Hyperglycemia- induced innate immune tolerance involves the metabolic and epigenetic rewiring in human alveolar...

Diabetic patients have increased susceptibility to pulmonary infections. However, whether hyperglycemia contributes to this susceptibility via the immune memory of alveolar macrophages (AMs) remains unclear.

Primary human AMs from patients with diabetes were isolated. An in vitro hyperglycemia-induced immune memory model was established. Immune memory phenotypes were assessed by cytokine secretion and phagocytosis upon secondary stimulation. Metabolic profiles were analyzed by Seahorse and LC-MS metabolomics. Transcriptional and epigenetic reprogramming were examined using RNA-seq, ATAC-seq, and CUT&Tag for H3K4me3.

AMs exposed to hyperglycemia, either in vitro or derived from diabetic patients, exhibited a persistent immune-tolerant phenotype in vitro with reduced pro-inflammatory cytokines and impaired phagocytosis. Metabolically, tolerant AMs showed a decrease in oxidative phosphorylation with no compensatory increase in glycolysis, accompanied by reprogramming of lipid metabolism program (acylcarnitine accumulation and downregulation of membrane lipids). Transcriptional analysis revealed downregulation of genes involved in inflammation and upregulation of autophagy and apoptosis-related genes. Epigenetically, tolerant AMs showed an association with increased chromatin accessibility and enhanced H3K4me3 modification at the regulatory regions of autophagy and apoptosis-related genes.

Hyperglycemia induces immune tolerance in human AMs through metabolic reprogramming (impaired fatty acid oxidation, lipid dysregulation) and epigenetic modifications at regulatory regions of autophagy and apoptosis-related genes. These findings suggest a potential mechanistic link between hyperglycemia and increased pulmonary infection susceptibility in diabetic patients, and identify candidate immunomodulatory targets for further investigation.