CX3CR1 promoter methylation impairs immune cell migration and exacerbates bacterial pneumonia.

Authors

Yanrui Jia, Qi Cao, Yanping Zhang, Yuanyuan Zhang, Xianjin Xie, Shi Zhang

Published in

Acta biochimica et biophysica Sinica. Jul 01, 2026. Epub Jul 01, 2026.

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 migration defect of CX3CR1-deficient immune cells. These findings delineate a pathogenic pathway wherein promoter hypermethylation silences CX3CR1, compromises immune cell homing, and aggravates disease severity, offering a mechanistic basis for prognostic assessment and a conceptual framework for host-directed therapies, although clinical translation warrants further investigation.

PMID:
42605183
Bibliographic data and abstract were imported from PubMed on 17 Aug 2026.

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