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• W3115707118 abstract "Under homeostatic conditions, macrophages are the most abundant immune cells in the lung. Pulmonary macrophages are a heterogeneous cell population that can be classified in at least two distinct subpopulations, that is, interstitial macrophages, located within the lung parenchyma, and alveolar macrophages (AM) which reside in the airway lumen, allowing direct contact with the environment (eg, allergens, particulate matter, and commensal bacteria).1 In recent years, AM have been shown to play an important role in environmental allergen-induced airway inflammation in asthma.2 Elimination of resident AM resulted in enhanced type 2 airway inflammation in a mouse asthma model, while depletion of blood monocytes resulted in abrogation of newly formed AM after allergen challenge and a decreased type 2 immune response.3, 4 Knowledge of phenotypic alterations of AM in allergic asthma in humans is limited.1, 2 In this study, we investigated the effect of house dust mite (HDM) and lipopolysaccharide (LPS) challenge on the transcriptome of AM from patients with mild asthma. We have shown previously that intrabronchial HDM/LPS challenge induces a mixed eosinophilic and neutrophil airways inflammation in asthma patients.5 Therefore, we hypothesize that exposure of AM to HDM/LPS would upregulate genes associated with eosinophil and neutrophil signaling. AM were harvested from asthma patients who participated in a double-blind randomized placebo-controlled trial investigating the effect of C1 inhibitor on allergen-induced airway inflammation.5 The Medical Ethics Committee of the Academic Medical Center, Amsterdam (the Netherlands), approved the study, and all patients gave their written informed consent. For the current analysis twelve patients (treated with placebo) with intermittent-to-mild asthma, defined according to the criteria of the Global Initiative for Asthma guideline,6 and HDM allergy, confirmed by a positive skin prick and radioallergosorbent test, were challenged via bronchoscopy with saline (as internal control) in one lung segment and HDM extract (50 biological units, Dermatophagoides pteronyssinus origin; Allergopharma, Zeist, the Netherlands), combined with LPS (75 ng; from Escherichia coli, Clinical Center Reference Endotoxin, kindly provided by Anthony Suffredini, National Institute of Health, Bethesda, MD, USA) in the contralateral lung segment. The addition of LPS to HDM mimics a natural allergen exposure as LPS is a widespread pollutant and coexisting with HDM in house dust.7 After seven hours, a bilateral bronchoalveolar lavage (BAL) was performed. BAL fluid was pooled (per lung subsegment) and centrifuged at 4°C and 400 g for 10 min. Cells were stained with CD45 phycoerythrin (PE)-CF594 and CD71 Brilliant Violet (BV)421 (both BD Biosciences). AM, defined as cells expressing CD45 and CD71, were isolated by flow cytometry sorting using FACSAria III (BD Biosciences) with high purity (>95%; gating strategy see Figure S1). This sorting strategy is a limitation of our study as it selects CD71 positive AMS and does not discriminate between different AM subsets. In addition, flow cytometry did not include other markers, precluding discrimination of macrophages subsets. Sorted AM were stored in RNA later (Qiagen) at −80°C until analysis. Total RNA was isolated using RNAeasy isolation kit (Qiagen) and quantified by Qubit® 2.0 (Life Technologies). Paired samples (AM from saline and HDM/LPS challenged lung segments of one individual) from eight patients had a RNA integrity number >6 and were selected for further analysis. RNA-seq libraries were prepared using the KAPA RNA HyperPrep with RiboErase (Roche) according to manufacturer's instructions and sequenced using the Illumina HiSeq4000 (Illumina) instrument. Sequences were evaluated for quality (FastQC version 0.11.5; Babraham Institute) and trimmed (Trimmomatic version 0.36).8 The remaining reads were used to align against the Genome Reference Consortium human genome build 38 (GRCh38) using HISAT2 (version 2.1.0)9 with parameters as default. The HTSeq and DESeq2 methods are standard bioinformatics methods used to calculate and compare sequence counts, respectively. Pathway analysis was done using Ingenuity Pathway Analysis (QIAGEN bioinformatics) software. To control the false discovery rate, Benjamini and Hochberg adjusted p-values <0.05 demarcated significance.10 Sequence libraries are publicly available through the National Center for Biotechnology Information under the following accession number GSE144576. The baseline characteristics of these patients and the leukocytes differentiation in BAL fluid are depicted in Table 1. None of the patients had any symptom at the study day. Principal component analysis of 24,555 transcripts (sequence counts ≥10) revealed clear separation of saline or HDM/LPS challenges (Figure 1A), showing that HDM/LPS induced a marked transcriptomic response in AM. Comparing HDM/LPS challenge to saline identified 1013 significantly altered transcripts (fold expression ≤−1.2 or ≥1.2), of which 485 were upregulated and 528 downregulated as consequence of HDM/LPS challenge (Figure 1B). Pathway analysis of upregulated genes revealed predominantly pro-inflammatory responses such as inducible nitric oxide synthase, Toll-like receptor, p38 mitogen-activated protein kinase, and interleukin (IL)-1, IL-8, and IL-17 signaling (Figure 1C). IL-1 signaling has been implicated in neutrophilic subtype of asthma, especially an increased IL-1β.2 Likewise, IL-17 has been identified as an important cytokine in the pathogenesis of asthma due to its capacity to promote neutrophilic airway inflammation, which is associated with a severe asthma phenotype.11 In agreement, our data show upregulation of CXCL1, a chemoattractant for neutrophils, suggesting that AM aid in neutrophil recruitment following HDM/LPS challenge (Figure 1D). In line with these finding, HDM/LPS challenge induced a marked neutrophil influx in the airways.5 Interestingly, genes associated with the anti-inflammatory IL-10 signaling pathway were also upregulated. This could be explained by heterogeneity among AM including both pro- and anti-inflammatory subpopulations and/or concurrent induction of both pro- and anti-inflammatory pathways in the same AM. This observation suggests a regulatory role for AM to maintain homeostasis by counteracting the pro-inflammatory processes inflicted by allergen challenge. Among downregulated transcripts were genes associated with cell cycle and growth (T-cell receptor, role of NFAT in cardiac hypertrophy), DNA damage and repair PI3/PI4-kinase family, including ATM, PIK3CB and PIK3CG (Table S1) (breast cancer regulation by stathmin 1) and metabolic pathways (eg, insulin receptor and leptin signaling, Figure 1C,D). Network graphs of the most enriched genes are displayed in Figures S2 and S3. To the best of our knowledge, this is the first investigation to examine gene expression profiles in AM from asthma patients challenged with HDM and LPS in vivo. Using a well-controlled study design allowing paired analysis of saline and HDM/LPS effects in the same patient, we identified different transcriptional profiles in AM as consequence of local exposure to HDM and LPS. These findings may provide a better understanding of AM functions in (exacerbations of) allergic asthma. Jack Yang was supported by ZonMw and the Netherlands Lung Foundation (project: 95104011). All authors declare that they have no conflict of interest to disclose. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article." @default.
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• W3115707118 date "2021-01-12" @default.
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• W3115707118 title "Transcriptional changes in alveolar macrophages from adults with asthma after allergen challenge" @default.
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• W3115707118 doi "https://doi.org/10.1111/all.14719" @default.
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