The m6A reader YTHDF2 alleviates the inflammatory response by inhibiting IL-6R/JAK2/STAT1 pathway-mediated high-mobility group box-1 release

Zhuo Zeng; Yingying Lan; Lijuan Zhang; Yu Chen; Yali Gong; Fangqing Zuo; Junda Li; Gaoxing Luo; Yizhi Peng; Zhiqiang Yuan

doi:10.1093/burnst/tkad023

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The m6A reader YTHDF2 alleviates the inflammatory response by inhibiting IL-6R/JAK2/STAT1 pathway-mediated high-mobility group box-1 release

更新时间：2024-02-04

- The m6A reader YTHDF2 alleviates the inflammatory response by inhibiting IL-6R/JAK2/STAT1 pathway-mediated high-mobility group box-1 release
- The m6A reader YTHDF2 alleviates the inflammatory response by inhibiting IL-6R/JAK2/STAT1 pathway-mediated high-mobility group box-1 release
- Burns & Trauma 2023年11卷第1期
- 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：
  
  The National Natural Science Foundation of China (82072171 and 81873935) provided funding for this work.
- DOI：10.1093/burnst/tkad023
  中图分类号：
- 纸质出版日期：2023，
  
  网络出版日期：2023-10-15，
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Zhuo Zeng, Yingying Lan, Lijuan Zhang, 等. The m6A reader YTHDF2 alleviates the inflammatory response by inhibiting IL-6R/JAK2/STAT1 pathway-mediated high-mobility group box-1 release[J]. Burns & Trauma, 2023,11(1).

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, 等. The m6A reader YTHDF2 alleviates the inflammatory response by inhibiting IL-6R/JAK2/STAT1 pathway-mediated high-mobility group box-1 release[J]. Burns & Trauma, 2023,11(1). DOI： 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

references

1.Cecconi M, Evans L, Levy M, Rhodes A. Sepsis and septic shock. Lancet. 2018;39210141.1474-547X 75-87:75–87. https://doi.org/10.1016/S0140-6736(18)30696-2.

2.Zhang P, Zou B, Liou Y-C, Huang C. The pathogenesis and diagnosis of sepsis post burn injury. Burns Trauma. 2021;9:tkaa047. https://doi.org/10.1093/burnst/tkaa047.

3.Song C, Zhang Y, Pei Q, Zheng L, Wang M, Shi Y, et al. HSP70 alleviates sepsis-induced cardiomyopathy by attenuating mitochondrial dysfunction-initiated NLRP3 inflammasome-mediated pyroptosis in cardiomyocytes. Burns. Trauma. 2022;10:tkac043. https://doi.org/10.1093/burnst/tkac043.

4.Reinhart K, Daniels R, Kissoon N, Machado FR, Schachter RD, Finfer S. Recognizing sepsis as a Global Health priority - a WHO resolution. N Engl J Med. 2017;377:414–7. https://doi.org/10.1056/NEJMp1707170.

5.Zhao BS, Roundtree IA, He C. Post-transcriptional gene regulation by mRNA modifications. Nat Rev Mol Cell Biol. 2017;18:31–42. https://doi.org/10.1038/nrm.2016.132.

6.Jiang X, Liu B, Nie Z, Duan L, Xiong Q, Jin Z, et al. The role of m6A modification in the biological functions and diseases. Signal Transduct Target Ther. 2021;6:74. https://doi.org/10.1038/s41392-020-00450-x.

7.Wang X, Lu Z, Gomez A, Hon GC, Yue Y, Han D, et al. N6-methyladenosine-dependent regulation of messenger RNA stability. Nature. 2014;505:117–20. https://doi.org/10.1038/nature12730.

8.Wang Y, Li Y, Toth JI, Petroski MD, Zhang Z, Zhao JC. N6-methyladenosine modification destabilizes developmental regulators in embryonic stem cells. Nat Cell Biol. 2014;16:191–8. https://doi.org/10.1038/ncb2902.

9.Zaccara S, Ries RJ, Jaffrey SR. Reading, writing and erasing mRNA methylation. Nat Rev Mol Cell Biol. 2019;20:608–24. https://doi.org/10.1038/s41580-019-0168-5.

10.Zhu T, Roundtree IA, Wang P, Wang X, Wang L, Sun C, et al. Crystal structure of the YTH domain of YTHDF2 reveals mechanism for recognition of N6-methyladenosine. Cell Res. 2014;24:1493–6. https://doi.org/10.1038/cr.2014.152.

11.Fang R, Chen X, Zhang S, Shi H, Ye Y, Shi H, et al. EGFR/SRC/ERK-stabilized YTHDF2 promotes cholesterol dysregulation and invasive growth of glioblastoma. Nat Commun. 2021;12:177. https://doi.org/10.1038/s41467-020-20379-7.

