Skip to main content

Advertisement

SpringerLink
Log in

High Expression of miR-6785-5p in the Serum Exosomes of Psoriasis Patients Alleviates Psoriasis-Like Skin Damage by Interfering with the MNK2/p-eIF4E Axis in Keratinocytes

  • RESEARCH
  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

Psoriasis is a chronic inflammatory skin disease characterized by abnormal keratinocyte proliferation and inflammation. MiRNAs and serum exosomes participate in the pathogenesis of many diseases. The objective of this study is to explore the function of miR-6785-5p in psoriatic keratinocytes and its upstream and downstream mechanisms. For our study, we employed qRT-PCR and fluorescence in situ hybridization to evaluate miR-6785-5p in psoriatic keratinocytes and conducted a microRNA microarray for identifying differentially expressed miRNAs in patient serum exosomes. We then cocultured keratinocytes with these exosomes, using immunofluorescence staining and qRT-PCR to assess uptake and miR-6785-5p overexpression. We explored miR-6785-5p’s role through transfection with specific mimics and inhibitors and confirmed MNK2 as its target using a luciferase assay. MNK2’s function was further examined using siRNA technology. Lastly, we applied an imiquimod-induced psoriasis mouse model, also employing siRNA, to investigate MNK2’s role in psoriasis. MiR-6785-5p demonstrates a notable overexpression in the keratinocytes of psoriasis patients as well as in their serum exosomes. These keratinocytes actively uptake the miR-6785-5p-enriched serum exosomes. Functionally, miR-6785-5p appears to alleviate psoriasis-like skin damage, observable both in vitro and in vivo, by downregulating MNK2 expression. Psoriasis keratinocytes uptake serum exosomes highly expressing miR-6785-5p. MiR-6785-5p inhibits the abnormal proliferation and inflammatory state of keratinocytes by reducing MNK2 expression and interfering with the MNK2/p-eIF4E axis.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data Availability

The data used to support the findings of this study are available from the corresponding author upon request.

References

  1. Griffiths, C.E.M., A.W. Armstrong, J.E. Gudjonsson, and J.N.W.N. Barker. 2021. Psoriasis. Lancet. 397 (10281): 1301–1315. https://doi.org/10.1016/S0140-6736(20)32549-6.

    Article  CAS  PubMed  Google Scholar 

  2. Griffiths, C.E., and J.N. Barker. 2007. Pathogenesis and clinical features of psoriasis. Lancet 370 (9583): 263–271. https://doi.org/10.1016/S0140-6736(07)61128-3.

    Article  CAS  PubMed  Google Scholar 

  3. Zhou, X., Y. Chen, L. Cui, Y. Shi, and C. Guo. 2022. Advances in the pathogenesis of psoriasis: From keratinocyte perspective. Cell Death & Disease 13 (1): 81. https://doi.org/10.1038/s41419-022-04523-3.

    Article  CAS  Google Scholar 

  4. Lu, T.X., and M.E. Rothenberg. 2018. MicroRNA. The Journal of Allergy and Clinical Immunology 141 (4): 1202–1207. https://doi.org/10.1016/j.jaci.2017.08.034.

    Article  CAS  PubMed  Google Scholar 

  5. Fabian, M.R., and N. Sonenberg. 2012. The mechanics of miRNA-mediated gene silencing: A look under the hood of miRISC. Nature Structural & Molecular Biology 19 (6): 586–593. https://doi.org/10.1038/nsmb.2296.

    Article  CAS  Google Scholar 

  6. Srivastava, A., L. Luo, W. Lohcharoenkal, et al. 2021. Cross-talk between IFN-γ and TWEAK through miR-149 amplifies skin inflammation in psoriasis. The Journal of Allergy and Clinical Immunology 147 (6): 2225–2235. https://doi.org/10.1016/j.jaci.2020.12.657.

    Article  CAS  PubMed  Google Scholar 

  7. Wu, R., J. Zeng, J. Yuan, et al. 2018. MicroRNA-210 overexpression promotes psoriasis-like inflammation by inducing Th1 and Th17 cell differentiation. The Journal of Clinical Investigation 128 (6): 2551–2568. https://doi.org/10.1172/JCI97426.

