Top

Published in:

01-05-2020 | Original Research Paper

H₂S counteracts proinflammatory effects of LPS through modulation of multiple pathways in human cells

Authors: M. M. Yurinskaya, G. S. Krasnov, D. A. Kulikova, O. G. Zatsepina, M. G. Vinokurov, L. N. Chuvakova, A. P. Rezvykh, S. Y. Funikov, A. V. Morozov, M. B. Evgen’ev

Published in: Inflammation Research | Issue 5/2020

Abstract

Background

Hydrogen sulfide donors reduce inflammatory signaling in vitro and in vivo. The biological effect mediated by H₂S donors depends on the kinetics of the gas release from the donor molecule. However, the molecular mechanisms of H₂S-induced immunomodulation were poorly addressed. Here, we studied the effect of two different hydrogen sulfide (H₂S)-producing agents on the generation of the LPS-induced inflammatory mediators. Importantly, we investigated the transcriptomic changes that take place in human cells after the LPS challenge, combined with the pretreatment with a slow-releasing H₂S donor-GYY4137.

Methods

We investigated the effects of GYY4137 and sodium hydrosulfide on the release of proinflammatory molecules such as ROS, NO and TNF-α from LPS-treated human SH-SY5Y neuroblastoma and the THP-1 promonocytic cell lines. Transcriptomic and RT-qPCR studies using THP-1 cells were performed to monitor the effects of the GYY4137 on multiple signaling pathways, including various immune-related and proinflammatory genes after combined action of LPS and GYY4137.

Results

The GYY4137 and sodium hydrosulfide differed in the ability to reduce the production of the LPS-evoked proinflammatory mediators. The pre-treatment with GYY4137 resulted in a drastic down-regulation of many TNF-α effectors that are induced by LPS treatment in THP-1 cells. Furthermore, GYY4137 pretreatment of LPS-exposed cells ameliorates the LPS-mediated induction of multiple pro-inflammatory genes and decreases expression of immunoproteasome genes. Besides, in these experiments we detected the up-regulation of several important pathways that are inhibited by LPS.

Conclusion

Based on the obtained results we believe that our transcriptomic analysis significantly contributes to the understanding of the molecular mechanisms of anti-inflammatory and cytoprotective activity of hydrogen sulfide donors, and highlights their potential against LPS challenges and other forms of inflammation.

Available only for authorised users

Munford RS. Endotoxemia-menace, marker, or mistake? J Leukoc Biol. 2016;100(4):687–98. https://doi.org/10.1189/jlb.3RU0316-151R.CrossRefPubMedPubMedCentral

Martins IJ. Overnutrition determines LPS regulation of mycotoxin induced neurotoxicity in neurodegenerative diseases. Int J Mol Sci. 2015;16(12):29554–73. https://doi.org/10.3390/ijms161226190.CrossRefPubMedPubMedCentral

Wang YW, Zhou Q, Zhang X, Qian QQ, Xu JW, Ni PF, et al. Mild endoplasmic reticulum stress ameliorates lipopolysaccharide-induced neuroinflammation and cognitive impairment via regulation of microglial polarization. J Neuroinflamm. 2017;14(1):233. https://doi.org/10.1186/s12974-017-1002-7.CrossRef

Kimura H. Physiological roles of hydrogen sulfide and polysulfides. In: Moore P, Whiteman M, editors. Chemistry, biochemistry and pharmacology of hydrogen sulfide. Handbook of experimental pharmacology, vol. 230. Springer, Cham;2015. p. 61–81. https://doi.org/10.1007/978-3-319-18144-8_3.

Rose P, Dymock BW, Moore PK. GYY4137, a novel water-soluble, H2S-releasing molecule. Methods Enzymol. 2015;554:143–67. https://doi.org/10.1016/bs.mie.2014.11.014.CrossRefPubMed

Whiteman M, Li L, Rose P, Tan CH, Parkinson DB, Moore PK. The effect of hydrogen sulfide donors on lipopolysaccharide-induced formation of inflammatory mediators in macrophages. Antioxid Redox Signal. 2010;12(10):1147–54. https://doi.org/10.1089/ars.2009.2899.CrossRefPubMedPubMedCentral

Li L, Fox B, Keeble J, Salto-Tellez M, Winyard PG, Wood ME, et al. The complex effects of the slow-releasing hydrogen sulfide donor GYY4137 in a model of acute joint inflammation and in human cartilage cells. J Cell Mol Med. 2013;17(3):365–76. https://doi.org/10.1111/jcmm.12016.CrossRefPubMedPubMedCentral

