The role of HHIP in COPD lymphocytic inflammation
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA630262 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| Other | ||||
| SRR11685368.fastq.gz | Fastqsanger.gz | |||
| SRR11685369.fastq.gz | Fastqsanger.gz | |||
| SRR11685371.fastq.gz | Fastqsanger.gz | |||
| SRR11685372.fastq.gz | Fastqsanger.gz |
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Project description:Chronic obstructive pulmonary disease (COPD) is characterized by persistent and amplified inflammation to cigarette smoke in vulnerable subjects. The genetic risk of persistent inflammation is poorly understood. A mouse model targeting hedgehog interacting protein (HHIP)(Hhip+--), a genetic risk factor for COPD, displays progressive, persistent inflammation resembling human cases, providing a valuable model to study the contribution of the genetic risk factor HHIP to inflammation in COPD. By single cell RNA sequencing of Hhip+-- lungs at different disease stages, we identified induction of IFN-gamma in activated CD8+T cells possibly driving the inflammatory phenotype in Hhip+-- lungs. Hhip expression was restricted to lung fibroblasts, which interaction with CD8+T cells were mediated by increased levels of IL-18 from Hhip+-- fibroblasts. Our finding provides insight into how a common genetic variation contributes to the amplified lymphocytic inflammation in COPD.
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Project description:Affinity purification mass spectrometry (AP-MS) was performed to identify protein interactions with HHIP, a well-established COPD GWAS gene. HA-immunoprecipitations (n = 3) were conducted using IMR90 and 16HBE cell lines stably expressing HA-tagged HHIP.
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Project description:BACKGROUND: The HHIP gene, encoding Hedgehog interacting protein, has been implicated in chronic obstructive pulmonary disease (COPD) by genome-wide association studies (GWAS), and our subsequent studies identified a functional upstream genetic variant that decreased HHIP transcription. However, little is known about how HHIP contributes to COPD pathogenesis. METHODS: Here, we exposed Hhip haploinsufficient mice (Hhip+/-) to cigarette smoke (CS) for 6 months to model the biological consequences caused by CS in human COPD risk-allele carriers at the HHIP locus. Gene expression profiling in murine lungs was performed followed by an integrative network inference analysis, PANDA (Passing Attributes between Networks for Data Assimilation) analysis. RESULTS: We detected more severe airspace enlargement in Hhip+/- mice vs. wild-type littermates (Hhip+/+) exposed to CS. Gene expression profiling in murine lungs suggested enhanced lymphocyte activation pathways in CS-exposed Hhip+/- vs. Hhip+/+ mice, which was supported by increased numbers of lymphoid aggregates and enhanced activation of CD8+ T cells after CS-exposure in the lungs of Hhip+/- mice compared to Hhip+/+ mice. Mechanistically, results from PANDA network analysis suggested a rewired and dampened Klf4 signaling network in Hhip+/- mice after CS exposure. CONCLUSIONS: In summary, HHIP haploinsufficiency exaggerated CS-induced airspace enlargement, which models CS-induced emphysema in human smokers carrying COPD risk alleles at the HHIP locus. Network modeling suggested rewired lymphocyte activation signaling circuits in the HHIP haploinsufficiency state. Total RNA was obtained from the lung tissue of C57BL/6J mice exposed to cigarette smoke (CS) or filtered air (air) for 6 months. Six mice from each of four groups with different genotypes (Hhip+/+ or Hhip+/-) and treatments (air or CS) were randomly chosen for gene expression profiling
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Project description:BACKGROUND: The HHIP gene, encoding Hedgehog interacting protein, has been implicated in chronic obstructive pulmonary disease (COPD) by genome-wide association studies (GWAS), and our subsequent studies identified a functional upstream genetic variant that decreased HHIP transcription. However, little is known about how HHIP contributes to COPD pathogenesis. METHODS: Here, we exposed Hhip haploinsufficient mice (Hhip+/-) to cigarette smoke (CS) for 6 months to model the biological consequences caused by CS in human COPD risk-allele carriers at the HHIP locus. Gene expression profiling in murine lungs was performed followed by an integrative network inference analysis, PANDA (Passing Attributes between Networks for Data Assimilation) analysis. RESULTS: We detected more severe airspace enlargement in Hhip+/- mice vs. wild-type littermates (Hhip+/+) exposed to CS. Gene expression profiling in murine lungs suggested enhanced lymphocyte activation pathways in CS-exposed Hhip+/- vs. Hhip+/+ mice, which was supported by increased numbers of lymphoid aggregates and enhanced activation of CD8+ T cells after CS-exposure in the lungs of Hhip+/- mice compared to Hhip+/+ mice. Mechanistically, results from PANDA network analysis suggested a rewired and dampened Klf4 signaling network in Hhip+/- mice after CS exposure. CONCLUSIONS: In summary, HHIP haploinsufficiency exaggerated CS-induced airspace enlargement, which models CS-induced emphysema in human smokers carrying COPD risk alleles at the HHIP locus. Network modeling suggested rewired lymphocyte activation signaling circuits in the HHIP haploinsufficiency state.
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