Trained immunity induced by high-salt diet impedes stroke recovery

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. imageHigh-salt intake induces trained immunity through metabolic reprogramming and downregulation of NR4a nuclear receptors. Trained monocyte-derived macrophages reduce reparative activities in the stroke brain, and consequently, hematoma clearance, brain repair, and functional recovery are impaired.Excessive dietary salt intake impedes long-term stroke recovery even after high-salt withdrawal prior to injury.High-salt intake triggers immunological priming and training of bone marrow progenitor cells.The trained property is retained, which leads to diminished reparative macrophage polarization in the stroke brain.Pharmacological activation of NR4a1 by celastrol treatment rescues the adverse effects induced by high-salt diet. High-salt intake induces trained immunity through metabolic reprogramming and downregulation of NR4a nuclear receptors. Trained monocyte-derived macrophages reduce reparative activities in the stroke brain, and consequently, hematoma clearance, brain repair, and functional recovery are impaired.image