Kaya-Yasar Y, Karaman Y, Bozkurt TE, Onder SC, Sahin-Erdemli I. Effects of intranasal treatment with slow (GYY4137) and rapid (NaHS) donors of hydrogen sulfide in lipopolysaccharide-induced airway inflammation in mice. Pulm Pharmacol Ther. 2017;45:170–80. https://doi.org/10.1016/j.pupt.2017.06.006.CrossRefPubMed

Meng G, Wang J, Xiao Y, Bai W, Xie L, Shan L, et al. GYY4137 protects against myocardial ischemia and reperfusion injury by attenuating oxidative stress and apoptosis in rats. J Biomed Res. 2015;29(3):203–13. https://doi.org/10.7555/jbr.28.20140037.CrossRefPubMed

10.

Bobkova NV, Garbuz DG, Nesterova I, Medvinskaya N, Samokhin A, Alexandrova I, et al. Therapeutic effect of exogenous hsp70 in mouse models of Alzheimer’s disease. J Alzheimer’s Dis. 2014;38(2):425–35. https://doi.org/10.3233/jad-130779.CrossRef

11.

Bobkova NV, Evgen'ev M, Garbuz DG, Kulikov AM, Morozov A, Samokhin A, et al. Exogenous Hsp70 delays senescence and improves cognitive function in aging mice. Proc Natl Acad Sci USA. 2015;112(52):16006–11. https://doi.org/10.1073/pnas.1516131112.CrossRefPubMedPubMedCentral

12.

Lu Z, Zhao T, Tao L, Yu Q, Yang Y, Cheng J, et al. Cystathionine beta-synthase-derived hydrogen sulfide correlates with successful aging in mice. Rejuvenation Res. 2019. https://doi.org/10.1089/rej.2018.2166.CrossRefPubMed

13.

Gerasimova E, Lebedeva J, Yakovlev A, Zefirov A, Giniatullin R, Sitdikova G. Mechanisms of hydrogen sulfide (H₂S) action on synaptic transmission at the mouse neuromuscular junction. Neuroscience. 2015;303:577–85. https://doi.org/10.1016/j.neuroscience.2015.07.036.CrossRefPubMed

14.

Lakshmikanth CL, Jacob SP, Chaithra VH, de Castro-Faria-Neto HC, Marathe GK. Sepsis: in search of cure. Inflamm Res. 2016;65(8):587–602. https://doi.org/10.1007/s00011-016-0937-y.CrossRefPubMed

15.

Petrushanko IY, Melnikova EV, Yurinskaya MM, Vinokurov MG, Suslikov AV, Mitkevich VA, et al. Influence of the donor of hydrogen sulfide GYY4137 on the activation of human neutrophils by E. coli lipopolysaccharides. Mol Biol. 2019;53(1):101–8. https://doi.org/10.1134/s0026898419010130.CrossRef

16.

Rozhkova E, Yurinskaya M, Zatsepina O, Garbuz D, Karpov V, Surkov S, et al. Exogenous mammalian extracellular HSP70 reduces endotoxin manifestations at the cellular and organism levels. Ann N Y Acad Sci. 2010;1197:94–107. https://doi.org/10.1111/j.1749-6632.2009.05375.x.CrossRefPubMed

17.

Yurinskaya MM, Kochetkova OY, Shabarchina LI, Antonova OY, Suslikov AV, Evgen'ev MB, et al. Encapsulated Hsp70 decreases endotoxin-induced production of ROS and TNFalpha in human phagocytes. Cell Stress Chaperones. 2017;22(1):163–71. https://doi.org/10.1007/s12192-016-0743-z.CrossRefPubMed

18.

Yurinskaya MM, Mit'kevich VA, Evgen'ev MB, Makarov AA, Vinokurov MG. Heat-shock protein HSP70 reduces the secretion of TNFalpha by neuroblastoma cells and human monocytes induced with beta-amyloid peptides. Mol Biol. 2016;50(6):1053–6. https://doi.org/10.7868/s0026898416060239.CrossRef

19.

Bolger AM, Lohse M, Usadel B. Trimmomatic: a flexible trimmer for Illumina sequence data. Bioinformatics. 2014;30(15):2114–200. https://doi.org/10.1093/bioinformatics/btu170.CrossRefPubMedPubMedCentral

20.

