Skip to main content

Advertisement

SpringerLink
Log in

S14G-humanin (HNG) protects retinal endothelial cells from UV-B-induced NLRP3 inflammation activation through inhibiting Egr-1

  • Original Research Paper
  • Published:
Inflammation Research Aims and scope Submit manuscript

Abstract

UV-B stimulation can induce retinopathy, whose pathogenesis is currently unclear. UV-B mediated inflammation in retinal endothelial cells is reported to be involved in the pathogenesis of retinopathy. S14G-humanin (HNG) is a neuroprotective peptide that has recently been reported to exert significant anti-inflammatory effects and protective properties against cell death. The present study aims to investigate the protective effects of HNG against UV-B-challenged retinal endothelial cells and explore the underlying mechanism. UV-B radiation was used to induce an injury model in human retinal endothelial cells (HRECs). First, exposure to UV-B induced the expression of TXNIP. Additionally, we found that treatment with HNG inhibited the activation of the TXNIP/NLRP3 signaling pathway and mitigated the excessive release of IL-1β and IL-18 in UV-B-challenged HRECs. UV-B increased the expression of the transcriptional factor endothelial growth response-1 (Egr-1). Interestingly, overexpression of Egr-1 increased the luciferase activity of the TXNIP promoter as well as the mRNA and protein expression of TXNIP. In contrast, the knockdown of Egr-1 reduced the expression of TXNIP under both the normal and UV-B exposure conditions. Importantly, treatment with HNG attenuated UV-B-induced expression of Egr-1. However, overexpression of Egr-1 abolished the inhibitory effects of HNG-induced activation of NLRP3 as well as the production of IL-1β and IL-18. Taken together, our findings reveal that HNG protected retinal endothelial cells from UV-B-induced NLRP3 inflammation activation through inhibiting TXNIP mediated by Egr-1.

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
Fig. 7
Fig. 8

Similar content being viewed by others

Data available statement

Data are available at a reasonable request to the corresponding author.

References

  1. Mohania D, Chandel S, Kumar P, Verma V, Digvijay K, Tripathi D, Choudhury K, Mitten SK, Shah D. Ultraviolet radiations: skin defense-damage mechanism. Adv Exp Med Biol. 2017;996:71–87.

    Article  CAS  Google Scholar 

  2. Tratsk KS, Thanos S. UV irradiation causes multiple cellular changes in cultured human retinal pigment epithelium cells. Graefes Arch Clin Exp Ophthalmol. 2003;241(10):852–9.

    Article  Google Scholar 

  3. Norval M, Lucas RM, Cullen AP, de Gruijl FR, Longstreth J, Takizawa Y, van der Leun JC. The human health effects of ozone depletion and interactions with climate change. Photochem Photobiol Sci. 2011;10(2):199–225.

    Article  CAS  Google Scholar 

  4. Steinle JJ. Retinal endothelial cell apoptosis. Apoptosis. 2012;17(12):1258–60.

    Article  CAS  Google Scholar 

  5. Lin H, Yue Y, Maidana DE, Bouzika P, Atik A, Matsumoto H, Miller JW, Vavvas DG. Drug delivery nanoparticles: toxicity comparison in retinal pigment epithelium and retinal vascular endothelial cells. Semin Ophthalmol. 2016;31(1–2):1–9.

    Article  Google Scholar 

  6. Dagher Z, Park YS, Asnaghi V, Hoehn T, Gerhardinger C, Lorenzi M. Studies of rat and human retinas predict a role for the polyol pathway in human diabetic retinopathy. Diabetes. 2004;53(9):2404–11.

    Article  CAS  Google Scholar 

  7. Stitt AW, McGoldrick C, Rice-McCaldin A, McCance DR, Glenn JV, Hsu DK, Liu FT, Thorpe SR, Gardiner TA. Impaired retinal angiogenesis in diabetes: role of advanced glycation end products and galectin-3. Diabetes. 2005;54(3):785–94.

    Article  CAS  Google Scholar 

  8. Guo Y, Gu R, Gan D, Hu F, Li G, Xu G. Mitochondrial DNA drives noncanonical inflammation activation via cGAS-STING signaling pathway in retinal microvascular endothelial cells. Cell Commun Signal. 2020;18(1):172.

    Article  CAS  Google Scholar 

  9. Sun X, Jiao X, Ma Y, Liu Y, Zhang L, He Y, Chen Y. Trimethylamine N-oxide induces inflammation and endothelial dysfunction in human umbilical vein endothelial cells via activating ROS-TXNIP-NLRP3 inflammasome. Biochem Biophys Res Commun. 2016;481(1–2):63–70.

