Trained immunity induced by high-salt diet impedes stroke recovery
Journal
EMBO reports
Journal Volume
24
Journal Volume
24
Journal Issue
12
Journal Issue
12
Start Page
e57164
ISSN
1469-221X
Date Issued
2023-12-06
Author(s)
Lin, Tze-Yen
Jiang, Danye
Chen, Wan-Ru
Lin, Jhih Syuan
Zhang, Xin-Yu
Chen, Chih-Hung
Hsu, Chia-Lang
Sansing, Lauren H
Abstract
A high-salt diet (HSD) elicits sustained sterile inflammation and worsens tissue injury. However, how this occurs after stroke, a leading cause of morbidity and mortality, remains unknown. Here, we report that HSD impairs long-term brain recovery after intracerebral hemorrhage, a severe form of stroke, despite salt withdrawal prior to the injury. Mechanistically, HSD induces innate immune priming and training in hematopoietic stem and progenitor cells (HSPCs) by downregulation of NR4a family and mitochondrial oxidative phosphorylation. This training compromises alternative activation of monocyte-derived macrophages (MDMs) without altering the initial inflammatory responses of the stroke brain. Healthy mice transplanted with bone marrow from HSD-fed mice retain signatures of reduced MDM reparative functions, further confirming a persistent form of innate immune memory that originates in the bone marrow. Loss of NR4a1 in macrophages recapitulates HSD-induced negative impacts on stroke outcomes while gain of NR4a1 enables stroke recovery in HSD animals. Together, we provide the first evidence that links HSD-induced innate immune memory to the acquisition of persistent dysregulated inflammatory responses and unveils NR4a1 as a potential therapeutic target.
Subjects
high-salt diet; intracerebral hemorrhage; macrophages; nr4a1; trained immunity
SDGs
Type
journal article