    Article  PubMed  PubMed Central  Google Scholar 

  8. Huang, C., W. Zhong, X. Ren, et al. 2021. MiR-193b-3p-ERBB4 axis regulates psoriasis pathogenesis via modulating cellular proliferation and inflammatory-mediator production of keratinocytes. Cell Death & Disease 12 (11): 963. https://doi.org/10.1038/s41419-021-04230-5.

    Article  CAS  Google Scholar 

  9. Chakraborty, C., A.R. Sharma, G. Sharma, and S.S. Lee. 2020. Therapeutic advances of miRNAs: A preclinical and clinical update. Journal of Advanced Research 28: 127–138. https://doi.org/10.1016/j.jare.2020.08.012.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Kalluri, R., and V.S. LeBleu. 2020. The biology, function, and biomedical applications of exosomes. Science 367 (eaau6478): 6977. https://doi.org/10.1126/science.aau6977.

    Article  CAS  Google Scholar 

  11. Yang, D., W. Zhang, H. Zhang, et al. 2020. Progress, opportunity, and perspective on exosome isolation - efforts for efficient exosome-based theranostics. Theranostics. 10 (8): 3684–3707. https://doi.org/10.7150/thno.41580.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Tenchov, R., J.M. Sasso, X. Wang, W.S. Liaw, C.A. Chen, and Q.A. Zhou. 2022. Exosomes─nature’s lipid nanoparticles, a rising star in drug delivery and diagnostics. ACS Nano 16 (11): 17802–17846. https://doi.org/10.1021/acsnano.2c08774.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Jiang, M., H. Fang, S. Shao, et al. 2019. Keratinocyte exosomes activate neutrophils and enhance skin inflammation in psoriasis. The FASEB Journal 33 (12): 13241–13253. https://doi.org/10.1096/fj.201900642R.

    Article  CAS  PubMed  Google Scholar 

  14. Shao, S., H. Fang, J. Zhang, et al. 2019. Neutrophil exosomes enhance the skin autoinflammation in generalized pustular psoriasis via activating keratinocytes. The FASEB Journal 33 (6): 6813–6828. https://doi.org/10.1096/fj.201802090RR.

    Article  CAS  PubMed  Google Scholar 

  15. Zhang, B., R.C. Lai, W.K. Sim, A.B.H. Choo, E.B. Lane, and S.K. Lim. 2021. Topical application of mesenchymal stem cell exosomes alleviates the imiquimod induced psoriasis-like inflammation. International Journal of Molecular Sciences 22 (2): 720. https://doi.org/10.3390/ijms22020720.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Jiang, M., H. Fang, E. Dang, et al. 2021. Small extracellular vesicles containing miR-381-3p from keratinocytes promote T helper type 1 and T helper type 17 polarization in psoriasis. The Journal of Investigative Dermatology 141 (3): 563–574. https://doi.org/10.1016/j.jid.2020.07.009.

    Article  CAS  PubMed  Google Scholar 

  17. Alvarez-Erviti, L., Y. Seow, H. Yin, C. Betts, S. Lakhal, and M.J. Wood. 2011. Delivery of siRNA to the mouse brain by systemic injection of targeted exosomes. Nature Biotechnology 29 (4): 341–345. https://doi.org/10.1038/nbt.1807.

    Article  CAS  PubMed  Google Scholar 

  18. Maimon, A., M. Mogilevsky, A. Shilo, et al. 2014. Mnk2 alternative splicing modulates the p38-MAPK pathway and impacts Ras-induced transformation. Cell Reports 7 (2): 501–513. https://doi.org/10.1016/j.celrep.2014.03.041.

    Article  CAS  PubMed  Google Scholar 

  19. Yang, X., W. Zhong, and R. Cao. 2020. Phosphorylation of the mRNA cap-binding protein eIF4E and cancer. Cellular Signalling 73: 109689. https://doi.org/10.1016/j.cellsig.2020.109689.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Piserà, A., A. Campo, and S. Campo. 2018. Structure and functions of the translation initiation factor eIF4E and its role in cancer development and treatment. Journal of Genetics and Genomics 45 (1): 13–24. https://doi.org/10.1016/j.jgg.2018.01.003.

