4.8 Article

Extracellular CIRP Induces Macrophage Extracellular Trap Formation Via Gasdermin D Activation

期刊

FRONTIERS IN IMMUNOLOGY
卷 12, 期 -, 页码 -

出版社

FRONTIERS MEDIA SA
DOI: 10.3389/fimmu.2021.780210

关键词

eCIRP; macrophages; extracellular traps; METs; gasdermin D; caspase-1; MPO

资金

  1. National Institutes of Health (NIH) [R35GM118337, U01AI133655, R01GM129633]

向作者/读者索取更多资源

Extracellular cold-inducible RNA-binding protein (eCIRP) promotes inflammation and tissue injury by inducing formation of macrophage extracellular traps (METs) via activation of Gasdermin D (GSDMD) and caspase-1. This study demonstrates that eCIRP serves as a novel inducer of MET formation through GSDMD and caspase-1 activation, providing insights into its role in inflammation and tissue damage.
Extracellular cold-inducible RNA-binding protein (eCIRP) is a damage-associated molecular pattern promoting inflammation and tissue injury. During bacterial or viral infection, macrophages release DNA decorated with nuclear and cytoplasmic proteins known as macrophage extracellular traps (METs). Gasdermin D (GSDMD) is a pore-forming protein that has been involved in extracellular trap formation in neutrophils. We hypothesized that eCIRP induces MET formation by activating GSDMD. Human monocytic cell line THP-1 cells were differentiated with phorbol 12-myristate 13-acetate (PMA) and treated with recombinant murine (rm) CIRP. The MET formation was detected by three methods: time-lapse fluorescence microscopy (video imaging), colorimetry, and ELISA. Cleaved forms of GSDMD, and caspase-1 were detected by Western blotting. Treatment of THP-1 cells with rmCIRP increased MET formation as revealed by SYTOX Orange Staining assay in a time- and dose-dependent manner. METs formed by rmCIRP stimulation were further confirmed by extracellular DNA, citrullinated histone H3, and myeloperoxidase. Treatment of THP-1 cells with rmCIRP significantly increased the cleaved forms of caspase-1 and GSDMD compared to PBS-treated cells. Treatment of macrophages with caspase-1, and GSDMD inhibitors z-VAD-fmk, and disulfiram, separately, significantly decreased rmCIRP-induced MET formation. We also confirmed rmCIRP-induced MET formation using primary cells murine peritoneal macrophages. These data clearly show that eCIRP serves as a novel inducer of MET formation through the activation of GSDMD and caspase-1.

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