Bulk RNAseq of ex vivo salt treated isolated human monocytes

Salt sensitivity of blood pressure (SSBP) is associated with persistent immune activation after sodium normalization, suggesting immune “salt memory.” Prior work identified that sodium entry into antigen-presenting cells (APCs) via epithelial sodium channels triggers NLRP3 inflammasome activation through the formation of isolevuglandins (IsoLGs), highly reactive lipid aldehydes. IsoLG scavenging with 2-hydroxybenzylamine (2-HOBA) reduces NLRP3 expression and attenuates salt-induced hypertension, implicating IsoLGs as upstream immune regulators. This study tested whether IsoLGs also act as epigenetic modifiers by covalently modifying histone H1, thereby altering chromatin accessibility at inflammatory loci such as NLRP3. PBMCs from 10 hypertensive adults classified as salt-sensitive (SS) or salt-resistant (SR) were collected at baseline, after salt loading, and after depletion. Integrated single-cell RNA-seq and ATAC-seq revealed that SS monocytes exhibited salt-induced enhancer activation and increased chromatin accessibility at the NLRP3 locus. IsoLG–protein adducts correlated with blood pressure changes and were most prominent in CD14⁺ monocytes. In murine APCs, high salt induced IsoLG adduction of histone H1, attenuated by 2-HOBA. Knockdown of H1F0 reduced high salt–induced NLRP3 expression, supporting a role for H1.0 in transcriptional regulation. These findings identify IsoLG modification of histone H1 as a potential mechanism linking extracellular sodium exposure to persistent chromatin remodeling and sustained inflammatory gene expression in SS individuals. IsoLG–histone adducts may represent novel therapeutic targets for immune-driven hypertension.