12.Einstein JM, Perelis M, Chaim IA, Meena JK, Nussbacher JK, Tankka AT, et al. Inhibition of YTHDF2 triggers proteotoxic cell death in MYC-driven breast cancer. Mol Cell. 2021;81:3048–3064.e9. https://doi.org/10.1016/j.molcel.2021.06.014.

13.Li J, Xie H, Ying Y, Chen H, Yan H, He L, et al. YTHDF2 mediates the mRNA degradation of the tumor suppressors to induce AKT phosphorylation in N6-methyladenosine-dependent way in prostate cancer. Mol Cancer. 2020;19:152. https://doi.org/10.1186/s12943-020-01267-6.

14.Yu R, Li Q, Feng Z, Cai L, Xu Q. m6A reader YTHDF2 regulates LPS-induced inflammatory response. Int J Mol Sci. 2019;20:1323. https://doi.org/10.3390/ijms20061323.

15.Xue J, Suarez JS, Minaai M, Li S, Gaudino G, Pass HI, et al. HMGB1 as a therapeutic target in disease. J Cell Physiol. 2021;236:3406–19. https://doi.org/10.1002/jcp.30125.

16.Lu B, Antoine DJ, Kwan K, Lundbäck P, Wähämaa H, Schierbeck H, et al. JAK/STAT1 signaling promotes HMGB1 hyperacetylation and nuclear translocation. Proc Natl Acad Sci U S A. 2014;111:3068–73. https://doi.org/10.1073/pnas.1316925111.

17.Liu Q, Xie W, Wang Y, Chen S, Han J, Wang L, et al. JAK2/STAT1-mediated HMGB1 translocation increases inflammation and cell death in a ventilator-induced lung injury model. Lab Investig. 2019;99:1810–21. https://doi.org/10.1038/s41374-019-0308-8.

18.Heinrich PC, Behrmann I, Müller-Newen G, Schaper F, Graeve L. Interleukin-6-type cytokine signalling through the gp130/Jak/STAT pathway. Biochem J. 1998;334:297–314.

19.Palumbo S, Shin Y-J, Ahmad K, Desai AA, Quijada H, Mohamed M, et al. Dysregulated Nox4 ubiquitination contributes to redox imbalance and age-related severity of acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2017;312:L297–308. https://doi.org/10.1152/ajplung.00305.2016.

20.Huang W, Tang Y, Li L. HMGB1, a potent proinflammatory cytokine in sepsis. Cytokine. 2010;51:119–26. https://doi.org/10.1016/j.cyto.2010.02.021.

21.Denning N-L, Aziz M, Gurien SD, Wang P. DAMPs and NETs in sepsis. Front Immunol. 2019;10:2536. https://doi.org/10.3389/fimmu.2019.02536.

22.Liu H, Yao Y-M, Yu Y, Dong N, Yin H-N, Sheng Z-Y. Role of Janus kinase/signal transducer and activator of transcription pathway in regulation of expression and inflammation-promoting activity of high mobility group box protein 1 in rat peritoneal macrophages. Shock. 2007;27:55–60.

23.Tsoyi K, Nizamutdinova IT, Jang HJ, Mun L, Kim HJ, Seo HG, et al. Carbon monoxide from CORM-2 reduces HMGB1 release through regulation of IFN-β/JAK2/STAT-1/INOS/NO signaling but not COX-2 in TLR-activated macrophages. Shock. 2010;34:608–14. https://doi.org/10.1097/SHK.0b013e3181e46f15.

24.Luo X, Li H, Liang J, Zhao Q, Xie Y, Ren J, et al. RMVar: an updated database of functional variants involved in RNA modifications. Nucleic Acids Res. 2021;49:D1405–12. https://doi.org/10.1093/nar/gkaa811.

25.Hou J, Zhang H, Liu J, Zhao Z, Wang J, Lu Z, et al. YTHDF2 reduction fuels inflammation and vascular abnormalization in hepatocellular carcinoma. Mol Cancer. 2019;18:163. https://doi.org/10.1186/s12943-019-1082-3.

26.Hesser CR, Karijolich J, Dominissini D, He C, Glaunsinger BA. N6-methyladenosine modification and the YTHDF2 reader protein play cell type specific roles in lytic viral gene expression during Kaposi's sarcoma-associated herpesvirus infection. PLoS Pathog. 2018;14:e1006995. https://doi.org/10.1371/journal.ppat.1006995.

27.Schwartz S, Mumbach MR, Jovanovic M, Wang T, Maciag K, Bushkin GG, et al. Perturbation of m6A writers reveals two distinct classes of mRNA methylation at internal and 5′ sites. Cell Rep. 2014;8:284–96. https://doi.org/10.1016/j.celrep.2014.05.048.