    Article  CAS  Google Scholar 

  10. Wang X, Jiang M, He X, Zhang B, Peng W, Guo L. N-acetyl cysteine inhibits the lipopolysaccharide-induced inflammatory response in bone marrow mesenchymal stem cells by suppressing the TXNIP/NLRP3/IL1beta signaling pathway. Mol Med Rep. 2020;22(4):3299–306.

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Chen W, Zhao M, Zhao S, Lu Q, Ni L, Zou C, Lu L, Xu X, Guan H, Zheng Z, Qiu Q. Activation of the TXNIP/NLRP3 inflammasome pathway contributes to inflammation in diabetic retinopathy: a novel inhibitory effect of minocycline. Inflamm Res. 2017;66(2):157–66.

    Article  CAS  Google Scholar 

  12. Hanamsagar R, Torres V, Kielian T. Inflammasome activation and IL-1beta/IL-18 processing are influenced by distinct pathways in microglia. J Neurochem. 2011;119(4):736–48.

    Article  CAS  Google Scholar 

  13. Lammerding L, Slowik A, Johann S, Beyer C, Zendedel A. Poststroke inflammasome expression and regulation in the peri-infarct area by gonadal steroids after transient focal ischemia in the rat brain. Neuroendocrinology. 2016;103(5):460–75.

    Article  CAS  Google Scholar 

  14. Nagyoszi P, Nyul-Toth A, Fazakas C, Wilhelm I, Kozma M, Molnar J, Hasko J, Krizbai IA. Regulation of NOD-like receptors and inflammasome activation in cerebral endothelial cells. J Neurochem. 2015;135(3):551–64.

    Article  CAS  Google Scholar 

  15. Hoeve AL, Hakimi HA, Barragan A. Sustained Egr-1 response via p38 MAP kinase signaling modulates early immune responses of dendritic cells parasitized by Toxoplasma gondii. Front Cell Infect Microbiol. 2019;9:349.

    Article  Google Scholar 

  16. Sarkar R, Verma SC. Egr-1 regulates RTA transcription through a cooperative involvement of transcriptional regulators. Oncotarget. 2017;8(53):91425–44.

    Article  Google Scholar 

  17. Gashler A, Sukhatme VP. Early growth response protein 1 (Egr-1): Prototype of a zinc-finger family of transcription factors. Prog Nucleic Acid Res Mol Biol. 1995;50:191–224.

    Article  CAS  Google Scholar 

  18. MacDonald M, Barbat-Artigas S, Cho C, Peng H, Shang J, Moustaine A, Carbonetto S, Robitaille R, Chalifour LE, Paudel H. A Novel Egr-1-agrin pathway and potential implications for regulation of synaptic physiology and homeostasis at the neuromuscular junction. Front Aging Neurosci. 2017;9:258.

    Article  Google Scholar 

  19. Chuang K, Chen FW, Tsai MH, Shieh JJ. EGR-1 plays a protective role in AMPK inhibitor compound C-induced apoptosis through ROS-induced ERK activation in skin cancer cells. Oncol Lett. 2021;21(4):304.

    Article  CAS  Google Scholar 

  20. Nishimoto I, Matsuoka M, Niikura T. Unravelling the role of Humanin. Trends Mol Med. 2004;10(3):102–5.

    Article  CAS  Google Scholar 

  21. Niikura T, Chiba T, Aiso S, Matsuoka M, Nishimoto I. Humanin: after the discovery. Mol Neurobiol. 2004;30(3):327–40.

    Article  CAS  Google Scholar 

  22. Jung SS, Van Nostrand WE. Humanin rescues human cerebrovascular smooth muscle cells from Abeta-induced toxicity. J Neurochem. 2003;84(2):266–72.

    Article  CAS  Google Scholar 

  23. Miao J, Zhang W, Yin R, Liu R, Su C, Lei G, Li Z. S14G-Humanin ameliorates Abeta25-35-induced behavioral deficits by reducing neuroinflammatory responses and apoptosis in mice. Neuropeptides. 2008;42(5–6):557–67.

    Article  CAS  Google Scholar 

  24. Shiroto Y, Terashima S, Hosokawa Y, Oka K, Isokawa K, Tsuruga E. The effect of ultraviolet B on fibrillin-1 and fibrillin-2 in human non-pigmented ciliary epithelial cells In Vitro. Acta Histochem Cytochem. 2017;50(3):105–9.

    Article  CAS  Google Scholar 

  25. Schroder K, Tschopp J. The inflammasomes. Cell. 2010;140(6):821–32.

    Article  CAS  Google Scholar 

  26. Ye X, Zuo D, Yu L, Zhang L, Tang J, Cui C, Bao L, Zan K, Zhang Z, Yang X, Chen H, Tang H, Zu J, Shi H, Cui G. ROS/TXNIP pathway contributes to thrombin induced NLRP3 inflammasome activation and cell apoptosis in microglia. Biochem Biophys Res Commun. 2017;485(2):499–505.

