabolic switch orchestrated by IL-18 and the cyclic dinucleotide cGAMP programs intestinal tolerance

Author: Randall T. Mertens, Aditya Misra, Peng Xiao, Seungbyn Baek, Joseph M. Rone, Davide Mangani, Kisha N. Sivanathan, Adedamola S. Arojojoye, Samuel G. Awuah, Insuk Lee, Guo-Ping Shi, Boryana Petrova, Jeannette R. Brook, Ana C. Anderson, Richard A. Flavell, Naama Kanarek, Martin Hemberg, Roni Nowarski

Issue&Volume: 2024-06-20

Abstract: Tissues are exposed to diverse inflammatory challenges that shape future inflammatoryresponses. While cellular metabolism regulates immune function, how metabolism programsand stabilizes immune states within tissues and tunes susceptibility to inflammationis poorly understood. Here, we describe an innate immune metabolic switch that programslong-term intestinal tolerance. Intestinal interleukin-18 (IL-18) stimulation elicitedtolerogenic macrophages by preventing their proinflammatory glycolytic polarizationvia metabolic reprogramming to fatty acid oxidation (FAO). FAO reprogramming was triggeredby IL-18 activation of SLC12A3 (NCC), leading to sodium influx, release of mitochondrialDNA, and activation of stimulator of interferon genes (STING). FAO was maintainedin macrophages by a bistable switch that encoded memory of IL-18 stimulation and byintercellular positive feedback that sustained the production of macrophage-derived2′3′-cyclic GMP–AMP (cGAMP) and epithelial-derived IL-18. Thus, a tissue-reinforcedmetabolic switch encodes durable immune tolerance in the gut and may enable reconstructingcompromised immune tolerance in chronic inflammation.

DOI: 10.1016/j.immuni.2024.06.001

Source: https://www.cell.com/immunity/abstract/S1074-7613(24)00305-4