Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Mass General Hospital, and Harvard Medical School, Boston, MA 02115, USA; Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA.
Gene Lay Institute of Immunology and Inflammation, Brigham and Women's Hospital, Mass General Hospital, and Harvard Medical School, Boston, MA 02115, USA; Ann Romney Center for Neurologic Diseases, Harvard Medical School and Brigham and Women's Hospital, Boston, MA 02115, USA; Department of Immunology, Blavatnik Institute, Harvard Medical School, Boston, MA 02115, USA; Harvard-MIT Program in Health Sciences and Technology, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
Immunity. 2024 Sep 10;57(9):2077-2094.e12. doi: 10.1016/j.immuni.2024.06.001. Epub 2024 Jun 20.
Tissues are exposed to diverse inflammatory challenges that shape future inflammatory responses. While cellular metabolism regulates immune function, how metabolism programs and stabilizes immune states within tissues and tunes susceptibility to inflammation is poorly understood. Here, we describe an innate immune metabolic switch that programs long-term intestinal tolerance. Intestinal interleukin-18 (IL-18) stimulation elicited tolerogenic macrophages by preventing their proinflammatory glycolytic polarization via metabolic reprogramming to fatty acid oxidation (FAO). FAO reprogramming was triggered by IL-18 activation of SLC12A3 (NCC), leading to sodium influx, release of mitochondrial DNA, and activation of stimulator of interferon genes (STING). FAO was maintained in macrophages by a bistable switch that encoded memory of IL-18 stimulation and by intercellular positive feedback that sustained the production of macrophage-derived 2'3'-cyclic GMP-AMP (cGAMP) and epithelial-derived IL-18. Thus, a tissue-reinforced metabolic switch encodes durable immune tolerance in the gut and may enable reconstructing compromised immune tolerance in chronic inflammation.
组织会受到各种炎症挑战，这些挑战会影响未来的炎症反应。虽然细胞代谢调节免疫功能，但代谢如何在组织内编程和稳定免疫状态，并调节对炎症的易感性，目前还知之甚少。在这里，我们描述了一种先天免疫代谢开关，它可以编程长期的肠道耐受。肠道白细胞介素 18（IL-18）的刺激通过代谢重编程为脂肪酸氧化（FAO）来防止其促炎糖酵解极化，从而诱导出耐受的巨噬细胞。FAO 的重编程是由 IL-18 激活 SLC12A3（NCC）触发的，导致钠离子内流、线粒体 DNA 释放和干扰素基因刺激物（STING）的激活。巨噬细胞中的 FAO 通过一个双稳态开关来维持，该开关编码了对 IL-18 刺激的记忆，并且通过细胞间正反馈来维持巨噬细胞衍生的 2'3'-环状 GMP-AMP（cGAMP）和上皮衍生的 IL-18 的产生。因此，组织强化的代谢开关在肠道中编码了持久的免疫耐受，并可能使重建慢性炎症中受损的免疫耐受成为可能。
