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Type I Interferon signaling controls the accumulation and transcriptomes of monocytes in the aged lung

D’Souza, Shanti S., Zhang, Yuanyue, Bailey, Jacob T., Fung, Ivan T. H., Kuentzel, Marcy L., Chittur, Sridar V., Yang, Qi·2021·Aging Cell
DOI 10.1111/acel.13470PMC PMC8520712
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Abstract

Aging is paradoxically associated with a deteriorated immune defense (immunosenescence) and increased basal levels of tissue inflammation (inflammaging). The lung is particularly sensitive to the effects of aging. The immune cell mechanisms underlying physiological lung aging remain poorly understood. Here we reveal that aging leads to increased interferon signaling and elevated concentrations of chemokines in the lung, which is associated with infiltration of monocytes into the lung parenchyma. scRNA‐seq identified a novel Type‐1 interferon signaling dependent monocyte subset (MO‐ifn) that upregulated IFNAR1 expression and exhibited greater transcriptomal changes with aging than the other monocytes. Blockade of type‐1 interferon signaling by treatment with anti‐IFNAR1 neutralizing antibodies rapidly ablated MO‐ifn cells. Treatment with anti‐IFNAR1 antibodies also reduced airway chemokine concentrations and repressed the accumulation of the overall monocyte population in the parenchyma of the aged lung. Together, our work suggests that physiological aging is associated with increased basal level of airway monocyte infiltration and inflammation in part due to elevated type‐1 interferon signaling.

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FIGURE 1 Increased Type I Interferon signaling and chemokines in lungs of aged mice. (a) Principle component analysis of microarray data from total lung cells of young (gray) and aged (orange) female mice. (b) Significant gene sets based on Gene Set Enrichment Analyses (GSEA) of microarray data from lungs of young and aged mice. (c) Heatmap depicting the expression of representative genes in young and aged mouse lungs. p value <0.05 for all gene shown in the heatmap. (d) Chemokine concentrations from the lung homogenates of naïve young and aged mice. Data are from 4–5 mice per group. (e) Representative flow cytometry plot of monocytes (CD45+ Gr1+ CD11b+ Ly6C+) and neutrophils (CD45+ Gr1+ CD11b+ Ly6G+) from lungs of young and aged mice. (f) Number of monocytes and neutrophils in lungs of young and aged mice. (g) Number of monocytes in lungs of young and aged mice. (h) Geometric mean fluorescence intensity of Ki67 staining of monocytes and neutrophils in lungs of young and aged mice. (i) Percentage of activated caspase+ monocytes and neutrophils in lungs of young and aged female mice. (j) Representative immunofluorescence staining of monocytes (Ly6C+) and vascular endothelial cells (CD31+) in the lungs of young and aged mice. (i) Distance between monocytes and vascular endothelium. Data are from female mice (a‐k). Data are from 3 mice per group (a‐c), or are from 4–6 mice per group, two independent experiments (d‐k). Error bars are mean ± SD. *, p < 0.05; **, p < 0.01
