Inflammatory blood neutrophils in COPD stem from activated bone marrow progenitors

Systemic inflammation is an important hallmark of severe chronic obstructive pulmonary disease (COPD), a chronic respiratory condition that features small airway inflammation and damage. However, the molecular changes in blood leukocytes from COPD patients remain elusive. Especially, the population structure of neutrophils, major contributors to lung pathophysiology, is still undetermined. We aimed to appreciate the heterogeneity of human blood and bronchoalveolar neutrophils and study the molecular alterations and their developmental path in COPD. Blood and bronchoalveolar neutrophils from COPD patients were analyzed with scRNA-seq, and a murine COPD model of smoke exposure was used to unravel the phenotypical changes in bone marrow progenitors with CyTOF. Blood neutrophils from COPD patients consisted of distinct transcriptomic clusters that included a pre-neutrophil subset and an interferon response gene (ISG) state that correlated with patient exacerbation history. Moreover, we observed that bronchoalveolar neutrophil states exhibited a pro-inflammatory phenotype expressing CCL chemokines, ISGs and S100 proteins. Investigation into the origin of the described circulating neutrophils states was performed with a murine smoke-induced model of COPD where analysis of the bone marrow compartment found that myeloid progenitors undergo proliferation and induce hematopoiesis and migratory programs. Conclusively, peripheral blood and bronchoalveolar neutrophils are highly heterogeneous and express activation signatures in COPD patients. The source of the systemic neutrophil inflammatory responses can be found in bone marrow myeloid precursors which are proliferative and can egress into the circulation.