PMID- 36462334 OWN - NLM STAT- MEDLINE DCOM- 20230105 LR - 20230111 IS - 1878-1705 (Electronic) IS - 1567-5769 (Print) IS - 1567-5769 (Linking) VI - 114 DP - 2023 Jan TI - IFIH1/IRF1/STAT1 promotes sepsis associated inflammatory lung injury via activating macrophage M1 polarization. PG - 109478 LID - S1567-5769(22)00963-8 [pii] LID - 10.1016/j.intimp.2022.109478 [doi] AB - BACKGROUND: A growing body of research has shown that the phenotypic change in macrophages from M0 to M1 is essential for the start of the inflammatory process in septic acute respiratory distress syndrome (ARDS). Potential treatment targets might be identified with more knowledge of the molecular regulation of M1 macrophages in septic ARDS. METHODS: A multi-microarray interrelated analysis of high-throughput experiments from ARDS patients and macrophage polarization was conducted to identify the hub genes associated with macrophage M1 polarization and septic ARDS. Lipopolysaccharide (LPS) and Poly (I:C) were utilized to stimulate bone marrow-derived macrophages (BMDMs) for M1-polarized macrophage model construction. Knock down of the hub genes on BMDMs via shRNAs was used to screen the genes regulating macrophage M1 polarization in vitro. The cecal ligation and puncture (CLP) mouse model was constructed in knockout (KO) mice and wild-type (WT) mice to explore whether the screened genes regulate macrophage M1 polarization in septic ARDS in vivo. ChIP-seq and further experiments on BMDMs were performed to investigate the molecular mechanism. RESULTS: The bioinformatics analysis of gene expression profiles from a clinical cohort of 26 ARDS patients and macrophage polarization found that the 5 hub genes (IFIH1, IRF1, STAT1, IFIT3, GBP1) may have a synergistic effect on macrophage M1 polarization in septic ARDS. Further in vivo investigations indicated that IFIH1, STAT1 and IRF1 contribute to macrophage M1 polarization. The histological evaluation and immunohistochemistry of the lungs from the IRF1(-/-) and WT mice indicated that knockout of IRF1 markedly alleviated CLP-induced lung injury and M1-polarized infiltration. Moreover, the molecular mechanism investigations indicated that knockdown of IFIH1 markedly promoted IRF1 translocation into the nucleus. Knockout of IRF1 significantly decreases the expression of STAT1. ChIP-seq and PCR further confirmed that IRF1, as a transcription factor of STAT1, binds to the promoter region of STAT1. CONCLUSION: IRF1 was identified as the key molecule that regulates macrophage M1polarization and septic ARDS development in vivo and in vitro. Moreover, as the adaptor in response to infection mimics irritants, IFIH1 promotes IRF1 (transcription factor) translocation into the nucleus to initiate STAT1 transcription. CI - Copyright (c) 2022 Elsevier B.V. All rights reserved. FAU - Wang, Ailing AU - Wang A AD - Department of Pulmonary and Critical Care Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Department of Ultrasound, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China. Electronic address: 1176432054@qq.com. FAU - Kang, Xueli AU - Kang X AD - Department of Pulmonary and Critical Care Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China. Electronic address: kangxueli1118@163.com. FAU - Wang, Jing AU - Wang J AD - Department of Pulmonary and Critical Care Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China. Electronic address: wj891927@126.com. FAU - Zhang, Shi AU - Zhang S AD - Department of Pulmonary and Critical Care Medicine, Central Hospital Affiliated to Shandong First Medical University, Jinan, Shandong, China; Jiangsu Provincial Key Laboratory of Critical Care Medicine, Department of Critical Care Medicine, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China. Electronic address: 394873967@qq.com. LA - eng PT - Journal Article DEP - 20221130 PL - Netherlands TA - Int Immunopharmacol JT - International immunopharmacology JID - 100965259 RN - EC 3.6.4.13 (Interferon-Induced Helicase, IFIH1) RN - 0 (Stat1 protein, mouse) RN - 0 (STAT1 Transcription Factor) SB - IM MH - Animals MH - Mice MH - *Lung Injury/metabolism MH - Interferon-Induced Helicase, IFIH1/metabolism MH - Mice, Knockout MH - Macrophages MH - *Respiratory Distress Syndrome/metabolism MH - *Sepsis/genetics/metabolism MH - Mice, Inbred C57BL MH - STAT1 Transcription Factor/genetics/metabolism PMC - PMC9709523 OTO - NOTNLM OT - ARDS OT - IFIH1 OT - IRF1 OT - STAT1 OT - macrophage M1 polarization COIS- Declaration of Competing Interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper. EDAT- 2022/12/04 06:00 MHDA- 2023/01/06 06:00 PMCR- 2022/11/30 CRDT- 2022/12/03 18:19 PHST- 2022/09/24 00:00 [received] PHST- 2022/11/12 00:00 [revised] PHST- 2022/11/16 00:00 [accepted] PHST- 2022/12/04 06:00 [pubmed] PHST- 2023/01/06 06:00 [medline] PHST- 2022/12/03 18:19 [entrez] PHST- 2022/11/30 00:00 [pmc-release] AID - S1567-5769(22)00963-8 [pii] AID - 109478 [pii] AID - 10.1016/j.intimp.2022.109478 [doi] PST - ppublish SO - Int Immunopharmacol. 2023 Jan;114:109478. doi: 10.1016/j.intimp.2022.109478. Epub 2022 Nov 30.