Interferon Gamma signaling triggers dysplastic alveolar remodeling during respiratory viral infection
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA994074 | ENA |
REPOSITORIES: ENA
Dataset's files
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| SRR25247778_1.fastq.gz | Fastqsanger.gz | |||
| SRR25247778_2.fastq.gz | Fastqsanger.gz | |||
| SRR25247779_1.fastq.gz | Fastqsanger.gz | |||
| SRR25247779_2.fastq.gz | Fastqsanger.gz |
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Project description:Interferon Gamma signaling triggers dysplastic alveolar remodeling during respiratory viral infection
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Project description:Chronic obstructive pulmonary disease (COPD) is characterized by inflammation and emphysema, leading to progressive alveolar destruction. Currently, no therapies effectively regenerate the alveolar epithelium. Here, we developed and characterized a feeder- and serum-free primary adult human organoid model to investigate how inflammatory conditions influence alveolar regeneration. Using Wnt activation and heregulin-β, we achieved long-term expansion of progenitor cells, while AT2 maturation protocols enhanced surfactant production, including the formation of tubular myelin. Introducing a LATS inhibitor to the expansion conditions induced an AT1 differentiation program without eliminating AT2 cells. Single-cell RNA-sequencing revealed multipotent progenitor-like populations, reflecting a state of heightened plasticity associated with regeneration. To model the effects of inflammation, we exposed these organoids to cytokines elevated in COPD. Notably, interferon-gamma (IFN-γ) exerted distinct effects on AT1 and AT2 cells: while it was cytotoxic to AT1 cells, it promoted growth in regenerating AT2 cells in a dose- and time-dependent manner. These findings underscore the nuanced influence of pro-inflammatory cytokines on alveolar regeneration. Our organoid model provides a reductionist platform for mechanistic studies in human cells, aiming to identify therapies that prevent alveolar destruction and improve alveolar regeneration in COPD
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Project description:Macrophage activation syndrome (MAS) is a life-threatening cytokine storm syndrome complicating systemic juvenile idiopathic arthritis (SJIA) and driven by IFN-gamma. SJIA and MAS are also associated with an unexplained emerging inflammatory lung disease (SJIA-LD), with our recent work supporting pulmonary activation of IFN-gamma pathways as a pathologic link between SJIA-LD and MAS. Our objective was to mechanistically define the novel observation of pulmonary inflammation in the TLR9 mouse model of MAS. In acute MAS, lungs exhibit mild but diffuse CD4-predominant, perivascular interstitial inflammation with elevated IFN-gamma, IFN-induced chemokines, and alveolar macrophage expression of IFN-gamma-induced genes. Single-cell RNA-sequencing confirmed IFN-driven transcriptional changes across immune and parenchymal lung cell types. Resolution of MAS was associated with increased alveolar macrophage and interstitial lymphocytic infiltration. alveolar macrophage microarrays confirmed IFN-gamma-induced proinflammatory polarization during acute MAS, which switches towards an anti-inflammatory phenotype during MAS resolution. Interestingly, recurrent MAS led to increased alveolar inflammation and lung injury, and reset alveolar macrophagepolarization towards a proinflammatory state. Furthermore, in mice bearing macrophages insensitive to IFN-gamma, both systemic feature of MAS and pulmonary inflammation were attenuated. These findings demonstrate that experimental MAS induces IFN-gamma-driven pulmonary inflammation replicating key features of SJIA-LD, and provides a model system for testing novel treatments directed towards SJIA-LD.
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