Selecting specific bio-markers and researching mechanisms of immune regulation from inhalation injury (ILI) and traumatic lung injury (TLI) based on single cell RNA sequencing technology
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE220699 | GEO | 2025/11/11
REPOSITORIES: GEO
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Project description:Molecular profiling of infiltrating monocyte-derived macrophages versus resident kupffer cells following acute liver injury The liver has a remarkable capacity to regenerate after injury; yet, the role of macrophages (MF) in this process remains controversial mainly due to difficulties in distinguishing between different MF-subsets. Here, we utilized a murine model of acute liver injury caused by overdose of acetaminophen (APAP) and defined three distinct MF subsets that populate the liver following injury. Accordingly, resident Kupffer cells (KC) were significantly reduced upon APAP-challenge and started recovering by self-renewal at resolution phase without contribution of circulating Ly6Chi monocytes. The latter were recruited in a CCR2 and M-CSF mediated pathway at the necro-inflammatory phase and differentiated into ephemeral Ly6Clo MF subset at resolution phase. Moreover, their inducible ablation resulted in impaired recovery. Microarray based molecular profiling uncovered high similarity between steady state KC and those recovered at the resolution phase. In contrast, KC and monocyte-derived MF displayed distinct pro-restorative genetic signature at the resolution phase. Finally, we show that infiltrating monocytes acquire a pro-restorative polarization manifested by unique expression of pro-angiogenesis mediators and genes involved with inhibition of neutrophil activity and recruitment and promotion of their clearance. Collectively, our results present a novel phenotypic, ontogenic and molecular definition of liver-MF compartment following acute injury.
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Project description: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.
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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.
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* is there a difference in acute kidney injury incidence in the two anesthetic modalities?
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* are there any patient characteristics or intraoperative factors that effect the incidence of acute kidney injury in either anesthetic modality?
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