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ER Stress is Involved in Mast Cells Degranulation via IRE1α/miR-125/Lyn Pathway in an Experimental Intracerebral Hemorrhage Mouse Model

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Abstract

The degranulation of mast cells accounts for the development of neuroinflammation following intracerebral hemorrhage (ICH). Inhibition of IRE1α, a sensor signaling protein related to endoplasmic reticulum stress, has been shown to exert anti-inflammatory effects in several neurological diseases. The objective of this study was to investigate the effects of IRE1α inhibition on mast cells degranulation in an ICH mouse model and to explore the contribution of miR-125/Lyn pathway in IRE1α-mediated mast cells degranulation. Male mice were subjected to ICH by intraparenchymal injection of autologous blood. STF083010, an inhibitor of IRE1α, was administered intranasally at 1 h after ICH induction. AntimiR-125 was delivered by intracerebroventricular (i.c.v.) injection prior to ICH induction to elucidate the possible mechanisms. Western blot analysis, immunofluorescence staining, neurological test, hematoma volume, brain water content, toluidine blue staining and reverse transcription quantitative real-time polymerase chain reaction (RT-qPCR) were performed. Endogenous phosphorylated IRE1α (p-IRE1α), tryptase, interleukin-17A (IL-17A), tumor necrosis factor α (TNF-α) and tryptase mRNA were increased in time dependent manner while miR-125b-2-3p was decreased after ICH. Inhibition of IRE1α, with STF083010, remarkably reduced brain water content, improved neurological function, decreased hematoma volume, upregulated the expression of miR-125b-2-3p, decreased the number of mast cells, and downregulated the protein expression of Lyn kinase, XBP1s (spliced X-box binding protein-1), tryptase, IL-17A and TNF-α. The downregulation of Lyn kinase, tryptase, IL-17A, TNF-α, and decreased mast cells number were reversed by antimiR-125. The present findings demonstrate that IRE1α inhibition attenuates mast cells degranulation and neuroinflammation, at least partially, through IRE1α/miR-125/Lyn signaling pathway after ICH.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (NSFC 81601051, NSFC 82171457).

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  1. Zhengyu Yang and Juan Huang have contributed equally to this work.

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  1. Department of Anatomy & Institute of Neuroscience, Basic Medical College, Chongqing Medical University, Chongqing, 400016, China

    Zhengyu Yang, Juan Huang, Yuhui Liao, Shengwei Gan, Shujuan Zhu, Shiye Xu, Yue Shu & Weitian Lu

  2. Institute of Neuroscience, Basic Medical College, Chongqing Medical University, Chongqing, China

    Zhengyu Yang, Juan Huang, Yuhui Liao, Shengwei Gan, Shujuan Zhu, Shiye Xu, Yue Shu & Weitian Lu

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Yang, Z., Huang, J., Liao, Y. et al. ER Stress is Involved in Mast Cells Degranulation via IRE1α/miR-125/Lyn Pathway in an Experimental Intracerebral Hemorrhage Mouse Model. Neurochem Res 47, 1598–1609 (2022). https://doi.org/10.1007/s11064-022-03555-7

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