Sustained induction of IP-10 by MRP8/14 via the IFNβ–IRF7 axis in macrophages exaggerates lung injury in endotoxemic mice
- Burns & Trauma Vol. 11, Issue 1, (2023)
- 作者机构：
Southern Medical University
- 作者简介：
- 基金信息：
DOI：10.1093/burnst/tkad006
CLC：Published：2023，
Published Online：11 September 2023，
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Juan Wang, Guiming Chen, Lei Li, Sidan Luo, Bingrong Hu, Jia Xu, Haihua Luo, Shan Li, Yong Jiang, Sustained induction of IP-10 by MRP8/14 via the IFNβ–IRF7 axis in macrophages exaggerates lung injury in endotoxemic mice, Burns & Trauma, Volume 11, 2023, tkad006, https://doi.org/10.1093/burnst/tkad006
Juan Wang, Guiming Chen, Lei Li, Sidan Luo, Bingrong Hu, Jia Xu, Haihua Luo, Shan Li, Yong Jiang, Sustained induction of IP-10 by MRP8/14 via the IFNβ–IRF7 axis in macrophages exaggerates lung injury in endotoxemic mice, Burns & Trauma, Volume 11, 2023, tkad006, https://doi.org/10.1093/burnst/tkad006 DOI：
摘要
Abstract
BackgroundAs a damage-associated molecular pattern
the myeloid-related protein 8/14 (MRP8/14) heterodimer mediates various inflammatory diseases
such as sepsis. However
how MRP8/14 promotes lung injury by regulating the inflammatory response during endotoxemia remains largely unknown. This study aims at illuminating the pathological functions of MRP8/14 in endotoxemia.MethodsAn endotoxemic model was prepared with wild-type and myeloid cell-specific Mrp8 deletion (Mrp8ΔMC) mice for evaluating plasma cytokine levels. Lung injury was evaluated by hematoxylin and eosin (H&E) staining
injury scoring and wet-to-dry weight (W/D) ratio. The dynamic profile of interferon γ (IFNγ)-inducible protein 10 (IP-10) mRNA expression induced by macrophage MRP8/14 was determined by quantitative real-time polymerase chain reaction (qPCR). Immunoblotting was used to evaluate the increase in IP-10 level induced by activation of the JAK–STAT signaling pathway. Luciferase reporter assay was performed to detect the involvement of IRF7 in Ip-10 gene transcription. In vivo air pouch experiments were performed to determine the biological function of IP-10 induced by MRP8/14.ResultsExperiments with Mrp8ΔMC mice showed that MRP8/14 promoted the production of cytokines
including IP-10
in the bronchoalveolar lavage fluid (BALF) and lung injury in endotoxic mice. The result of qPCR showed sustained expression of Ip-10 mRNA in macrophages after treatment with MRP8/14 for 12 h. Neutralization experiments showed that the MRP8/14-induced Ip-10 expression in RAW264.7 cells was mediated by extracellular IFNβ. Western blotting with phosphorylation-specific antibodies showed that the JAK1/TYK2-STAT1 signaling pathway was activated in MRP8/14-treated RAW264.7 cells
leading to the upregulation of Ip-10 gene expression. IRF7 was further identified as a downstream regulator of the JAK–STAT pathway that mediated Ip-10 gene expression in macrophages treated with MRP8/14. In vivo air pouch experiments confirmed that the IFNβ-JAK1/TYK2-STAT1-IRF7 pathway was required for chemokine (C-X-C motif) receptor 3 (CXCR3)+ T lymphocyte migration
which promoted lung injury in the context of endotoxemia.ConclusionsIn summary
our study demonstrates that MRP8/14 induces sustained production of IP-10 via the IFNβ-JAK1/TYK2-STAT1-IRF7 pathway to attract CXCR3+ T lymphocytes into lung tissues and ultimately results in lung injury by an excessive inflammatory response in the context of endotoxemia.
关键词
Keywords
EndotoxemiaInterferon-inducible protein 10Interferon betaMacrophageMyeloid-related protein 8/14Interferon regulatory factor-7
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