FIGURE 1 Increased Type I Interferon signaling and chemokines in lungs of aged mice. (a) Principle component analysis of microarray data from total lung cells of young (gray) and aged (orange) female mice. (b) Significant gene sets based on Gene Set Enrichment Analyses (GSEA) of microarray data from lungs of young and aged mice. (c) Heatmap depicting the expression of representative genes in young and aged mouse lungs. p value <0.05 for all gene shown in the heatmap. (d) Chemokine concentrations from the lung homogenates of naïve young and aged mice. Data are from 4–5 mice per group. (e) Representative flow cytometry plot of monocytes (CD45+ Gr1+ CD11b+ Ly6C+) and neutrophils (CD45+ Gr1+ CD11b+ Ly6G+) from lungs of young and aged mice. (f) Number of monocytes and neutrophils in lungs of young and aged mice. (g) Number of monocytes in lungs of young and aged mice. (h) Geometric mean fluorescence intensity of Ki67 staining of monocytes and neutrophils in lungs of young and aged mice. (i) Percentage of activated caspase+ monocytes and neutrophils in lungs of young and aged female mice. (j) Representative immunofluorescence staining of monocytes (Ly6C+) and vascular endothelial cells (CD31+) in the lungs of young and aged mice. (i) Distance between monocytes and vascular endothelium. Data are from female mice (a‐k). Data are from 3 mice per group (a‐c), or are from 4–6 mice per group, two independent experiments (d‐k). Error bars are mean ± SD. *, p < 0.05; **, p < 0.01CC BY · PubMed Central
FIGURE 2 Aging alters the single‐cell transcriptomes of pulmonary monocytes. Single‐cell RNA‐seq were performed with FACS‐sorted Ly6C+ monocytes and Ly6G+ neutrophils from lungs of young and aged female mice. (a) Unsupervised clustering of cell subsets by UMAP analysis. (b) Pathways of genes highly expressed in MO‐ifn cells, or in MO‐c1 and MO‐c2 cells. p value < 0.05, and absolute log (FC) value >0.3 were used as threshold to identify differentially expressed genes. (c) Dot map depicts expressional levels of interferon‐stimulated genes that were highly expressed in MO‐ifn cells. (d) List of genes that were differentiated expressed with aging in each monocyte subset. (e). Violin plots depicts expression of the indicated genes in each monocyte subset in young and aged mice. Data are from 5 mice pooled, per group. * p < 0.05
FIGURE 2 Aging alters the single‐cell transcriptomes of pulmonary monocytes. Single‐cell RNA‐seq were performed with FACS‐sorted Ly6C+ monocytes and Ly6G+ neutrophils from lungs of young and aged female mice. (a) Unsupervised clustering of cell subsets by UMAP analysis. (b) Pathways of genes highly expressed in MO‐ifn cells, or in MO‐c1 and MO‐c2 cells. p value < 0.05, and absolute log (FC) value >0.3 were used as threshold to identify differentially expressed genes. (c) Dot map depicts expressional levels of interferon‐stimulated genes that were highly expressed in MO‐ifn cells. (d) List of genes that were differentiated expressed with aging in each monocyte subset. (e). Violin plots depicts expression of the indicated genes in each monocyte subset in young and aged mice. Data are from 5 mice pooled, per group. * p < 0.05CC BY · PubMed Central
FIGURE 3 Type I Interferon, but not IFNγ promote monocyte accumulation in the aged lung. Young and aged female mice were treated with either Isotype, anti‐IFNAR1 or anti‐IFNγ antibodies for 1 week. (a) Representative flow cytometry plots showing lung monocytes (CD45+ Gr1+ Ly6G− Ly6C+ CD11b+) and neutrophils (CD45+ Gr1+ CD11b+ Ly6C− Ly6G+). (b) Total number of lung monocytes from flow cytometry analysis. (c) Immunofluorescence staining of monocytes and vascular endothelial cells in the lungs of aged mice treated with isotype control or anti‐IFNAR1 antibody. (d) Average numbers of monocytes by immunofluorescence staining. (e) Distance between monocytes and vascular endothelium. (f) Chemokine concentrations from the lung homogenates of naïve young and aged mice treated with Isotype or anti‐IFNAR1 antibody for one week. (g) Levels of IFNα and IFNβ in the lung homogenate. (h) CD4+ and CD8+ T cells were sorted from the lungs of young and aged mice by fluorescence activated cell sorting (FACS). QPCR analyses were performed to examine the expression of Ifnar1 and Ifnar2. (i) Expressional levels of Ccl4 in FACS‐sorted CD4+ and CD8+ T cells. (j) Expressional levels of Ccl4 in CD4+ and CD8+ T cells from the lungs of aged mice treated with isotype control or anti‐IFNAR1 antibody. Data are from 4–6 mice per group, two independent experiments. Error bars are mean ± SD. *, p<0.05; **, p<0.01
