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1- Department of Medicine, Ardabil Branch, Islamic Azad University, Ardabil, Iran , leilapirdel@yahoo.com
2- Department of Biology, Tabriz Branch, Islamic Azad University, Tabriz, Iran
2- Department of Biology, Tabriz Branch, Islamic Azad University, Tabriz, Iran
Abstract: (27 Views)
ABSTARCT
Background and objectives: Mesenchymal stem cells (MSCs) are well known as a major immune modulator. A subgroup of the nucleotide-binding oligomerization domain (NOD) like receptors (NLRs) has been recently found to play an immune/inflammatory regulatory role.
We aimed to analyze and compare the gene expression level of the NOD‐like receptor family pyrin domain containing protein (NLRP), such as NLRP6 and NLRP12, in Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) treated with interferon-gamma (IFN-γ), the pro-inflammatory cytokine, and untreated cells as well.
Methods: The immunophenotypic characterization of the isolated WJ-MSCs was performed by flow cytometry. Next, they were cultured with or without IFN-g, followed by the comparison of expression level of NLRP6 and NLRP12 genes by using qPCR.
Results: The treatment of cells with IFN-γ indicated a statistically significant increased expression of NLRP12 gene as compared to untreated cells while the expression of NLRP6 was failed to detect in the cells with or without IFN-γ treatment.
Conclusion: The altered expression level of NLRP12 might be suggested its contributory role in the inflammatory regulation mediated by WJ-MSCs in response to the exposure to IFN-g; however, additional studies are needed to validate its role in experimental inflammatory-related disease models.
Background and objectives: Mesenchymal stem cells (MSCs) are well known as a major immune modulator. A subgroup of the nucleotide-binding oligomerization domain (NOD) like receptors (NLRs) has been recently found to play an immune/inflammatory regulatory role.
We aimed to analyze and compare the gene expression level of the NOD‐like receptor family pyrin domain containing protein (NLRP), such as NLRP6 and NLRP12, in Wharton’s jelly-derived mesenchymal stem cells (WJ-MSCs) treated with interferon-gamma (IFN-γ), the pro-inflammatory cytokine, and untreated cells as well.
Methods: The immunophenotypic characterization of the isolated WJ-MSCs was performed by flow cytometry. Next, they were cultured with or without IFN-g, followed by the comparison of expression level of NLRP6 and NLRP12 genes by using qPCR.
Results: The treatment of cells with IFN-γ indicated a statistically significant increased expression of NLRP12 gene as compared to untreated cells while the expression of NLRP6 was failed to detect in the cells with or without IFN-γ treatment.
Conclusion: The altered expression level of NLRP12 might be suggested its contributory role in the inflammatory regulation mediated by WJ-MSCs in response to the exposure to IFN-g; however, additional studies are needed to validate its role in experimental inflammatory-related disease models.
Keywords: Gene Expression, Interferon-gamma, Inflammation, Mesenchymal stem cells, NOD like receptors
Research Article: Research Article |
Subject:
Biochemistry
Received: 2023/08/21 | Accepted: 2024/02/28
Received: 2023/08/21 | Accepted: 2024/02/28
References
1. Slaminejad MB, Fani N, Shahhoseini M. Epigenetic Regulation of Osteogenic and Chondrogenic Differentiation of Mesenchymal Stem Cells in Culture. Cell J. 2013;15(1): 1-10. [View at Publisher] [PMID] [Google Scholar]
2. Saidi N, Ghalavand M, Hashemzadeh MS, Dorostkar R, Mohammadi H, Mahdian-shakib A. Dynamic changes of epigenetic signatures during chondrogenic and adipogenic differentiation of mesenchymal stem cells. Biomed pharmacother.2017; 89:719-731. [View at Publisher] [DOI] [PMID] [Google Scholar]
3. Huang P, Lin LM, Wu XY, Tang QL, Feng XY, Lin GY, et al. Differentiation of human umbilical cord Wharton's jelly‐derived mesenchymal stem cells into germ‐like cells in vitro. J Cell Bbiochem. 2010; 109(4):747-54. [View at Publisher] [DOI] [PMID] [Google Scholar]
