IL-18 associated with lung lymphoid aggregates drives IFN[gamma] 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]. Keywords: Interleukin-18, Interferon gamma, Tertiary follicles, Lymphoid aggregates, Lymphocytes, Chronic obstructive pulmonary disease