Dobin A, Davis CA, Schlesinger F, Drenkow J, Zaleski C, Jha S, et al. STAR: ultrafast universal RNA-seq aligner. Bioinformatics. 2013;29(1):15–211. https://doi.org/10.1093/bioinformatics/bts635.CrossRefPubMed

21.

Liao Y, Smyth GK, Shi W. FeatureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics. 2014;30(7):923–30. https://doi.org/10.1093/bioinformatics/btt656.CrossRefPubMed

22.

Wang L, Wang S, Li W. RSeQC: quality control of RNA-seq experiments. Bioinformatics. 2012;28(16):2184–5. https://doi.org/10.1093/bioinformatics/bts356.CrossRefPubMed

23.

Krasnov GS, Dmitriev AA, Kudryavtseva AV, Shargunov AV, Karpov DS, Uroshlev LA, et al. PPLine: an automated pipeline for SNP, SAP, and splice variant detection in the context of proteogenomics. J Proteom Res. 2015;14(9):3729–37. https://doi.org/10.1021/acs.jproteome.5b00490.CrossRef

24.

Robinson MD, McCarthy DJ, Smyth GK. edgeR: a Bioconductor package for differential expression analysis of digital gene expression data. Bioinformatics. 2010;26(1):139–40. https://doi.org/10.1093/bioinformatics/btp616.CrossRefPubMed

25.

Yu G, Wang LG, Han Y, He QY. clusterProfiler: an R package for comparing biological themes among gene clusters. OMICS. 2012;16(5):284–7. https://doi.org/10.1089/omi.2011.0118.CrossRefPubMedPubMedCentral

26.

Ferrington DA, Gregerson DS. Immunoproteasomes: structure, function, and antigen presentation. Prog Mol Biol Transl Sci. 2012;109:75–112. https://doi.org/10.1016/b978-0-12-397863-9.00003-1.CrossRefPubMedPubMedCentral

27.

Pan W, Kang Y. Gut microbiota and chronic kidney disease: implications for novel mechanistic insights and therapeutic strategies. Int Urol Nephrol. 2018;50(2):289–99. https://doi.org/10.1007/s11255-017-1689-5.CrossRefPubMed

28.

Kuzmich NN, Sivak KV, Chubarev VN, Porozov YB, Savateeva-Lyubimova TN, Peri F. TLR4 signaling pathway modulators as potential therapeutics in inflammation and sepsis. Vaccines. 2017;5(4):34–75. https://doi.org/10.3390/vaccines5040034.CrossRefPubMedCentral

29.

Shapouri-Moghaddam A, Mohammadian S, Vazini H, Taghadosi M, Esmaeili SA, Mardani F, et al. Macrophage plasticity, polarization, and function in health and disease. J Cell Physiol. 2018;233(9):6425–40. https://doi.org/10.1002/jcp.26429.CrossRefPubMed

30.

Chen LS, Singh SP, Schuster M, Grinenko T, Bornstein SR, Kanczkowski W. RNA-seq analysis of LPS-induced transcriptional changes and its possible implications for the adrenal gland dysregulation during sepsis. J Steroid Biochem Mol Biol. 2019;191:105360. https://doi.org/10.1016/j.jsbmb.2019.04.009.CrossRefPubMed

31.

Kim SJ, Kim HM. Dynamic lipopolysaccharide transfer cascade to TLR4/MD2 complex via LBP and CD14. BMB Rep. 2017;50(2):55–7. https://doi.org/10.5483/bmbrep.2017.50.2.011.CrossRefPubMedPubMedCentral

32.

Pfeiffer JR, McAvoy BL, Fecteau RE, Deleault KM, Brooks SA. CARHSP1 is required for effective tumor necrosis factor alpha mRNA stabilization and localizes to processing bodies and exosomes. Mol Cell Biol. 2011;31(2):277–86. https://doi.org/10.1128/mcb.00775-10.CrossRefPubMed

33.

Mouzaoui S, Rahim I, Djerdjouri B. Aminoguanidine and curcumin attenuated tumor necrosis factor (TNF)-alpha-induced oxidative stress, colitis and hepatotoxicity in mice. Int Immunopharmacol. 2012;12(1):302–11. https://doi.org/10.1016/j.intimp.2011.10.010.CrossRefPubMed

34.

Blaser H, Dostert C, Mak TW, Brenner D. TNF and ROS crosstalk in inflammation. Trends Cell Biol. 2016;26(4):249–61. https://doi.org/10.1016/j.tcb.2015.12.002.CrossRefPubMed

35.