4. Weiss ML, Anderson C, Medicetty S, Seshareddy KB, Weiss RJ, VanderWerff I, et al. Immune properties of human umbilical cord Wharton's jelly‐derived cells. Stem cells. 2008; 26(11):2865-74. [View at Publisher] [DOI] [PMID] [Google Scholar]
5. Prasanna SJ, Gopalakrishnan D, Shankar SR, Vasandan AB. Pro-inflammatory cytokines, IFNγ and TNFα, influence immune properties of human bone marrow and Wharton jelly mesenchymal stem cells differentially. PLoS One. 2010;5(2):e9016. [View at Publisher] [DOI] [PMID] [Google Scholar]
6. Kyurkchiev D, Bochev I, Ivanova-Todorova E, Mourdjeva M, Oreshkova T, Belemezova K, et al. Secretion of immunoregulatory cytokines by mesenchymal stem cells. World J Stem Cells. 2014;6(5):552-70. [View at Publisher] [DOI] [PMID] [Google Scholar]
7. Deuse T, Stubbendorff M, Tang-Quan K, Phillips N, Kay MA, Eiermann T, et al. Immunogenicity and immunomodulatory properties of umbilical cord lining mesenchymal stem cells. Cell transplant. 2011;20(5):655-7. [View at Publisher] [DOI] [PMID] [Google Scholar]
8. François M, Romieu-Mourez R, Li M, Galipeau J. Human MSC suppression correlates with cytokine induction of indoleamine 2, 3-dioxygenase and bystander M2 macrophage differentiation. Mol ther. 2012;20(1):187-95. [View at Publisher] [DOI] [PMID] [Google Scholar]
9. Noone C, Kihm A, English K, O'Dea S, Mahon BP. IFN-γ stimulated human umbilical-tissue-derived cells potently suppress NK activation and resist NK-mediated cytotoxicity in vitro. Stem Cells Dev. 2013;22(22):3003-14. [View at Publisher] [DOI] [PMID] [Google Scholar]
10. François M, Romieu-Mourez R, Stock-Martineau S, Boivin M-N, Bramson JL, Galipeau J. Mesenchymal stromal cells cross-present soluble exogenous antigens as part of their antigen-presenting cell properties. Blood. 2009;114(13):2632-8. [View at Publisher] [DOI] [PMID] [Google Scholar]
11. Haddad R, Saldanha-Araujo F. Mechanisms of T-cell immunosuppression by mesenchymal stromal cells: what do we know so far? Biomed Res Int. 2014;2014:216806. [View at Publisher] [DOI] [PMID] [Google Scholar]
12. Tse WT, Pendleton JD, Beyer WM, Egalka MC, Guinan EC. Suppression of allogenic T-cell proliferation by human marrow stromal cells: implications in transplantation. Transplantation. 2003;75(3):389-97. [View at Publisher] [DOI] [PMID] [Google Scholar]
13. Espagnolle N, Balguerie A, Arnaud E, Sensebé L, Varin A. CD54-mediated interaction with pro-inflammatory macrophages increases the immunosuppressive function of human mesenchymal stromal cells. Stem cell reports. 2017;8(4):961-76. [View at Publisher] [DOI] [PMID] [Google Scholar]
14. Luper CR, Stokes KL, Kuriakose T, Kanneganti TD. Deficiency of the NOD-Like receptor NLRC5 results in decreased CD8+ T cell function and impaired viral clearance. J Viol. 2017;91(17):e00377-17. [View at Publisher] [DOI] [PMID] [Google Scholar]
15. Gültekin Y, Eren E, Özören N. Overexpressed NLRC3 acts as an anti-inflammatory cytosolic protein. J Innate Immun. 2015;7(1):25-36. [View at Publisher] [DOI] [PMID] [Google Scholar]
16. Janowski AM, Kolb R, Zhang W, Sutterwala FS. Beneficial and Detrimental roles of NLRs in carcinogenesis. Front Immunol. 2013;4:370. [View at Publisher] [DOI] [PMID] [Google Scholar]
17. Linz BM, Neely CJ, Kartchner LB, Mendoza AE, Khoury AL, Truax A, et al. Innate immune cell recovery positively regulated by NLRP12 during emergency hematopoiesis. J Immunol. 2017;198(6):2426-33. [View at Publisher] [DOI] [PMID] [Google Scholar]
18. Lukens JR, Gurung P, Shaw PJ, Barr MJ, Zaki MH, Brown SA, et al. The NLRP12 sensor negatively regulates autoinflammatory disease by modulating interleukin-4 production in T cells. Immunity. 2015;42(4): 654-64. [View at Publisher] [DOI] [PMID] [Google Scholar]
19. Coutermarsh-Ott S, Eden K, Allen IC. Beyond the inflammasome: regulatory NOD-like receptor modulation of the host immune response following virus exposure. J Gen Virol. 2016;97(4):825-38. [View at Publisher] [DOI] [PMID] [Google Scholar]
20. Rao X, Zhou X, Wang G, Jie X, Xine B, Xu Y, et al. NLRP6 is required for cancer-derived exosome-modified macrophage M2 polarization and promotes metastasis in small cell lung cancer. Cell Death Dis. 2022;13(10):891. [View at Publisher] [DOI] [PMID] [Google Scholar]
