Chronic lung inflammation in cystic fibrosis (CF) often persists even after treatment with newly-approved gene therapies or small molecule CFTR modulators—an unresolved clinical paradox. A new study published in EXO - Beyond the Cell identifies a potential explanation: inflammation is driven not only by intrinsic defects in immune cells, but also by lasting changes in the lung microenvironment.
Using induced pluripotent stem cell (iPSC)-derived macrophages from both healthy donors and CF patients, researchers from Gordana Vunjak-Novakovic's team at Columbia University developed an all-human, in vitro model to disentangle these effects. By combining patient-derived immune cells with decellularized extracellular matrix (ECM) from end-stage CF lungs, the study separates cell-intrinsic and microenvironmental contributions to disease.
The study found that macrophages carrying CFTR mutations already display a "pre-activated" inflammatory state at baseline. Transcriptomic analysis identified 221 differentially expressed genes, with enrichment in pathways related to cell communication and signaling. Pro-inflammatory cytokines such as IL-8, IL-18, and MCP-1 were elevated even in the absence of external stimulation. When challenged with lipopolysaccharide (LPS), an inflammation-causing endotoxin, these cells showed exaggerated activation of NF-κB signaling, confirming dysregulated inflammatory responses.
However, intrinsic defects tell only part of the story.
When healthy macrophages were exposed to ECM derived from diseased CF lungs, their transcriptional profiles shifted dramatically toward an inflammatory phenotype. Pathways associated with immune activation, leukocyte migration, TNF signaling, and NF-κB signaling were significantly upregulated, accompanied by increased secretion of TNF-α and IFN-γ. These findings demonstrate that the remodeled ECM itself acts as a persistent inflammatory stimulus.
Interestingly, macrophages derived from CF patients responded less strongly to ECM stimulation compared with healthy cells. This attenuated response suggests that CF macrophages may have adapted to chronic inflammatory exposure, potentially reflecting a shift in their activation threshold.
Together, these findings provide a potential explanation for the fact that lung inflammation persists in patients on CFTR modulator therapy: immune cells remain embedded in a pathologically remodeled microenvironment despite restoration of CFTR function. The study further highlights the extracellular matrix not just as a structural scaffold, but as an active regulator of immune behavior through biochemical signaling.
Beyond cystic fibrosis, this research provides a new experimental framework for studying complex interactions between immune cells and diseased tissue environments. The approach may be applicable to other chronic lung diseases, including COPD and idiopathic pulmonary fibrosis.
Moreover, by separating intrinsic cellular defects from external environmental cues, the framework also provides a platform for testing combination therapies that target both immune dysfunction and tissue remodeling in humanized settings, consistent with the rise of new approach methodologies (NAMs) in complementing animal models as suggested by the U.S. Food & Drug Administration's Modernization Act 3.0.
Experimental study
Cells
Human iPSC-derived macrophages for studying intrinsic and extrinsic factors in cystic fibrosis
14-Apr-2026
No competing interests.