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Isolation of Cortical Microglia with Preserved Immunophenotype and Functionality From Murine Neonates
Published on: January 30, 2014
Influenza A infection accelerates disease-associated microglia formation during physiological aging
Rogan A Grant1, Constance E Runyan1, Grace A Minogue2,3
1Division of Pulmonary and Critical Care Medicine, Department of Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
Abstract:
Severe pneumonia is associated with an increased risk of cognitive decline and dementia, particularly in the elderly. Changes in microglia, the most abundant immune cell population in the brain, are also associated with cognitive decline and dementia, including the emergence of a transcriptional cell state referred to as disease-associated microglia (DAM). We sought to test the hypothesis that non-neuroinvasive influenza A virus (IAV) pneumonia results in transcriptional responses in brain microglia that drive premature expansion of DAM. Using bulk and single-cell RNA-sequencing, metabolomics, and spatial transcriptomics, we profiled neuroimmune populations in young, middle-aged, and old male mice during IAV infection and recovery. We observed an increased abundance of DAM, interferon-responsive microglia (IRM), CD4+ T cells, and CD8+ T cells in white matter regions beginning in middle age and persisting in old animals, irrespective of IAV infection. DAM exhibited a metabolic shift toward aerobic glycolysis with disrupted TCA cycling, citrulline depletion, and an elevated itaconate/α-ketoglutarate ratio. Spatial transcriptomic profiling of the human middle frontal gyrus (MFG) in normal agers, SuperAgers, and patients with dementia revealed an analogous accumulation of DAM and CD8+ T cells in white matter. IAV pneumonia induced a transient immunosenescent-like response in microglia, marked by glucocorticoid-responsive gene expression and Ccnd3 upregulation. In response to IAV pneumonia, DAM expanded in middle-aged mice, whereas old mice were elevated at baseline and were largely unaffected by IAV infection. The age-related expansion of DAM was unaffected by pharmacological depletion and repopulation of microglia with a CSF1R antagonist or genetic gain or loss of function of the phagocytic receptor MERTK, suggesting the DAM phenotype is driven by the CNS microenvironment, rather than cell-intrinsic mechanisms. Our findings suggest that IAV pneumonia induces an acute immunosenescence response in microglia and accelerates the age-dependent expansion of DAM in white matter.
Insights
Influenza A virus pneumonia accelerates brain aging by promoting disease-associated microglia (DAM) expansion in white matter, particularly in older individuals. This exacerbates cognitive decline risk.
Area of Science:
- Neuroscience
- Immunology
- Aging Research
Background:
- Severe pneumonia is linked to cognitive decline and dementia, especially in the elderly.
- Disease-associated microglia (DAM) are implicated in cognitive decline and dementia.
- The impact of influenza A virus (IAV) pneumonia on brain microglia and its contribution to cognitive aging is not fully understood.
Purpose of the Study:
- To investigate how non-neuroinvasive influenza A virus (IAV) pneumonia affects brain microglia transcriptional responses.
- To determine if IAV pneumonia drives premature expansion of disease-associated microglia (DAM).
- To explore the age-dependent changes in neuroimmune populations and their response to IAV infection.
Main Methods:
- Bulk and single-cell RNA sequencing, metabolomics, and spatial transcriptomics were used in young, middle-aged, and old male mice.
- Neuroimmune populations were profiled during IAV infection and recovery.
- Human middle frontal gyrus (MFG) tissue from normal agers, SuperAgers, and dementia patients was analyzed using spatial transcriptomics.
Main Results:
- An increased abundance of DAM, interferon-responsive microglia (IRM), CD4+, and CD8+ T cells was observed in white matter, starting in middle age and persisting in old mice.
- DAM showed a metabolic shift towards aerobic glycolysis with disrupted TCA cycling and altered metabolite ratios.
- IAV pneumonia induced an acute immunosenescence-like response in microglia, accelerating DAM expansion in middle-aged mice, while old mice showed baseline elevations.
- Human MFG analysis revealed analogous DAM and CD8+ T cell accumulation in white matter of normal agers, SuperAgers, and dementia patients.
- The age-related DAM expansion was independent of microglia-intrinsic mechanisms, suggesting a role for the central nervous system (CNS) microenvironment.
Conclusions:
- IAV pneumonia induces an acute immunosenescence response in microglia.
- The study accelerates the age-dependent expansion of DAM in white matter, linking pneumonia to accelerated brain aging.
- Findings suggest that pneumonia-induced neuroinflammation contributes to cognitive decline risk, particularly in aging populations.
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