Neutrophil-derived itaconate facilitates tiered pulmonary inflammation via Kdm5b-associated epigenetic remodeling in alveolar macrophages.

Summary

Using multi-omics and biochemical approaches, the study identifies neutrophil-derived itaconate as an extracellular cue that orchestrates sequential immune cell infiltration in ALI/ARDS. Itaconate reprograms alveolar macrophage chromatin via Kdm5b at Il6/Ccl5/Cxcl10 promoters, linking innate immunometabolism to epigenetic control of lung inflammation.

Key Findings

• Neutrophil-derived extracellular itaconate correlates with sequential infiltration of neutrophils, T cells, and monocytes in ALI/ARDS models.
• Itaconate promotes Kdm5b-associated epigenetic remodeling at Il6, Ccl5, and Cxcl10 promoters in alveolar macrophages.
• Multi-omics and biochemical data converge on an immunometabolic–epigenetic mechanism of leukocyte recruitment.

Clinical Implications

Although preclinical, targeting the itaconate–KDM5B axis may modulate chemokine-driven leukocyte recruitment in ALI/ARDS. Related transcripts (IL6/CCL5/CXCL10) could support biomarker development for inflammatory staging.

Limitations

• Preclinical models may not capture ARDS heterogeneity in humans
• Extent of human validation and in vivo pharmacologic modulation of the itaconate–Kdm5b axis is limited in the available text

Future Directions

Quantify airway/alveolar itaconate in ARDS patients, test KDM5B modulators in vivo, and assess the axis as a stage-specific therapeutic target and biomarker.