Abstract
Accumulated evidence has demonstrated that the macrophage phenotypic switch from M0 to M1 is crucial in the initiation of the inflammatory process of acute respiratory distress syndrome (ARDS). Better insight into the molecular control of M1 macrophages in ARDS may identify potential therapeutic targets. In the current study, 36 candidate genes associated with the severity of ARDS and simultaneously involved in M1-polarized macrophages were first screened through a weighted network algorithm on all gene expression profiles from the 26 ARDS patients and empirical Bayes analysis on the gene expression profiles of macrophages. STAT1, IFIH1, GBP1, IFIT3, and IRF1 were subsequently identified as hub genes according to connectivity degree analysis and multiple external validations. Among these candidate genes, IFIH1 had the strongest connection with ARDS through the RobustRankAggreg algorithm. It was selected as a crucial gene for further investigation. For in vitro validation, the RAW264.7 cell line and BMDMs were transfected with shIFIH1 lentivirus and plasmid expression vectors of IFIH1. Cellular experimental studies further confirmed that IFIH1 was a novel regulator for promoting M1 macrophage polarization. Moreover, gene set enrichment analysis (GSEA) and in vitro validations indicated that IFIH1 regulated M1 polarization by activating IRF3. In addition, previous studies demonstrated that activation of IFIH1-IRF3 was stimulated by viral RNAs or RNA mimics. Surprisingly, the current study found that LPS could also induce IFIH1-IRF3 activation via a MyD88-dependent mechanism. We also found that only IFIH1 expression without LPS or RNA mimic stimulation could not affect IRF3 activation and M1 macrophage polarization. These findings were validated on two types of macrophages, RAW264.7 cells and BMDMs, which expanded the knowledge on the inflammatory roles of IFIH1 and IRF3, suggesting IFIH1 as a potential target for ARDS treatment.
Highlights
Acute respiratory distress syndrome (ARDS), a common and severe pulmonary complication of critical illness, affects approximately 10%–15% of patients hospitalized in the intensive care unit (ICU) [1, 2]
To screen genes associated with the severity of acute respiratory distress syndrome (ARDS), we utilized the weighted gene coexpression network analysis (WGCNA) algorithm on all gene expression profiles from 26 ARDS patients
To investigate the genes potentially involved in M1 macrophage polarization, we identified significantly differentially expressed genes between M1 macrophages and M0 and M2 macrophages [2-fold difference, false discovery rate (FDR
Summary
Acute respiratory distress syndrome (ARDS), a common and severe pulmonary complication of critical illness, affects approximately 10%–15% of patients hospitalized in the intensive care unit (ICU) [1, 2]. Uncontrolled inflammatory responses in the lungs induce perpetuation of lung injury, impacting the severity of ARDS and patient prognosis, and macrophages/monocytes play a causal role in this pathogenesis. At any point in this initial inflammatory process of ARDS, alveolar macrophages and monocytes can be polarized into pro-inflammatory populations (M1 phenotype). Macrophages with an M1 phenotype further promote lung inflammation through secretion of inflammatory cytokines and chemokines, which consistently activate and recruit immune cells, leading to continuous lung injury [11,12,13,14,15]. It may be therapeutically valuable to attenuate macrophage polarization into the M1 phenotype in the initial stage of ARDS
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