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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE268367 | GEO | 2026/05/25

REPOSITORIES: GEO

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Project description: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.

Project description:Sepsis is the most common cause of hospitalization worldwide. Millions of people survive sepsis each year and are at risk for rehospitalization and death. Pulmonary complications such as respiratory failure due to pneumonia and exacerbation of chronic respiratory disease are among the most common reasons for rehospitalization in sepsis survivors. In order to prevent additional morbidity and death in patients surviving sepsis, we must establish biomarkers to identify patients at risk for pulmonary complications and develop treatments. Late complications in sepsis survivors, particularly nosocomial infections, are proposed to occur through persistent immune reprogramming after sepsis known as immunoparalysis. However, pro-inflammatory immune reprogramming in the form of primed or enhanced responses to secondary stimuli has also been described and could directly contribute to tissue injury and death. Primed immune responses and their contribution to long-term sepsis complications remains understudied. We hypothesize that primed immune responses to inflammatory stimuli in the lung after sepsis are associated with pulmonary complications in survivors of sepsis. To this end, we developed a model of antibiotic treated sepsis induced by cecal ligation and puncture followed three weeks later by secondary challenge with intranasal lipopolysaccharide to induce inflammatory lung injury. We find that mice surviving sepsis have enhanced lung injury responses in the setting of an exaggerated proinflammatory immune response, including primed Ly6Chi monocyte Tnf expression. Using RNA sequencing, we identified derangements in lung gene expression after CLP prior to LPS administration which may mediate enhanced lung injury in this model. One potential mediator, S100A8/A9, was also found to be elevated in the circulation of human sepsis survivors for up to 180 days after sepsis. These findings validate our model and identify S100A8/A9 as one of many potential biomarkers and therapeutic targets for patients at risk for long-term pulmonary complications after sepsis. The role of S100A8/A9, monocyte priming, and other factors predisposing to enhanced lung injury responses and pulmonary complications after sepsis warrant further investigation in humans and mice.

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

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