Long-term reprogramming of classical monocytes with altered ontogeny mediates enhanced lung injury in sepsis survivors

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

doi:10.1172/jci.insight.198551

Long-term reprogramming of classical monocytes with altered ontogeny mediates enhanced lung injury in sepsis survivors

Scott J. Denstaedt,¹ Breanna McBean,² Alan P. Boyle,² Brett C. Arenberg,¹ Matthias Mack,³ Bethany B. Moore,¹ Michael W. Newstead,¹ Yamei Deng,⁴ Alexey I. Nesvizhskii,⁴ Benjamin H. Singer,¹ Jennifer Cano,⁵ Hallie C. Prescott,¹ Helen S. Goodridge,⁶ and Rachel L. Zemans¹

Published September 24, 2026 - More info

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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 intra-nasal lipopolysaccharide. 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 three weeks and three 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 pro-inflammatory 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 exhibit transcriptional and proteomic neutrophil-like signatures. We conclude that sepsis reprograms monocytes into a pro-inflammatory phenotype and skews bone marrow progenitors and monocytes toward the neutrophil-like lineage, predisposing them to induce neutrophil degranulation and lung injury.

Long-term reprogramming of classical monocytes with altered ontogeny mediates enhanced lung injury in sepsis survivors

Scott J. Denstaedt,¹ Breanna McBean,² Alan P. Boyle,² Brett C. Arenberg,¹ Matthias Mack,³ Bethany B. Moore,¹ Michael W. Newstead,¹ Yamei Deng,⁴ Alexey I. Nesvizhskii,⁴ Benjamin H. Singer,¹ Jennifer Cano,⁵ Hallie C. Prescott,¹ Helen S. Goodridge,⁶ and Rachel L. Zemans¹

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Long-term reprogramming of classical monocytes with altered ontogeny mediates enhanced lung injury in sepsis survivors

Scott J. Denstaedt,1 Breanna McBean,2 Alan P. Boyle,2 Brett C. Arenberg,1 Matthias Mack,3 Bethany B. Moore,1 Michael W. Newstead,1 Yamei Deng,4 Alexey I. Nesvizhskii,4 Benjamin H. Singer,1 Jennifer Cano,5 Hallie C. Prescott,1 Helen S. Goodridge,6 and Rachel L. Zemans1

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Scott J. Denstaedt,¹ Breanna McBean,² Alan P. Boyle,² Brett C. Arenberg,¹ Matthias Mack,³ Bethany B. Moore,¹ Michael W. Newstead,¹ Yamei Deng,⁴ Alexey I. Nesvizhskii,⁴ Benjamin H. Singer,¹ Jennifer Cano,⁵ Hallie C. Prescott,¹ Helen S. Goodridge,⁶ and Rachel L. Zemans¹