The m6A reader YTHDF2 alleviates the inflammatory response by inhibiting IL-6R/JAK2/STAT1 pathway-mediated high-mobility group box-1 release
- Burns & Trauma Vol. 11, Issue 1, (2023)
- 作者机构：
Institute of Burn Research, State Key Laboratory of Trauma, Burns and Combined Injury, Southwest Hospital, Army Medical University (Third Military Medical University)
- 作者简介：
- 基金信息：
DOI：10.1093/burnst/tkad023
CLC：Published：2023，
Published Online：15 October 2023，
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Zhuo Zeng, Yingying Lan, Lijuan Zhang, Yu Chen, Yali Gong, Fangqing Zuo, Junda Li, Gaoxing Luo, Yizhi Peng, Zhiqiang Yuan, The m6A reader YTHDF2 alleviates the inflammatory response by inhibiting IL-6R/JAK2/STAT1 pathway-mediated high-mobility group box-1 release, Burns & Trauma, Volume 11, 2023, tkad023, https://doi.org/10.1093/burnst/tkad023
Zhuo Zeng, Yingying Lan, Lijuan Zhang, Yu Chen, Yali Gong, Fangqing Zuo, Junda Li, Gaoxing Luo, Yizhi Peng, Zhiqiang Yuan, The m6A reader YTHDF2 alleviates the inflammatory response by inhibiting IL-6R/JAK2/STAT1 pathway-mediated high-mobility group box-1 release, Burns & Trauma, Volume 11, 2023, tkad023, https://doi.org/10.1093/burnst/tkad023 DOI：
摘要
Abstract
BackgroundSepsis is a common severe complication in major burn victims and is characterized by a dysregulated systemic response to inflammation. YTH domain family 2 (YTHDF2)
a well-studied N6-methyladenosine (m6A) reader that specifically recognizes and binds to m6A-modified transcripts to mediate their degradation
is connected to pathogenic and physiological processes in eukaryotes
but its effect on sepsis is still unknown. We aimed to discover the effects and mechanisms of YTHDF2 in sepsis.MethodsQuantitative reverse transcription-polymerase chain reaction (qRT-PCR) and western blot analyses were used to measure the expression of YTHDF2
the interleukin 6 receptor (IL-6R)
high-mobility group box-1 (HMGB1)
Janus kinase 2 (JAK2) and signal transducer and activator of transcription 1 (STAT1) under different in vitro conditions. Enzyme-linked immunosorbent assays were utilized to evaluate the expression of HMGB1
IL-6
IL-1β and tumor necrosis factor-α. To confirm that YTHDF2 specifically targets IL-6R mRNA
RNA immunoprecipitation and dual-luciferase reporter assays were performed. Finally
we utilized a mouse model of lipopolysaccharide (LPS)-induced sepsis to verify the effects of YTHDF2 in vivo.ResultsAccording to our findings
YTHDF2 was expressed at a low level in peripheral blood mononuclear cells from septic mice and patients as well as in LPS-induced RAW264.7 cells. Overexpression of YTHDF2 alleviated the inflammatory response by inhibiting HMGB1 release and JAK2/STAT1 signalling in LPS-stimulated cells. Mechanistically
YTHDF2 suppressed JAK2/STAT1 signalling by directly recognizing the m6A-modified site in IL-6R and decreasing the stability of IL-6R mRNA
thereby inhibiting HMGB1 release. In vivo experiments showed that YTHDF2 played a protective role in septic mice by suppressing the IL-6R/JAK2/STAT1/HMGB1 axis.ConclusionsIn summary
these findings demonstrate that YTHDF2 plays an essential role as an inhibitor of inflammation to reduce the release of HMGB1 by inhibiting the IL-6R/JAK2/STAT1 pathway
indicating that YTHDF2 is a novel target for therapeutic interventions in sepsis.
关键词
Keywords
YTH domain family 2high-mobility group box-1interleukin 6 receptorJanus kinase 2signal transducer and activator of transcription 1InflammationSepsis
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