Interleukin-35 regulates the differentiation of regulatory T cells through the JAK-STAT pathway and influences glutamine metabolism in ARDS.

Summary

Using clinical samples, a sepsis-induced lung injury model, and multi-omic assays, the authors show that IL-35 reduces lung inflammation, promotes Treg differentiation, and rewires glutamine/TCA metabolism in ARDS models via JAK-STAT signaling. Pharmacologic JAK/STAT inhibition with cerdulatinib reversed IL-35–induced Foxp3 upregulation and metabolic changes, implicating STAT phosphorylation as a mediator.

Key Findings

• IL-35 decreased inflammatory mediators and increased Foxp3 expression, promoting Treg differentiation.
• IL-35 altered glutamine metabolites and TCA cycle intermediates, indicating immunometabolic rewiring.
• IL-35 increased phosphorylation of STAT isoforms; the JAK/SYK inhibitor cerdulatinib reversed these effects.
• In a CLP-induced lung injury model, IL-35 reduced lung inflammation; effects on Foxp3 and metabolism were abrogated by cerdulatinib.

Clinical Implications

Findings support exploration of IL-35–based or JAK-STAT–targeted immunometabolic therapies in ARDS, with attention to patient selection and metabolic phenotypes.

Limitations

• Translational gap: preclinical models and limited clinical sampling without trial-level outcomes.
• Potential off-target effects of cerdulatinib and reliance on A549/EL-4 systems.

Future Directions

Test IL-35/JAK-STAT modulation in ARDS-relevant translational models and early-phase trials; integrate metabolic phenotyping and genetic perturbation (e.g., STAT/Foxp3) to confirm causality.