Immune responses of lung mesenchymal cells during pneumonia
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA1013590 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR25933723.fastq.gz | Fastqsanger.gz | |||
| SRR25933724.fastq.gz | Fastqsanger.gz | |||
| SRR25933725.fastq.gz | Fastqsanger.gz | |||
| SRR25933726.fastq.gz | Fastqsanger.gz | |||
| SRR25933727.fastq.gz | Fastqsanger.gz |
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Project description:During bacterial pneumonia, alveolar epithelial cells are critical for maintaining gas exchange and providing antimicrobial as well as pro-immune properties. We previously demonstrated that leukemia inhibitory factor (LIF), an IL-6 family cytokine, is produced by type II alveolar epithelial cells (ATII) and is critical for tissue protection during bacterial pneumonia. However, the target cells and mechanisms of LIF-mediated protection remain unknown. Here, we demonstrate that antibody-induced LIF blockade remodels the lung epithelial transcriptome in association with increased apoptosis. Based on these data, we performed pneumonia studies using a novel mouse model in which LIFR (the unique receptor for LIF) is absent in lung epithelium. While LIFR was detected on the surface of epithelial cells, its absence only minimally contributed to tissue protection during pneumonia. Single-cell RNA-sequencing (scRNAseq) was conducted to identify adult murine lung cell types most prominently expressing LIFR, revealing endothelial cells, mesenchymal cells, and ATIIs as major sources of LIFR. Sequencing data indicated that ATII cells were significantly impacted as a result of pneumonia, with additional differences observed in response to LIF neutralization, including but not limited to gene programs related to cell death, injury, and inflammation. Overall, our data suggest that LIF signaling on epithelial cells alters responses in this cell type during pneumonia. However, our results also suggest separate and perhaps more prominent roles of LIFR in other cell types, such as endothelial cells or mesenchymal cells, which provide grounds for future investigation.
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Project description:A developmental murine model of pneumonia was used to investigate how lower respiratory tract E. coli infections differentially affects lung immune responses and cell behavior in young mice (neonates; PND5 and juveniles; PND12). Acutely, juveniles recover more quickly than neonates, but alveolar simplification occurred in both groups 6-8 weeks post-infection. Single-cell RNA sequencing revealed transient inflammatory responses in neutrophils, macrophages, and fibroblasts at 48 h post infection in both age groups with a partial return to baseline by 96h. The highly proliferative neonatal alveolar type 2 (AT2) cells showed a modest decrease at 48h post infection, whereas the quiescent juvenile AT2 cells exhibited a proliferative response only post-infection. Neonatal PDGFRα+ fibroblasts had higher expression of inflammatory genes post infection than juveniles and in vitro stimulation of PDGFRα+ fibroblasts with LPS-exposed primary macrophages alone, induced expression of the inflammatory marker SAA3. We conclude that early-life pneumonia alters lung homeostasis in an age-differential manner, potentially affecting lung structure and function in adulthood.
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Project description:A developmental murine model of pneumonia was used to investigate how lower respiratory tract E. coli infections differentially affects lung immune responses and cell behavior in young mice (neonates; PND5 and juveniles; PND12). Acutely, juveniles recover more quickly than neonates, but alveolar simplification occurred in both groups 6-8 weeks post-infection. Single-cell RNA sequencing revealed transient inflammatory responses in neutrophils, macrophages, and fibroblasts at 48 h post infection in both age groups with a partial return to baseline by 96h. The highly proliferative neonatal alveolar type 2 (AT2) cells showed a modest decrease at 48h post infection, whereas the quiescent juvenile AT2 cells exhibited a proliferative response only post-infection. Neonatal PDGFRα+ fibroblasts had higher expression of inflammatory genes post infection than juveniles and in vitro stimulation of PDGFRα+ fibroblasts with LPS-exposed primary macrophages alone, induced expression of the inflammatory marker SAA3. We conclude that early-life pneumonia alters lung homeostasis in an age-differential manner, potentially affecting lung structure and function in adulthood.
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Project description:Although modern clinical practices such as cesarean sections and perinatal antibiotics have improved infant survival, treatment with broad-spectrum antibiotics alters intestinal microbiota and causes dysbiosis. Infants exposed to perinatal antibiotics have an increased likelihood of life-threatening infections, including pneumonia. Here, we investigated how the gut microbiota sculpt pulmonary immune responses, promoting recovery and resolution of infection in newborn rhesus macaques. Early-life antibiotic exposure interrupted the maturation of intestinal commensal bacteria and disrupted the developmental trajectory of the pulmonary immune system, as assessed by single-cell proteomic and transcriptomic analyses. Early-life antibiotic exposure rendered newborn macaques more susceptible to bacterial pneumonia, concurrent with increases in neutrophil senescence and hyperinflammation, broad inflammatory cytokine signaling, and macrophage dysfunction. This pathogenic reprogramming of pulmonary immunity was further reflected by a hyperinflammatory signature in all pulmonary immune cell subsets coupled with a global loss of tissue-protective, homeostatic pathways in the lungs of dysbiotic newborns. Fecal microbiota transfer was associated with partial correction of the broad immune maladaptations and protection against severe pneumonia. These data demonstrate the importance of intestinal microbiota in programming pulmonary immunity and support the idea that gut microbiota promote the balance between pathways driving tissue repair and inflammatory responses associated with clinical recovery from infection in infants. Our results highlight a potential role for microbial transfer for immune support in these at-risk infants.
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Project description:During influenza pneumonia, the alveolar epithelial cells of the lungs are targeted by influenza virus. The distal airway stem cells (DASCs) and proliferating alveolar type II (AT2) cells are reported to be putative lung repair cells. However, their relative spatial and temporal distribution is still unknown during influenza-induced acute lung injury. Here, we investigated the distribution of these cells, and concurrently performed global proteomic analysis of the infected lungs to elucidate and link the cellular and molecular events during influenza pneumonia recovery. BALB/c mice were infected with a sub-lethal dose of influenza H1N1 virus. From 5 to 25 days post-infection (dpi), mouse lungs were subjected to histopathologic and immunofluorescence analysis to probe for global distribution of lung repair cells (using P63 and KRT5 markers for DASCs; PCNA and SPC markers for AT2 cells). At 7 and 15 dpi, infected mouse lungs were also subjected to protein mass spectrometry for relative protein quantification. DASCs appeared only in the damaged area of the lung from 7 dpi onwards, reaching a peak at 21 dpi, and persisted at 25 dpi. However, no differentiation of DASCs to AT2 cells was observed by 25 dpi. In contrast, AT2 cells began proliferating from 7 dpi to replenish its population. Mass spectrometry and gene ontology analysis revealed prominent innate immune response at 7 dpi, which shifted towards adaptive immune responses by 15 dpi. Hence, proliferating AT2 cells but not DASCs contribute to AT2 cell regeneration following transition from innate to adaptive immune responses during the early phase of recovery from influenza pneumonia up to 25 dpi.
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Project description:The goal of this study was to evaluate the impact of mechanical ventilation on immune and mitochondrial dysfunctions, in the setting of pneumococcal pneumonia in rabbits. Then, in a randomized trial, we assessed the effect of human umbilical cord-derived mesenchymal stem cells (MSCs), either alone, or in association with an atibiotic treatment (Ceftaroline) in the setting of pneumococcal pneumonia submitted to adverse mechanical ventilation. Pulmonary gene expression was analysed in an attempt to elucidate the effects of MSCs.
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