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Alterations in Monocyte Reprogramming and Ontogeny Enhance Lipopolysaccharide-Induced Lung Injury in Sepsis Survivor Mice [ATAC-Seq]

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE268368 | GEO | 2026/05/25

REPOSITORIES: GEO

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			Action	DRS
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	GSE268368_Q894_fseq2_result_peaks.narrowPeak.gz	Bed
	GSE268368_Q895_fseq2_result_peaks.narrowPeak.gz	Bed
	GSE268368_Q896_fseq2_result_peaks.narrowPeak.gz	Bed
	GSE268368_Q897_fseq2_result_peaks.narrowPeak.gz	Bed

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Project description:Hepatic macrophages play a central role in the initiation, progression and resolution of various liver diseases. Specifically, infiltrating Ly6Chi monocytes and their-derived macrophage (MoMFs) descendants prevail in acute or chronic liver injury, display marked transcriptional variance and provide crucial functional plasticity. A specific example of MoMFs are lipid associated macrophages (LAMs) involved in progression of metabolic liver disease (Remmerie et al., 2020). Recent studies have uncovered binary developmental trajectories of monocytes in the BM with Neutrophil-like (NeuMo) and dendritic cell (DC)-like (DCMo) monocytes (Weinreb et al., 2020; Yanez et al., 2017), hence further challenging our current comprehension of macrophage heterogeneity in the diseased liver. Yet, the molecular factors regulating their inflammatory versus restorative activity remains enigmatic. The COMMD (copper metabolism MURR1 domain) family includes 10 evolutionarily conserved proteins. Functions of COMMD proteins are still being defined, but they seem to play non-redundant roles in regulating transcription and protein trafficking. Utilizing conditional COMMD10 knockout mice we uncovered a role for COMMD10 in limiting inflammasome activation in Ly6Chi monocytes during experimental sepsis and colitis (Mouhadeb et al., 2018), and in supporting phagolysosomal biogenesis and maturation in KCs and BM-derived macrophages infected with Staphylococcus aureus (Ben Shlomo et al., 2019). Hence, these studies mark COMMD10 as a candidate mediator of monocyte and macrophage fate and immune responses. Here we studeid the effect of COMMD10-deficiency on Ly6Chi monocyte differentiation and inflammatory behaviour in the injured liver, using an acute model of acetaminophen-induced liver injury (AILI). Bulk RNAseq analysis of sorted Ly6Chi monocytes, comparing between COMMD10+ and COMMD10-deficient cells, revealed an increased differentiation bias of Ly6Chi monocytes towards NeuMo and LAM differentiation fates. Collectively, COMMD10 appears as an important regulator of Ly6Chi monocyte fate decisions and reparative behavior in the diseased liver.

Project description:Hepatic macrophages play a central role in the initiation, progression and resolution of various liver diseases. Specifically, infiltrating Ly6Chi monocytes and their-derived macrophage (MoMFs) descendants prevail in acute or chronic liver injury, display marked transcriptional variance and provide crucial functional plasticity. A specific example of MoMFs are lipid associated macrophages (LAMs) involved in progression of metabolic liver disease (Remmerie et al., 2020). Recent studies have uncovered binary developmental trajectories of monocytes in the BM with Neutrophil-like (NeuMo) and dendritic cell (DC)-like (DCMo) monocytes (Weinreb et al., 2020; Yanez et al., 2017), hence further challenging our current comprehension of macrophage heterogeneity in the diseased liver. Yet, the molecular factors regulating their inflammatory versus restorative activity remains enigmatic. The COMMD (copper metabolism MURR1 domain) family includes 10 evolutionarily conserved proteins. Functions of COMMD proteins are still being defined, but they seem to play non-redundant roles in regulating transcription and protein trafficking. Utilizing conditional COMMD10 knockout mice we uncovered a role for COMMD10 in limiting inflammasome activation in Ly6Chi monocytes during experimental sepsis and colitis (Mouhadeb et al., 2018), and in supporting phagolysosomal biogenesis and maturation in KCs and BM-derived macrophages infected with Staphylococcus aureus (Ben Shlomo et al., 2019). Hence, these studies mark COMMD10 as a candidate mediator of monocyte and macrophage fate and immune responses. Here we studeis the effect of COMMD10-deficiency on Ly6Chi monocyte differentiation and inflammatory behaviour in the injured liver, using an acute model of acetaminophen-induced liver injury (AILI). Single cell RNAseq analysis of sorted Ly6Chi monocytes, comparing between COMMD10+ and COMMD10-deficient cells, revealed increased differentiation bias of Ly6Chi monocytes towards NeuMo and LAM differentiation fates. Collectively, COMMD10 appears as an important regulator of Ly6Chi monocyte fate decisions and reparative behavior in the diseased liver.

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.

Dataset Information

Alterations in Monocyte Reprogramming and Ontogeny Enhance Lipopolysaccharide-Induced Lung Injury in Sepsis Survivor Mice [ATAC-Seq]

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