Sakuma S, Minamino S, Takase M, Ishiyama Y, Hosokura H, Kohda T, et al. Hydrogen sulfide donor GYY4137 suppresses proliferation of human colorectal cancer Caco-2 cells by inducing both cell cycle arrest and cell death. Heliyon. 2019;5(8):e02244. https://doi.org/10.1016/j.heliyon.2019.e02244.CrossRefPubMedPubMedCentral

36.

Dauphinee SM, Karsan A. Lipopolysaccharide signaling in endothelial cells. Lab Investig. 2006;86(1):9–22. https://doi.org/10.1038/labinvest.3700366.CrossRefPubMed

37.

Reis J, Guan XQ, Kisselev AF, Papasian CJ, Qureshi AA, Morrison DC, et al. LPS-induced formation of immunoproteasomes: TNF-alpha and nitric oxide production are regulated by altered composition of proteasome-active sites. Cell Biochem Biophys. 2011;60(1–2):77–88. https://doi.org/10.1007/s12013-011-9182-8.CrossRefPubMedPubMedCentral

38.

Shen J, Reis J, Morrison DC, Papasian C, Raghavakaimal S, Kolbert C, et al. Key inflammatory signaling pathways are regulated by the proteasome. Shock. 2006;25(5):472–84. https://doi.org/10.1097/01.shk.0000209554.46704.64.CrossRefPubMed

39.

Kustanova GA, Murashev AN, Karpov VL, Margulis BA, Guzhova IV, Prokhorenko IR, et al. Exogenous heat shock protein 70 mediates sepsis manifestations and decreases the mortality rate in rats. Cell Stress Chaperones. 2006;11(3):276–86. https://doi.org/10.1379/csc-195r.1.CrossRefPubMedPubMedCentral

40.

Yurinskaya MM, Mitkevich VA, Kozin SA, Evgen'ev MB, Makarov AA, Vinokurov MG. HSP70 protects human neuroblastoma cells from apoptosis and oxidative stress induced by amyloid peptide isoAsp7-Abeta(1–42). Cell Death Dis. 2015;6:e1977. https://doi.org/10.1038/cddis.2015.336.CrossRefPubMedPubMedCentral

41.

Evgen'ev MB, Krasnov GS, Nesterova IV, Garbuz DG, Karpov VL, Morozov AV, et al. Molecular mechanisms underlying neuroprotective effect of intranasal administration of human Hsp70 in mouse model of Alzheimer’s disease. J Alzheimer’s Dis. 2017;59(4):1415–26. https://doi.org/10.3233/jad-170398.CrossRef

42.

Yadav V, Gao XH, Willard B, Hatzoglou M, Banerjee R, Kabil O. Hydrogen sulfide modulates eukaryotic translation initiation factor 2alpha (eIF2alpha) phosphorylation status in the integrated stress-response pathway. J Biol Chem. 2017;292(32):13143–53. https://doi.org/10.1074/jbc.M117.778654.CrossRefPubMedPubMedCentral

43.

Aneja R, Odoms K, Dunsmore K, Shanley TP, Wong HR. Extracellular heat shock protein-70 induces endotoxin tolerance in THP-1 cells. J Immunol. 2006;177(10):7184–92. https://doi.org/10.4049/jimmunol.177.10.7184.CrossRefPubMed

44.

Asea A, Kraeft SK, Kurt-Jones EA, Stevenson MA, Chen LB, Finberg RW, et al. HSP70 stimulates cytokine production through a CD14-dependant pathway, demonstrating its dual role as a chaperone and cytokine. Nat Med. 2000;6(4):435–42. https://doi.org/10.1038/74697.CrossRefPubMed

45.

Yurinskaya M, Zatsepina OG, Vinokurov MG, Bobkova NV, Garbuz DG, Morozov AV, et al. The fate of exogenous human HSP70 introduced into animal cells by different means. Curr Drug Deliv. 2015;12(5):524–32.CrossRefPubMed

46.

Pockley AG, Henderson B. Extracellular cell stress (Heat shock) proteins—immune responses and disease: an overview. Philos Trans R Soc Lond Ser B Biol Sci. 2018;373(1738):20160522. https://doi.org/10.1098/rstb.2016.0522.CrossRef

47.

Filipovic MR, Zivanovic J, Alvarez B, Banerjee R. Chemical biology of H₂S signaling through persulfidation. Chem Rev. 2018;118(3):1253–337. https://doi.org/10.1021/acs.chemrev.7b00205.CrossRefPubMed

48.

