AUTHOR=Zhang Shi , Chu Cuilin , Wu Zongsheng , Liu Feng , Xie Jianfeng , Yang Yi , Qiu Haibo 

TITLE=IFIH1 Contributes to M1 Macrophage Polarization in ARDS

JOURNAL=Frontiers in Immunology

VOLUME=11

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.580838

DOI=10.3389/fimmu.2020.580838

ISSN=1664-3224

ABSTRACT=<p>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. <italic>STAT1, IFIH1, GBP1, IFIT3</italic>, and <italic>IRF1</italic> were subsequently identified as hub genes according to connectivity degree analysis and multiple external validations. Among these candidate genes, <italic>IFIH1</italic> had the strongest connection with ARDS through the RobustRankAggreg algorithm. It was selected as a crucial gene for further investigation. <italic>For in vitro</italic> validation, the RAW264.7 cell line and BMDMs were transfected with sh<italic>IFIH1</italic> lentivirus and plasmid expression vectors of <italic>IFIH1</italic>. Cellular experimental studies further confirmed that <italic>IFIH1</italic> was a novel regulator for promoting M1 macrophage polarization. Moreover, gene set enrichment analysis (GSEA) and <italic>in vitro</italic> validations indicated that <italic>IFIH1</italic> regulated M1 polarization by activating <italic>IRF3</italic>. In addition, previous studies demonstrated that activation of <italic>IFIH1-IRF3</italic> was stimulated by viral RNAs or RNA mimics. Surprisingly, the current study found that LPS could also induce <italic>IFIH1</italic>-<italic>IRF3</italic> activation <italic>via a</italic> MyD88-dependent mechanism. We also found that only <italic>IFIH1</italic> expression without LPS or RNA mimic stimulation could not affect <italic>IRF3</italic> 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 <italic>IFIH1</italic> and <italic>IRF3</italic>, suggesting <italic>IFIH1</italic> as a potential target for ARDS treatment.</p>