    Article  CAS  PubMed  Google Scholar 

  21. Culjkovic, B., K. Tan, S. Orolicki, A. Amri, S. Meloche, and K.L. Borden. 2008. The eIF4E RNA regulon promotes the Akt signaling pathway. Journal of Cell Biology 181 (1): 51–63. https://doi.org/10.1083/jcb.200707018.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Ueda, T., R. Watanabe-Fukunaga, H. Fukuyama, S. Nagata, and R. Fukunaga. 2004. Mnk2 and Mnk1 are essential for constitutive and inducible phosphorylation of eukaryotic initiation factor 4E but not for cell growth or development. Molecular and Cellular Biology 24 (15): 6539–6549. https://doi.org/10.1128/MCB.24.15.6539-6549.2004.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Xu, W., S. Kannan, C.S. Verma, and K. Nacro. 2022. Update on the development of MNK inhibitors as therapeutic agents. Journal of Medicinal Chemistry 65 (2): 983–1007. https://doi.org/10.1021/acs.jmedchem.1c00368.

    Article  CAS  PubMed  Google Scholar 

  24. Zhu, L., H.T. Sun, S. Wang, et al. 2020. Isolation and characterization of exosomes for cancer research. Journal of Hematology & Oncology 13 (1): 152. https://doi.org/10.1186/s13045-020-00987-y.

    Article  CAS  Google Scholar 

  25. Gao, J., F. Chen, H. Fang, J. Mi, Q. Qi, and M. Yang. 2020. Daphnetin inhibits proliferation and inflammatory response in human HaCaT keratinocytes and ameliorates imiquimod-induced psoriasis-like skin lesion in mice. Biological Research 53 (1): 48. https://doi.org/10.1186/s40659-020-00316-0.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Rabeony, H., I. Petit-Paris, J. Garnier, et al. 2014. Inhibition of keratinocyte differentiation by the synergistic effect of IL-17A, IL-22, IL-1α, TNFα and oncostatin M. PLoS ONE 9 (7): e101937. https://doi.org/10.1371/journal.pone.0101937.

    Article  ADS  PubMed  PubMed Central  Google Scholar 

  27. Varghese, F., A.B. Bukhari, R. Malhotra, and A. De. 2014. IHC Profiler: An open source plugin for the quantitative evaluation and automated scoring of immunohistochemistry images of human tissue samples. PLoS ONE 9 (5): e96801. https://doi.org/10.1371/journal.pone.0096801.

    Article  ADS  CAS  PubMed  PubMed Central  Google Scholar 

  28. Moos, S., A.N. Mohebiany, A. Waisman, and F.C. Kurschus. 2019. Imiquimod-induced psoriasis in mice depends on the IL-17 signaling of keratinocytes. The Journal of Investigative Dermatology 139 (5): 1110–1117. https://doi.org/10.1016/j.jid.2019.01.006.

    Article  CAS  PubMed  Google Scholar 

  29. Korman, N.J. 2020. Management of psoriasis as a systemic disease: What is the evidence? British Journal of Dermatology 182 (4): 840–848. https://doi.org/10.1111/bjd.18245.

    Article  CAS  PubMed  Google Scholar 

  30. Blauvelt, A., and A. Chiricozzi. 2018. The immunologic role of IL-17 in psoriasis and psoriatic arthritis pathogenesis. Clinical Reviews in Allergy and Immunology 55 (3): 379–390. https://doi.org/10.1007/s12016-018-8702-3.

    Article  CAS  PubMed  Google Scholar 

  31. Shuai, Y., Z. Ma, W. Liu, et al. 2020. TEAD4 modulated LncRNA MNX1-AS1 contributes to gastric cancer progression partly through suppressing BTG2 and activating BCL2. Molecular Cancer 19 (1): 6. https://doi.org/10.1186/s12943-019-1104-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Xiong, Y., M. Pang, Y. Du, et al. 2022. The LINC01929/miR-6875-5p/ADAMTS12 axis in the ceRNA network regulates the development of advanced bladder cancer. Frontiers in Oncology 12: 856560. https://doi.org/10.3389/fonc.2022.856560.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Chuang, H.C., M.H. Chen, Y.M. Chen, et al. 2021. BPI overexpression suppresses Treg differentiation and induces exosome-mediated inflammation in systemic lupus erythematosus. Theranostics. 11 (20): 9953–9966. https://doi.org/10.7150/thno.63743.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Zhang, Y., L. Chen, X. Ye, et al. 2021. Expression and mechanism of exosome-mediated A FOXM1 related long noncoding RNA in gastric cancer. J Nanobiotechnology. 19 (1): 133. https://doi.org/10.1186/s12951-021-00873-w.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Wei, X.B., W.Q. Jiang, J.H. Zeng, et al. 2022. Exosome-derived lncRNA NEAT1 exacerbates sepsis-associated encephalopathy by promoting ferroptosis through regulating miR-9-5p/TFRC and GOT1 axis. Molecular Neurobiology 59 (3): 1954–1969. https://doi.org/10.1007/s12035-022-02738-1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Ding, Y., P. Gong, J. Jiang, et al. 2022. Mesenchymal stem/stromal cells primed by inflammatory cytokines alleviate psoriasis-like inflammation via the TSG-6-neutrophil axis. Cell Death & Disease 13 (11): 996. https://doi.org/10.1038/s41419-022-05445-w.

