Alterations in Monocyte Reprogramming and Ontogeny Enhance Lipopolysaccharide-Induced Lung Injury in Sepsis Survivor Mice [ATAC-Seq]

Sepsis is the leading cause of infection-related hospitalization. Persistent inflammation after sepsis is associated with poor long-term outcomes including rehospitalization for new injurious lung conditions. Prior infection can elicit durable epigenetic changes in immune cells and their progenitors leading to inflammatory reprogramming, but the role of persistent immune programming in mediating complications in sepsis survivors remains unclear. We previously established that survival of murine polymicrobial sepsis is associated with enhanced lung injury responses to lipopolysaccharide. This is associated with enhanced cytokine expression in classical (Ly6Chi) monocytes in the lungs, suggesting a role for monocytes in enhancing lung injury in sepsis survival. We performed monocyte depletion and adoptive transfer in mice three weeks and three months after sepsis. We establish that Ly6Chi monocytes are persistently reprogrammed to enhance lung injury and identify neutrophil degranulation as a potential mechanism. Three weeks after sepsis, murine monocytes show persistently altered transcription and chromatin alterations enriched for TLR4, HIF1α, and JAK-STAT signaling and AP-1 binding consistent with persistent immune reprogramming. As novel Ly6Chi monocyte subsets have been recently identified, but functional relevance remains unknown, we evaluated the presence of monocyte subsets and their association with sepsis and acute lung injury. We show for the first time, to our knowledge, that sepsis provokes an ontogenic shift in monocytes towards a granulocyte-monocyte progenitor-derived neutrophil-like lineage in mice and humans. These data suggest that altered myelopoiesis in sepsis survival may be predictive of poor long-term outcome, to this end we show that monocyte and neutrophil counts are associated with 90-day mortality and are complimentary in predicting outcome. Taken together this work supports a conceptual model whereby prior sepsis elicits durable changes in bone marrow progenitors and a shift in monocyte subsets leading to a predisposition to lung injury. This study highlights gaps in our knowledge relating to the interaction of monocyte subsets and immune reprogramming from prior stimuli in governing the response to organ injury.