Abstract
Background: Airway macrophages (AMs) are the most abundant leukocytes in the healthy airway lumen and have a highly specialised but plastic phenotype that is governed by signals in the local microenvironment. AMs are thought to maintain immunological homeostasis in the steady state, but have also been implicated in the pathogenesis of allergic airway disease (AAD). In this study, we aimed to better understand these potentially contrasting AM functions using transcriptomic analysis. Methods: Bulk RNA sequencing was performed on AMs flow cytometry sorted from C57BL/6 mice during experimental AAD driven by repeated house dust mite inhalation (AMs HDM), compared to control AMs from non-allergic mice. Differentially expressed genes were further analysed by hierarchical clustering and biological pathway analysis. Results: AMs HDM showed increased expression of genes associated with antigen presentation, inflammatory cell recruitment and tissue repair, including several chemokine and matrix metalloproteinase genes. This was accompanied by increased expression of mitochondrial electron transport chain subunit genes and the retinoic acid biosynthetic enzyme gene Raldh2. Conversely, AMs HDM displayed decreased expression of a number of cell cycle genes, genes related to cytoskeletal functions and a subset of genes implicated in antimicrobial innate immunity, such as Tlr5, Il18 and Tnf. Differential gene expression in AMs HDM was consistent with upstream effects of the cytokines IL-4 and IFN-γ, both of which were present at increased concentrations in lung tissue after HDM treatment. Conclusions: These data highlight diverse gene expression changes in the total AM population in a clinically relevant mouse model of AAD, collectively suggestive of contributions to inflammation and tissue repair/remodelling, but with decreases in certain steady state cellular and immunological functions.
Highlights
Airway macrophages (AMs) are the most abundant leukocytes in the healthy airway lumen and have a highly specialised but plastic phenotype that is governed by signals in the local microenvironment
Differential expression of discrete clusters of genes in airway macrophages during house dust mite-driven allergic airway disease To examine gene expression changes in AMs during AAD driven by a clinically-relevant aeroallergen, mice were repeatedly exposed to inhaled HDM extract for 3 weeks (Figure 1A), Figure 1
CD11c+ sialic acid-binding lectin (Siglec) F+ CD64+ CD45+ SSChi AMs were flow cytometry sorted from bronchoalveolar lavage (BAL) (Figure 1C) of HDM- and PBS-treated mice, before rapidly lysing cells for RNA extraction and RNA sequencing (RNA-seq)
Summary
Airway macrophages (AMs) are the most abundant leukocytes in the healthy airway lumen and have a highly specialised but plastic phenotype that is governed by signals in the local microenvironment. Results: AMs HDM showed increased expression of genes associated with antigen presentation, inflammatory cell recruitment and tissue repair, including several chemokine and matrix metalloproteinase genes. This was accompanied by increased expression of mitochondrial electron transport chain subunit genes and the retinoic acid biosynthetic enzyme gene Raldh[2 ]. Conclusions: These data highlight diverse gene expression changes in the total AM population in a clinically relevant mouse model of AAD, collectively suggestive of contributions to inflammation and tissue repair/remodelling, but with decreases in certain steady state cellular and immunological functions
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