    Article  CAS  Google Scholar 

  37. Xu, Y., S. Liao, L. Wang, et al. 2021. Galeterone sensitizes breast cancer to chemotherapy via targeting MNK/eIF4E and β-catenin. Cancer Chemotherapy and Pharmacology 87 (1): 85–93. https://doi.org/10.1007/s00280-020-04195-w.

    Article  CAS  PubMed  Google Scholar 

  38. Guo, Z., G. Peng, E. Li, et al. 2017. MAP kinase-interacting serine/threonine kinase 2 promotes proliferation, metastasis, and predicts poor prognosis in non-small cell lung cancer. Science and Reports 7 (1): 10612. https://doi.org/10.1038/s41598-017-10397-9.

    Article  ADS  CAS  Google Scholar 

  39. Gao, J., L. Teng, S. Yang, et al. 2021. MNK as a potential pharmacological target for suppressing LPS-induced acute lung injury in mice. Biochemical Pharmacology 186: 114499. https://doi.org/10.1016/j.bcp.2021.114499.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgements

We sincerely thank all patients with psoriasis and healthy controls for participating in this study. And we show our best honour to the experimental mice for their sacrifice.

Funding

This work was funded by the National Natural Science Foundation of China (Grant Numbers: 81972937, 82173419, and 82003344), the Natural Science Foundation of Shandong Province (ZR2023QH333), and the China Postdoctoral Science Foundation (2023M742110).

Author information

Author notes

  1. Ruijie Wang and Yingjian Huang are co-first authors and contributed equally to this work.

  2. Jianjun Yan and Qing Sun are corresponding authors and contributed equally to this work.

Authors and Affiliations

  1. Department of Dermatology, Qilu Hospital, Shandong University, Jinan, Shandong, 250012, China

    Ruijie Wang, Yingjian Huang, Kaixin Shao, Jianjun Yan & Qing Sun

  2. Laboratory of Basic Medical Science, Qilu Hospital, Shandong University, Jinan, Shandong, 250012, China

    Ruijie Wang, Yingjian Huang & Kaixin Shao

Authors
  1. Ruijie Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Yingjian Huang
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Kaixin Shao
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Jianjun Yan
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Qing Sun
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Ruijie Wang first proposed the article topic. Ruijie Wang, Qing Sun, and Jianjun Yan designed the experiments. Ruijie Wang, Yingjian Huang, and Kaixin Shao performed the experiments. Ruijie Wang, Yingjian Huang, and Jianjun Yan analysed the data. The first draft of the manuscript was written by Ruijie Wang, and all the authors commented on previous versions of the manuscript. All the authors read and approved the final manuscript.

Corresponding authors

Correspondence to Jianjun Yan or Qing Sun.

Ethics declarations

Ethics Approval

This work was supported by the Ethics Committee of Shandong University (Ethics Committee No. KYLL-2017(KS)-152) and fulfilled the Declaration of Helsinki Principles.

Consent to Participate

Informed consent was obtained from all individual participants included in the study.

Conflict of Interest

The authors declare no competing interests.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Supplementary Information

Below is the link to the electronic supplementary material.

Supplementary file1 (DOCX 17 KB)

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Wang, R., Huang, Y., Shao, K. et al. High Expression of miR-6785-5p in the Serum Exosomes of Psoriasis Patients Alleviates Psoriasis-Like Skin Damage by Interfering with the MNK2/p-eIF4E Axis in Keratinocytes. Inflammation (2024). https://doi.org/10.1007/s10753-024-01995-7

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • DOI: https://doi.org/10.1007/s10753-024-01995-7

KEY WORDS

Search

Navigation