A systematic review identifies trained immunity, a form of immune cell reprogramming, as a shared mechanism perpetuating low-grade inflammation in atherosclerosis, type 2 diabetes, kidney disease, and neurodegeneration. Evidence is strongest for atherosclerosis (eight studies), but remains preliminary for other conditions, and human data are sparse .
Trained immunity traditionally protects us against infections by allowing innate immune cells to "remember" threats and respond faster on re-exposure. But this review synthesizes evidence that the same reprogramming process, when triggered by endogenous sterile signals from damaged tissue, lipids, or metabolic byproducts, can paradoxically fuel chronic sterile inflammation that persists long after the initial trigger resolves.
The clearest evidence emerged in atherosclerosis research (eight studies). Oxidized LDL cholesterol, aldosterone, and Western diet lipids reprogram monocytes and macrophages through epigenetic changes, particularly enrichment of H3K4me3, a histone modification that marks genes for higher expression. These reprogrammed cells shift toward glycolysis and fatty acid metabolism, producing excessive TNF-alpha and IL-6 cytokines and forming foam cells that accelerate plaque buildup. Notably, these changes appear transmissible: reprogrammed monocytes can seed naive progenitor cells in the bone marrow with the same maladaptive inflammatory phenotype, creating a self-perpetuating cycle even without ongoing lipid exposure.
In type 2 diabetes and hyperglycemia (three studies), high glucose levels trigger MLL-mediated epigenetic reprogramming that creates "metabolic memory." This phenomenon allows myeloid cells to remain in a hyperinflammatory state even after blood glucose normalizes. The mechanism involves sustained glycolytic reprogramming of myelopoiesis, which then accelerates atherosclerosis downstream. This explains, at least in part, why tight glucose control in established T2DM doesn't immediately reverse cardiovascular risk: the immune cells retain their pathological training.
Evidence for chronic kidney disease and neurodegenerative disorders is more limited. In CKD (one study), the uremic toxin indoxyl sulfate activates aryl hydrocarbon receptor (AhR) signaling and arachidonic acid metabolism in immune cells, sustaining systemic inflammation. In neurodegeneration (one study), peripheral immune signals reprogram microglia, the brain's resident immune cells, into either hyperresponsive or tolerized states that modulate amyloid-beta pathology progression. Across all conditions, convergent mechanisms emerged: epigenetic histone modifications, glycolytic shifts, and activation of mTOR, NLRP3, and AhR signaling pathways.
This research identifies a biological bottleneck: chronic diseases may persist through immune cell reprogramming that continues independently of the original trigger. The practical implication is that addressing acute risk factors (lipids, glucose, uremia) without addressing the underlying immune dysfunction may yield incomplete clinical benefit.
The review highlights three therapeutic entry points, all still preclinical or early-stage:
Metabolic reprogramming: Inhibiting glycolysis in trained immune cells, or shifting them away from mTOR-dependent pathways, could theoretically reset their inflammatory phenotype. This isn't yet a clinical intervention, but it explains why metabolic interventions like intermittent fasting or very low carbohydrate diets show some benefit in atherosclerosis and T2DM: they may limit the metabolic signals (glucose, lactate) that sustain immune training.
Epigenetic targeting: Blocking H3K4me3 enrichment or related histone modifications could prevent the initial reprogramming. These approaches remain in preclinical development, with no approved drugs currently targeting this mechanism clinically.
Dietary and lifestyle approaches: The review doesn't explicitly evaluate supplements or habits, but the identified mechanisms suggest that reducing endogenous sterile stimuli is foundational. For atherosclerosis, this means aggressive lipid management and dietary reduction of oxidized lipids (oxidized seed oils, charred meats). For T2DM, it underscores the importance of early, intensive glucose control and sustained glycemic stability to prevent metabolic memory formation. For kidney disease, dietary uremia toxin reduction through controlled protein intake and fiber intake to lower indoxyl sulfate levels may be relevant, though this requires clinical confirmation.
The major limitation is that most evidence derives from cellular and animal studies. Only a handful of human studies anchor these mechanisms, and the review authors explicitly flag gaps in CKD and neurodegeneration research. Translation to clinical practice remains premature for most proposed interventions.
| Aspect | Details |
|---|---|
| Study type | Systematic review with narrative synthesis |
| Guidelines | PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analyses) |
| Studies included | 12 primary studies |
| Diseases reviewed | Atherosclerosis (8), Type 2 diabetes/hyperglycemia (3), Chronic kidney disease (1), Neurodegeneration (1) |
| Key mechanisms identified | H3K4me3 epigenetic marks, glycolytic reprogramming, mTOR/NLRP3/AhR activation, metabolic shifts in myeloid cells |
| Primary inducers | Oxidized LDL, aldosterone, high glucose, indoxyl sulfate, post-MI signals |
| Journal | Innate Immunity |
| PubMed ID | 42017903 |
| Evidence quality | Predominantly preclinical; limited human data; no meta-analysis possible |
Systematic review: "The role of trained immunity in chronic non-communicable inflammatory diseases." PubMed: 42017903
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