Pathogenic Rewiring of IL6 Signaling Fuels Macrophage Immunometabolic reprogramming in COPD.

Authors

Xiaoli Zou, Qiqing Huang, Chenxi Cao, Shaoran Shen, Pinping Shao, Xuening Zhang, Yibo Bian, Wei Xu, Jianqing Wu

Published in

American journal of respiratory cell and molecular biology. Jun 23, 2026. Epub Jun 23, 2026.

Abstract

While human genetics implicate the interleukin-6 (IL6) signaling pathway as a potential therapeutic target in chronic obstructive pulmonary disease (COPD), its functional role in pulmonary macrophages remains paradoxical given its established role in promoting cholesterol efflux. Here, integrating single-cell transcriptomics of human COPD lungs with mechanistic studies, we resolve this paradox by identifying a pathogenic rewiring of the IL6/STAT3 pathway. We discovered a disease-enriched macrophage subpopulation exhibiting co-activation of IL6/STAT3 signaling, cholesterol biosynthesis, and inflammatory pathways. In a murine COPD model, chronic cigarette smoke (CS) exposure recapitulated this immunometabolic phenotype. We defined a linear pathway wherein CS-induced IL6 activates STAT3, which directly transactivates the sterol regulatory element-binding protein 2 (SREBP2) to drive de novo cholesterol synthesis. This SREBP2-dependent cholesterol accumulation was essential for NLRP3 inflammasome activation and pro-inflammatory cytokine release. In vitro, pharmacological inhibition of STAT3 or SREBP2, as well as IL6 silencing, disrupted this cascade, suppressing cholesterol-driven inflammation. Critically, in vivo macrophage-specific Il6 knockdown attenuated pulmonary inflammation, cholesterol accumulation, and emphysema development by disrupting the entire IL6/STAT3/SREBP2 axis. Thus, we define the IL6/STAT3/SREBP2 axis as a core immunometabolic driver of COPD pathogenesis, which directly couples CS exposure to sustained macrophage inflammation via pathological cholesterol synthesis, thereby providing a mechanistic basis for targeting this druggable pathway.

PMID:
42334931
Bibliographic data and abstract were imported from PubMed on 24 Jun 2026.

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