28.Du H, Zhao Y, He J, Zhang Y, Xi H, Liu M, et al. YTHDF2 destabilizes m(6)A-containing RNA through direct recruitment of the CCR4-NOT deadenylase complex. Nat Commun. 2016;7:12626. https://doi.org/10.1038/ncomms12626.

29.Pan Z, Zhang Q, Liu X, Zhou H, Jin T, Hao L-Y, et al. Methyltransferase-like 3 contributes to inflammatory pain by targeting TET1 in YTHDF2-dependent manner. Pain. 2021;162:1960–76. https://doi.org/10.1097/j.pain.0000000000002218.

30.Wu C, Chen W, He J, Jin S, Liu Y, Yi Y, et al. Interplay of mA and H3K27 trimethylation restrains inflammation during bacterial infection. Sci Adv. 2020;6:eaba0647. https://doi.org/10.1126/sciadv.aba0647.

31.Karlsson S, Pettilä V, Tenhunen J, Laru-Sompa R, Hynninen M, Ruokonen E. HMGB1 as a predictor of organ dysfunction and outcome in patients with severe sepsis. Intensive Care Med. 2008;34:1046–53. https://doi.org/10.1007/s00134-008-1032-9.

32.Sundén-Cullberg J, Norrby-Teglund A, Rouhiainen A, Rauvala H, Herman G, Tracey KJ, et al. Persistent elevation of high mobility group box-1 protein (HMGB1) in patients with severe sepsis and septic shock. Crit Care Med. 2005;33:564–73.

33.Abdulmahdi W, Patel D, Rabadi MM, Azar T, Jules E, Lipphardt M, et al. HMGB1 redox during sepsis. Redox Biol. 2017;13:600–7. https://doi.org/10.1016/j.redox.2017.08.001.

34.Deng C, Zhao L, Yang Z, Shang J-J, Wang C-Y, Shen M-Z, et al. Targeting HMGB1 for the treatment of sepsis and sepsis-induced organ injury. Acta Pharmacol Sin. 2022;43:520–8. https://doi.org/10.1038/s41401-021-00676-7.

35.Zeng Z, Lan Y, Chen Y, Zuo F, Gong Y, Luo G, et al. LncRNA GAS5 suppresses inflammatory responses by inhibiting HMGB1 release via miR-155-5p/SIRT1 axis in sepsis. Eur J Pharmacol. 2023;942:175520. https://doi.org/10.1016/j.ejphar.2023.175520.

36.Chen G, Zhao Q, Yuan B, Wang B, Zhang Y, Li Z, et al. ALKBH5-modified HMGB1-STING activation contributes to radiation induced liver disease via innate immune response. Int J Radiat Oncol Biol Phys. 2021;111:491–501. https://doi.org/10.1016/j.ijrobp.2021.05.115.

37.Gong L, Manaenko A, Fan R, Huang L, Enkhjargal B, McBride D, et al. Osteopontin attenuates inflammation via JAK2/STAT1 pathway in hyperglycemic rats after intracerebral hemorrhage. Neuropharmacology. 2018;138:160–9. https://doi.org/10.1016/j.neuropharm.2018.06.009.

38.Ge X, Meng Q, Wei L, Liu J, Li M, Liang X, et al. Myocardial ischemia-reperfusion induced cardiac extracellular vesicles harbour proinflammatory features and aggravate heart injury. J Extracell Vesicles. 2021;10:e12072. https://doi.org/10.1002/jev2.12072.

39.Cai B, Cai J-p, Luo Y-l, Chen C, Zhang S. The specific roles of JAK/STAT Signaling pathway in sepsis. Inflammation. 2015;38:1599–608. https://doi.org/10.1007/s10753-015-0135-z.

40.Xue Z, Zhao F, Sang X, Qiao Y, Shao R, Wang Y, et al. Combination therapy of tanshinone IIA and puerarin for pulmonary fibrosis via targeting IL6-JAK2-STAT3/STAT1 signaling pathways. Phytother Res. 2021;35:5883–98. https://doi.org/10.1002/ptr.7253.

41.Patel RT, Deen KI, Youngs D, Warwick J, Keighley MR. Interleukin 6 is a prognostic indicator of outcome in severe intra-abdominal sepsis. Br J Surg. 1994;81:1337–08.

42.Song J, Park DW, Moon S, Cho H-J, Park JH, Seok H, et al. Diagnostic and prognostic value of interleukin-6, pentraxin 3, and procalcitonin levels among sepsis and septic shock patients: a prospective controlled study according to the Sepsis-3 definitions. BMC Infect Dis. 2019;19:968. https://doi.org/10.1186/s12879-019-4618-7.

43.Barak V, Schwartz A, Kalickman I, Nisman B, Gurman G, Shoenfeld Y. Prevalence of hypophosphatemia in sepsis and infection: the role of cytokines. Am J Med. 1998;104:40–7.

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