Spatial Transcriptomic Analysis Reveals Dysregulated Pro-Inflammatory Signaling in the Aged Lung
Brianna M Doratt1, Ethan G Napier1, Mahdi Eskandarian Boroujeni1
1Department of Microbiology, Immunology, and Molecular Genetics, College of Medicine, University of Kentucky, Lexington, KY, USA.
Abstract:
Older individuals are more susceptible to viral and bacterial respiratory infections than younger people. While structural lung changes and a hyperinflammatory milieu have been proposed to contribute to worsened clinical outcomes, exact mechanisms remain elusive. Clinical specimens are challenging to obtain and although rodents are valuable models of human disease, their specific pathogen free status and inbred genetics limit translation of findings obtained from these models. We sought to address this question by analyzing the transcriptional landscape of lung tissue obtained from young and aged rhesus macaque using Visium spatial transcriptomics. Unlike rodents, captive rhesus macaques are genetically outbred and exposed to natural particulates and respiratory microbes that modulate their lung immunity. Analysis identified immune and structural cells clusters. Differential gene expression revealed a strong pro-inflammatory bias in aged animals while transcriptional signatures in young animals were consistent with a regulatory phenotype. Moreover, cellular signaling important for adhesion, tissue maintenance, and cell migration was significantly reduced in the aged compared to young lungs. These data indicate that aged lungs are skewed towards hyperinflammatory responses which are likely to result in higher immune mediated damage following challenge.
Insights
Aged lungs show a pro-inflammatory bias, increasing susceptibility to respiratory infections. This study used spatial transcriptomics in rhesus macaques to reveal immune and cellular differences between young and old lungs.
Area of Science:
- Immunology
- Aging Research
- Respiratory Medicine
Background:
- Older individuals face higher risks of respiratory infections due to lung changes and inflammation.
- Mechanisms underlying age-related respiratory vulnerability are not fully understood.
- Rodent models have limitations in translating findings to human respiratory diseases.
Purpose of the Study:
- To investigate age-related differences in lung transcriptional landscapes.
- To identify cellular and molecular mechanisms contributing to increased respiratory infection susceptibility in older individuals.
- To utilize rhesus macaques as a translational model for human lung aging.
Main Methods:
- Visium spatial transcriptomics was employed to analyze lung tissue from young and aged rhesus macaques.
- Gene expression patterns were compared between age groups to identify differential cellular responses.
- Immune and structural cell clusters were identified and characterized.
Main Results:
- Aged lungs exhibited a pro-inflammatory transcriptional bias compared to a regulatory phenotype in young lungs.
- Key cellular signaling pathways for adhesion and tissue maintenance were reduced in aged lungs.
- Significant differences in immune cell populations and gene expression were observed between young and aged macaques.
Conclusions:
- Aged lungs are predisposed to hyperinflammatory responses, potentially leading to increased immune-mediated damage.
- These findings highlight age-related immune dysregulation in the lung.
- Rhesus macaques offer a valuable model for studying human lung aging and disease.
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