FIGURE 3 Type I Interferon, but not IFNγ promote monocyte accumulation in the aged lung. Young and aged female mice were treated with either Isotype, anti‐IFNAR1 or anti‐IFNγ antibodies for 1 week. (a) Representative flow cytometry plots showing lung monocytes (CD45+ Gr1+ Ly6G− Ly6C+ CD11b+) and neutrophils (CD45+ Gr1+ CD11b+ Ly6C− Ly6G+). (b) Total number of lung monocytes from flow cytometry analysis. (c) Immunofluorescence staining of monocytes and vascular endothelial cells in the lungs of aged mice treated with isotype control or anti‐IFNAR1 antibody. (d) Average numbers of monocytes by immunofluorescence staining. (e) Distance between monocytes and vascular endothelium. (f) Chemokine concentrations from the lung homogenates of naïve young and aged mice treated with Isotype or anti‐IFNAR1 antibody for one week. (g) Levels of IFNα and IFNβ in the lung homogenate. (h) CD4+ and CD8+ T cells were sorted from the lungs of young and aged mice by fluorescence activated cell sorting (FACS). QPCR analyses were performed to examine the expression of Ifnar1 and Ifnar2. (i) Expressional levels of Ccl4 in FACS‐sorted CD4+ and CD8+ T cells. (j) Expressional levels of Ccl4 in CD4+ and CD8+ T cells from the lungs of aged mice treated with isotype control or anti‐IFNAR1 antibody. Data are from 4–6 mice per group, two independent experiments. Error bars are mean ± SD. *, p<0.05; **, p<0.01CC BY · PubMed Central
FIGURE 4 Neutralizing anti‐IFNAR1 treatment alters the transcriptome of aged lung monocytes. (a) Ly6C+ monocytes and Ly6G+ neutrophils from lungs of aged mice treated with isotype or anti‐IFNAR1 antibody were sorted, and single‐cell RNA sequencing was carried out. UMAP plot reveals two populations of cells. (b) Venn diagram showing the overlap between genes either upregulated or downregulated with one day or one week of anti‐IFNAR1 treatment in aged mouse monocytes. p value < 0.05, and absolute log (FC) value >0.3 were used as threshold to identify differentially expressed genes. Genes in red colors were highly expressed in MO‐ifn cells. (c) List of genes that were upregulated or downregulated with one day or one week of anti‐IFNAR1 treatment in aged mouse monocytes. Gene in red colors were genes that were highly expressed in MO‐ifn cells. (d) Dot plots showing representative differentially expressed genes. Gene in red colors were highly expressed in MO‐ifn cells. Data are from 5 mice pooled, per group
FIGURE 4 Neutralizing anti‐IFNAR1 treatment alters the transcriptome of aged lung monocytes. (a) Ly6C+ monocytes and Ly6G+ neutrophils from lungs of aged mice treated with isotype or anti‐IFNAR1 antibody were sorted, and single‐cell RNA sequencing was carried out. UMAP plot reveals two populations of cells. (b) Venn diagram showing the overlap between genes either upregulated or downregulated with one day or one week of anti‐IFNAR1 treatment in aged mouse monocytes. p value < 0.05, and absolute log (FC) value >0.3 were used as threshold to identify differentially expressed genes. Genes in red colors were highly expressed in MO‐ifn cells. (c) List of genes that were upregulated or downregulated with one day or one week of anti‐IFNAR1 treatment in aged mouse monocytes. Gene in red colors were genes that were highly expressed in MO‐ifn cells. (d) Dot plots showing representative differentially expressed genes. Gene in red colors were highly expressed in MO‐ifn cells. Data are from 5 mice pooled, per groupCC BY · PubMed Central
