CX3CR1 promoter methylation impairs immune cell migration and exacerbates bacterial pneumonia
Abstract
Severe pneumonia remains a major contributor to infection-related deaths globally, often driven by inadequate pathogen clearance. Impaired immune cell trafficking to infected sites critically contributes to this outcome, yet the underlying regulatory mechanisms remain incompletely understood. Here, we analyze peripheral blood transcriptomic data from a public cohort of 184 pneumonia patients to identify prognosis-related genes, followed by prospective enrollment of 38 patients for integrated multi-omics profiling. Low CX3CR1 expression is associated with 28-day mortality and correlates with hypermethylation at the promoter CpG site cg00262061. Mechanistically, this methylation modification impedes RNA polymerase II recruitment to the CX3CR1 promoter, thereby suppressing transcription. CRISPR-dCas9-based targeted methylation or demethylation at cg00262061 in primary human CD14+ monocytes directly manipulates endogenous CX3CR1 expression, establishing causality. Notably, cg00262061 hypermethylation is detected exclusively in the CX3CR1- subset of patient peripheral blood mononuclear cells, indicating selective epigenetic silencing. Functionally, this methylation or direct CX3CR1 knockdown markedly impairs monocyte and T cell migration. In a murine bacterial pneumonia model, systemic CX3CR1 inhibition reduces pulmonary immune cell infiltration, increases bacterial burden, exacerbates lung injury, and decreases survival. Competitive adoptive transfer confirms a cell-intrinsic…
How strong is the evidence?
Evidence Hub reads this as a cohort study, done in people. Its evidence level is 3 of 5 (Moderate · trial / cohort / secondary analysis). Trials without a large randomized design, cohorts and secondary analyses give moderate evidence. Reported size: 184 participants or records.
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