Alveolar Macrophage Iron Overload in COPD Pathogenesis

PROJECT SUMMARY Chronic obstructive pulmonary disease (COPD) is a smoking-associated respiratory disease and is the 3rd lead- ing cause of death worldwide. There are increased numbers of dysfunctional airway and alveolar macrophages (AMs) in the lungs of smokers and COPD patients, localizing to areas of injury. Despite this connection, the mechanisms behind how cigarette smoke (CS) elicits AM dysfunction, and how AM dysfunction facilitates the development of small airways disease and emphysema, two defining features of COPD, are poorly understood. This proposal addresses this critical gap in knowledge and tests the hypothesis that AM dysfunction in COPD is mechanistically linked to abnormal iron accumulation in these cells. Using a multicenter prospective COPD (SPIROMICS) cohort, we previously associated increased levels of iron and iron-related proteins in the bron- choalveolar lavage fluid of smokers and COPD patients with adverse clinical COPD outcomes. AMs are the putative source for this lung extracellular iron, as AMs from smokers and COPD patients are iron-overloaded and release iron in culture. We replicated this clinical phenomenon of AM iron accumulation and release using a murine CS-exposure model. We then used single-cell RNA sequencing and discovered novel AM subsets which have a unique iron-related gene expression signature that is consistent with increased iron uptake. These “iron macrophages”, which we designate as FeMacs, have decreased expression of genes associated with phagocytosis and immune activation, suggesting that this CS-induced AM iron accumulation may have functional consequences for AMs, and potentially for the CS-exposed lung. We will test our hypothesis that FeMacs or- chestrate lung injury development in COPD both mechanistically using our murine CS model and translationally using the SPIROMICS cohort. Aim 1 will compare CS-induced small airways damage and emphysema develop- ment between control mice and mice with AMs deficient in nuclear receptor coactivator 4 (Ncoa4ΔCd11c), an iron metabolism defect which mitigates CS-induced iron accumulation. Aim 2 examines Ncoa4ΔCd11c and Ncoa4fl/fl control mice in a CS-Streptococcus pneumoniae infection 2-hit model, thereby determining whether reducing AM iron overload can alleviate CS-induced AM dysfunction and improve response to pathogen. Aim 3 defines the clinical relevance of AM iron accumulation in human COPD and tests AM expression of iron genes and AM iron content as markers of COPD severity. This proposal presents a five-year career development plan that builds on my previous research and integrates the different domains of expertise of my mentorship and advisory teams. It entails a targeted training plan that is tailored towards the development of specific areas related to immunology, macrophage biology, iron biology, and translational research, facilitated by the physical and intel- lectual resources provided by the academic environment at Weill Cornell Medicine. The proposed experiments, didactic training, as well as mentorship team will position me with a unique set of interdisciplinary skills that will enable my transition to independence as a physician-scientist in lung and macrophage biology and iron biology.