    Article  CAS  Google Scholar 

  27. Spindel ON, World C, Berk BC. Thioredoxin interacting protein: redox dependent and independent regulatory mechanisms. Antioxid Redox Signal 2012;16 (6):587-96

  28. Yin Y, Zhou Z, Liu W, Chang Q, Sun G, Dai Y. Vascular endothelial cells senescence is associated with NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation via reactive oxygen species (ROS)/thioredoxin-interacting protein (TXNIP) pathway. Int J Biochem Cell Biol. 2017;84:22–34.

    Article  CAS  Google Scholar 

  29. Wang XX, Cheng Q, Zhang SN, Qian HY, Wu JX, Tian H, Pei DS, Zheng JN. PAK5-Egr1-MMP2 signaling controls the migration and invasion in breast cancer cell. Tumour Biol. 2013;34(5):2721–9.

    Article  CAS  Google Scholar 

  30. Wang NP, Pang XF, Zhang LH, Tootle S, Harmouche S, Zhao ZQ. Attenuation of inflammatory response and reduction in infarct size by postconditioning are associated with downregulation of early growth response 1 during reperfusion in rat heart. Shock. 2014;41(4):346–54.

    Article  CAS  Google Scholar 

  31. Veyrac A, Gros A, Bruel-Jungerman E, Rochefort C, Kleine Borgmann FB, Jessberger S, Laroche S. Zif268/egr1 gene controls the selection, maturation and functional integration of adult hippocampal newborn neurons by learning. Proc Natl Acad Sci U S A. 2013;110(17):7062–7.

    Article  CAS  Google Scholar 

  32. Saben J, Zhong Y, Gomez-Acevedo H, Thakali KM, Borengasser SJ, Andres A, Shankar K. Early growth response protein-1 mediates lipotoxicity-associated placental inflammation: role in maternal obesity. Am J Physiol Endocrinol Metab. 2013;305(1):E1-14.

    Article  CAS  Google Scholar 

  33. McCaffrey TA, Fu C, Du B, Eksinar S, Kent KC, Bush H, Jr. Kreiger K, Rosengart T, Cybulsky MI, Silverman ES, Collins T. High-level expression of Egr-1 and Egr-1 inducible genes in mouse and human atherosclerosis. J Clin Invest 2000;105 (5): 653–62.

  34. Brevetti G, Giugliano G, Brevetti L, Hiatt WR. Inflammation in peripheral artery disease. Circulation. 2010;122(18):1862–75.

    Article  Google Scholar 

  35. Harja E, Bucciarelli LG, Lu Y, Stern DM, Zou YS, Schmidt AM, Yan SF. Early growth response-1 promotes atherogenesis: mice deficient in early growth response-1 and apolipoprotein E display decreased atherosclerosis and vascular inflammation. Circ Res. 2004;94(3):333–9.

    Article  CAS  Google Scholar 

Download references

Acknowledgements

This study is funded by “the Postdoctoral Foundation of Heilongjiang Province (No. LBH-Z12190)” and the “the Ph.D. Research Fund of the Second Affiliated Hospital of Harbin Medical University (No.BS2010-04)”.

Author information

Author notes

  1. Dejing Shi and Xuemei Zhou are contributed equally.

Authors and Affiliations

  1. Department of Ophthalmology, The Fourth Affiliated Hospital of Harbin Medical University, Heilongjiang Province, Harbin, 150001, China

    Dejing Shi & Hongxia Wang

  2. Department of Ophthalmology, The Second Affiliated Hospital of Harbin Medical University, 246 Xuefu RoadHeilongjiang Province, Harbin, 150086, China

    Xuemei Zhou

Authors
  1. Dejing Shi
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Xuemei Zhou
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hongxia Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

Dejing Shi and Xuemei Zhou contributed to the conception, investigation, data curation, and manuscript preparation; Hongxia Wang contributed to materials preparation.

Corresponding author

Correspondence to Xuemei Zhou.

Ethics declarations

Conflict of interest

None.

Additional information

Responsible Editor: John Di Battista.

Publisher's Note

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

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Shi, D., Zhou, X. & Wang, H. S14G-humanin (HNG) protects retinal endothelial cells from UV-B-induced NLRP3 inflammation activation through inhibiting Egr-1. Inflamm. Res. 70, 1141–1150 (2021). https://doi.org/10.1007/s00011-021-01489-4

Download citation

  • Received:

  • Revised:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00011-021-01489-4

Keywords

Search

Navigation