Hulina A, Grdic Rajkovic M, Jaksic Despot D, Jelic D, Dojder A, Cepelak I, et al. Extracellular Hsp70 induces inflammation and modulates LPS/LTA-stimulated inflammatory response in THP-1 cells. Cell Stress Chaperones. 2018;23(3):373–84. https://doi.org/10.1007/s12192-017-0847-0.CrossRefPubMed

49.

Lee KH, Jeong J, Yoo CG. Positive feedback regulation of heat shock protein 70 (Hsp70) is mediated through toll-like receptor 4-PI3K/Akt-glycogen synthase kinase-3beta pathway. Exp Cell Res. 2013;319(1):88–95. https://doi.org/10.1016/j.yexcr.2012.09.018.CrossRefPubMed

50.

Du M, Yuan L, Tan X, Huang D, Wang X, Zheng Z, et al. The LPS-inducible lncRNA Mirt2 is a negative regulator of inflammation. Nat Commun. 2017;8(1):2049. https://doi.org/10.1038/s41467-017-02229-1.CrossRefPubMedPubMedCentral

51.

Ji K, Xue L, Cheng J, Bai Y. Preconditioning of H₂S inhalation protects against cerebral ischemia/reperfusion injury by induction of HSP70 through PI3K/Akt/Nrf2 pathway. Brain Res Bull. 2016;121:68–74. https://doi.org/10.1016/j.brainresbull.2015.12.007.CrossRefPubMed

Title: H2S counteracts proinflammatory effects of LPS through modulation of multiple pathways in human cells
Authors: M. M. Yurinskaya
G. S. Krasnov
D. A. Kulikova
O. G. Zatsepina
M. G. Vinokurov
L. N. Chuvakova
A. P. Rezvykh
S. Y. Funikov
A. V. Morozov
M. B. Evgen’ev
Publication date: 01-05-2020
Publisher: Springer International Publishing
Published in: Inflammation Research / Issue 5/2020
Print ISSN: 1023-3830
Electronic ISSN: 1420-908X
DOI: https://doi.org/10.1007/s00011-020-01329-x

Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine

Highlights from the ACC 2024 Congress

Year in Review: Pediatric cardiology

Pediatric Cardiology Video

Watch Dr. Anne Marie Valente present the last year's highlights in pediatric and congenital heart disease in the official ACC.24 Year in Review session.

Year in Review: Pulmonary vascular disease

Cardiopulmonary Comorbidity Video

The last year's highlights in pulmonary vascular disease are presented by Dr. Jane Leopold in this official video from ACC.24.

Year in Review: Valvular heart disease

Valvular Heart Disease Video

Watch Prof. William Zoghbi present the last year's highlights in valvular heart disease from the official ACC.24 Year in Review session.

Year in Review: Heart failure and cardiomyopathies

Heart Failure Video

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

ACC 2024 Congress Coverage

Heart Failure Video

Year in Review: Heart failure and cardiomyopathies

Watch now

Watch this official video from ACC.24. Dr. Biykem Bozkurt discuss last year's major advances in heart failure and cardiomyopathies.

Semaglutide benefits people with type 2 diabetes and obesity-related heart failure

16-04-2024 Type 2 Diabetes News

Incentivised to exercise

11-04-2024 Lifestyle Modifications News

New intervention for STEMI-related cardiogenic shock

10-04-2024 Myocardial Infarction News

» View more highlights on the ACC 2024 congress hub page

Image Credits

STEP AAG HeroTeaserCollection image/© Tarek / Generated with AI / Stock.adobe.com, ACC 2024 Pediatric and Congenital Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Pulmonary Vascular Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 Valvular Heart Disease: Year in Review/© 2024 American College of Cardiology, ACC 2024 HF and Cardiomyopathies: Year in Review/© 2024 American College of Cardiology, Woman out walking/© Seventyfour / stock.adobe.com (symbolic image with model), Woman checking smartwatch /© saltdium / stock.adobe.com (symbolic image with model), Cardiac catheterization/© Damian / stock.adobe.com

At a glance: The STEP trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 5/2020

Interleukin 23 and autoimmune diseases: current and possible future therapies

Aquaporin 1 alleviates acute kidney injury via PI3K-mediated macrophage M2 polarization

Vitamin D and connective tissue diseases

Influence of estradiol treatment on bone marrow cell differentiation in collagenase-induced arthritis

Tumor-derived exosomes in the regulation of macrophage polarization

IL-18/IL-18R1 promotes circulating fibrocyte differentiation in the aging population

Highlights from the ACC 2024 Congress

ACC 2024 Congress Coverage