FIGURE 5 Neutralizing anti‐IFNAR1 treatment differentially alters the transcriptomes of MO‐ifn and MO‐c cells. Single‐cell RNA‐seq (scRNA‐seq) was performed with Ly6C+ monocytes and Ly6G+ neutrophils sorted from lungs of aged female mice treated with isotype or anti‐IFNAR1 antibody. (a) Unsupervised clustering by UMAP analysis. (b) Dot plots showing genes that were highly expressed in MO‐ifn cells. p value < 0.05, and absolute log (FC) value >0.3 were used as threshold to identify differentially expressed genes. (c) Percentages of MO‐ifn and MO‐cells in aged mice treated with isotype or anti‐IFNAR1 antibody. (d) List of genes that were differentially expressed with aging in MO‐c cells. Data are from 5 mice pooled, per group
FIGURE 5 Neutralizing anti‐IFNAR1 treatment differentially alters the transcriptomes of MO‐ifn and MO‐c cells. Single‐cell RNA‐seq (scRNA‐seq) was performed with Ly6C+ monocytes and Ly6G+ neutrophils sorted from lungs of aged female mice treated with isotype or anti‐IFNAR1 antibody. (a) Unsupervised clustering by UMAP analysis. (b) Dot plots showing genes that were highly expressed in MO‐ifn cells. p value < 0.05, and absolute log (FC) value >0.3 were used as threshold to identify differentially expressed genes. (c) Percentages of MO‐ifn and MO‐cells in aged mice treated with isotype or anti‐IFNAR1 antibody. (d) List of genes that were differentially expressed with aging in MO‐c cells. Data are from 5 mice pooled, per groupCC BY · PubMed Central
FIGURE 6 Aging monocytes further expand during Influenza infection in an IFNAR1‐dependent manner. Young and aged mice were either treated with anti‐IFNAR1 and/or infected with IAV and sacrificed on day 6 of infection. (a) Representative flow cytometry plots showing lung monocytes (CD45+ Gr1+ CD11b+ Ly6G− Ly6C+) and neutrophils (CD45+ Gr1+ CD11b+ Ly6C− Ly6G+). (b) Total number of lung monocytes. (c) Total number of lung neutrophils. (d) Chemokine concentrations from the lung homogenates. Data are from 5–6 mice per group, two independent experiments. Error bars are mean ± SD. *, p < 0.05; **, p < 0.01
FIGURE 6 Aging monocytes further expand during Influenza infection in an IFNAR1‐dependent manner. Young and aged mice were either treated with anti‐IFNAR1 and/or infected with IAV and sacrificed on day 6 of infection. (a) Representative flow cytometry plots showing lung monocytes (CD45+ Gr1+ CD11b+ Ly6G− Ly6C+) and neutrophils (CD45+ Gr1+ CD11b+ Ly6C− Ly6G+). (b) Total number of lung monocytes. (c) Total number of lung neutrophils. (d) Chemokine concentrations from the lung homogenates. Data are from 5–6 mice per group, two independent experiments. Error bars are mean ± SD. *, p < 0.05; **, p < 0.01CC BY · PubMed Central

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Metadata

Authors
D’Souza, S. S., Zhang, Y., Bailey, J. T., Fung, I. T. H., Kuentzel, M. L., Chittur, S. V., & Yang, Q.
Affiliations
  • Department of Immunology and Microbial Disease Albany Medical College Albany NY USA
  • Center for Functional Genomics University at Albany‐SUNY Rensselaer NY USA
ORCID
Yang, Qi
Venue
Aging Cell
Publisher
Wiley
Published
2021-09-21
Volume
20
Issue
10
ISSN
  • 1474-9718
  • 1474-9726
DOI
10.1111/acel.13470
PMC
PMC8520712
Cited by
32
References
13
Language
en
Licence
creativecommons.org/licenses/by/4.0/ (vor)
Funders
  • National Institutes of Health (R01HL155021)
  • National Heart, Lung, and Blood Institute (R01HL137813)
  • National Institute on Aging (R01AG057782)

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