IL-18 associated with lung lymphoid aggregates drives IFNγ production in severe COPD

Background: Increased interferon gamma (IFN gamma) release occurs in Chronic Obstructive Pulmonary Disease (COPD) lungs. IFN gamma supports optimal viral clearance, but if dysregulated could increase lung tissue destruction. Methods: The present study investigates which mediators most closely correlate with IFN gamma in sputum in stable and exacerbating disease, and seeks to shed light on the spatial requirements for innate production of IFN gamma, as reported in mouse lymph nodes, to observe whether such microenvironmental cellular organisation is relevant to IFN gamma production in COPD lung. Results: We show tertiary follicle formation in severe disease alters the dominant mechanistic drivers of IFN gamma production, because cells producing interleukin-18, a key regulator of IFN gamma, are highly associated with such structures. Interleukin-1 family cytokines correlated with IFN gamma in COPD sputum. We observed that the primary source of IL-18 in COPD lungs was myeloid cells within lymphoid aggregates and IL-18 was increased in severe disease. IL-18 released from infected epithelium or from activated myeloid cells, was more dominant in driving IFN gamma when IL-18-producing and responder cells were in close proximity. Conclusions: Unlike tight regulation to control infection spread in lymphoid organs, this local interface between IL-18-expressing and responder cell is increasingly supported in lung as disease progresses, increasing its potential to increase tissue damage via IFN gamma.