Abstract
Patients who survive sepsis are predisposed to new hospitalizations for respiratory failure, but the underlying mechanisms are unknown. Using a murine model in which prior sepsis predisposes to enhanced lung injury, we previously discovered that classical monocytes persist in the lungs after long-term recovery from sepsis and exhibit enhanced cytokine expression after secondary challenge with intranasal LPS. Here, we hypothesized that immune reprogramming of post-sepsis monocytes and altered ontogeny predispose to enhanced lung injury. Monocyte depletion and/or adoptive transfer was performed 3 weeks and 3 months after sepsis. Monocytes from post-sepsis mice were necessary and sufficient for enhanced LPS-induced lung injury and promoted neutrophil degranulation. Prior sepsis enhanced JAK/STAT signaling and AP-1 accessibility in monocytes and shifted monocytes toward the neutrophil-like monocyte lineage. Neutrophil-like monocytes demonstrated a proinflammatory phenotype with enhanced IL-1β expression and reduced phagocytic capacity. In human sepsis and/or pneumonia survivors, monocytes were predictive of 90-day mortality and exhibited transcriptional and proteomic neutrophil-like signatures. We conclude that sepsis reprograms monocytes into a proinflammatory phenotype and skews bone marrow progenitors and monocytes toward the neutrophil-like lineage, predisposing them to induce neutrophil degranulation and lung injury.
Authors
Scott J. Denstaedt, Breanna McBean, Alan P. Boyle, Brett C. Arenberg, Matthias Mack, Bethany B. Moore, Michael W. Newstead, Yamei Deng, Alexey I. Nesvizhskii, Benjamin H. Singer, Jennifer Cano, Hallie C. Prescott, Helen S. Goodridge, Rachel L. Zemans
