Altered Monocyte Inflammatory Program and Ontogeny Mediate Enhanced Lung Injury in Sepsis Survivors [RNA-Seq]

Persistent inflammation after sepsis is associated with poor long-term outcomes including rehospitalization for new injurious lung conditions. Prior infection elicits durable reprogramming in myeloid cells and their progenitors in other contexts. We previously established a murine model of sepsis survival induced by cecal ligation and puncture which results in enhanced lung injury responses to lipopolysaccharide. In this model, classical (Ly6Chi) monocytes in the lungs of post-sepsis mice expressed more inflammatory cytokines, suggesting a primed phenotype and direct role in enhancing lung injury. Therefore, we hypothesized that persistent inflammatory reprogramming of monocytes predisposes to lung injury in sepsis survivors. Here, deplete and/or adoptively transfer monocytes three weeks and three months after sepsis in mice. We evaluate transcriptomic and epigenomic pathways associated with monocyte reprogramming and explore the effect of sepsis on novel monocyte subsets in mice and humans. We find that monocytes from sepsis survivor mice mediate enhanced lung injury responses to LPS and promote neutrophil degranulation. Sepsis elicits durable changes monocytes characterized by JAK-STAT signaling and AP-1 binding and shifts in monocytes and progenitors toward the neutrophil-like subset. We confirm a similar monocyte subset shift in humans with acute sepsis and show that monocyte counts are predictive of 90-day mortality in a cohort of adult sepsis patients. We conclude that sepsis induces inflammatory memory affecting bone marrow progenitors and monocyte subsets predisposing to lung injury. This study sheds light on the interaction of monocyte subsets and immune reprogramming from prior stimuli in governing secondary organ injury responses.