21. Wang H, Xu G, Huang Z, Li W, Cai H, Zhang Y, et al. Correction: NLRP6 targeting suppresses gastric tumorigenesis via P14ARF-Mdm2-P53-dependent cellular senescence. Oncotarget. 2018;9(84):35512 [View at Publisher] [DOI] [PMID] [Google Scholar]
22. Linz LBM, Neely CJ, Kartchner KB, Mendoza AE, Khoury AL, Truax A, et al. Innate Immune Cell Recovery Is Positively Regulated by NLRP12 during Emerg,ency Hematopoiesis. J Immunol. 2017;198(6):2426-33. [View at Publisher] [DOI] [PMID] [Google Scholar]
23. Lin Q, Wu L, Ma Z, Chowdhury FA, Mazumder HH, Du W. Persistent DNA damage-induced NLRP12 improves hematopoietic stem cell function. JCI Insight . 2020;5(10):e133365. [View at Publisher] [DOI] [PMID] [Google Scholar]
24. Anand PK, Malireddi RK, Lukens JR, Vogel P, Bertin J, Lamkanfi M, et al. NLRP6 Negatively Regulates Innate Immunity and Host Defense Against Bacterial Pathogens. Nature. 2012;488(7411):389-93. [View at Publisher] [DOI] [PMID] [Google Scholar]
25. Silveira TN, Gomes MT, Oliveira LS, Campos PC, Machado GG, Oliveira SC. NLRP12 negatively regulates proinflammatory cytokine production and host defense against Brucella abortus. Eur J Immunol. 2017;47(1): 51-9. [View at Publisher] [DOI] [PMID] [Google Scholar]
26. Khatami SM, Zahri S, Maleki M, Hamidi K. Stem Cell Isolation from Human Wharton's Jelly: A Study of Their Differentiation Ability into Lens Fiber Cells. Cell J. 2014;15(4):364-71. [View at Publisher] [PMID] [Google Scholar]
27. Hendijani F, Javanmard ShH, Rafiee L, Sadeghi-Aliabadi H. Effect of human Wharton's jelly mesenchymal stem cell secretome on proliferation, apoptosis and drug resistance of lung cancer cells. Res Pharm Sci. 2015;10(2):134-42. [View at Publisher] [PMID] [Google Scholar]
28. Huang Y, Wu Q, Tam PKH. Immunomodulatory Mechanisms of Mesenchymal Stem Cells and Their Potential Clinical Applications. Int J Mol Sci. 2022;23(17):10023. [View at Publisher] [DOI] [PMID] [Google Scholar]
29. Sivanathan KN, Gronthos S, Rojas-Canales D, Thierry B, Coates PT. Interferon-gamma modification of mesenchymal stem cells: implications of autologous and allogeneic mesenchymal stem cell therapy in allotransplantation. Stem Cell Rev Rep. 2014;10(3):351-75. [View at Publisher] [DOI] [PMID] [Google Scholar]
30. Ma OK-F, Chan KH. Immunomodulation by mesenchymal stem cells: Interplay between mesenchymal stem cells and regulatory lymphocytes. World J Stem Cells. 2016;8(9):268-78. [View at Publisher] [DOI] [PMID] [Google Scholar]
31. Gharagozloo M, Mahvelati TM, Imbeault E, Gris P, Zerif E, Bobbala D, et al. The nod-like receptor, NLRP12, plays an anti-inflammatory role in experimental autoimmune encephalomyelitis. J Neuroinflammation. 2015;12:198. [View at Publisher] [DOI] [PMID] [Google Scholar]
32. Lukens JR, Gurung P, Shaw PJ, Barr MJ, Zaki MH, Brown SA, et al. NLRP12 negatively regulates autoinflammatory disease by modulating interleukin-4 production in T cells. Immunity. 2015;42(4):654-64. [View at Publisher] [DOI] [PMID] [Google Scholar]
33. Waldner MJ, Neurath MF. Mechanisms of Immune Signaling in Colitis-Associated Cancer. Cell mol gastroenterol hepatol. 2014;1(1):6-16. [View at Publisher] [DOI] [PMID] [Google Scholar]
34. Chan JL, Tang KC, Patel AP, Bonilla LM, Pierobon N, Ponzio NM, et al. Antigen property of mesenchymal stem cells occurs during a narrow window at low levels of interferon-gamma. Blood. 2006;107(12):4817-24. [View at Publisher] [DOI] [PMID] [Google Scholar]
35. Stagg J, Pommey S, Eliopoulos N, Galipeau J. Interferon-gamma stimulated marrow stromal cells: a new type nonhematopoietic antigen-presenting cell. Blood. 2006;107(6):2570-7. [View at Publisher] [DOI] [PMID] [Google Scholar]
36. Nie H, Hu Y, Guo W, Wang W, Yang Q, Dong Q, et al. miR-331-3p inhibits inflammatory response after intracerebral hemorrhage by directly targeting NLRP6. Biomed Res Int. 2020;2020:6182464. [View at Publisher] [DOI] [PMID] [Google Scholar]
37. Tsao YP, Tseng FY, Chao CW, Chen MH, Yeh YC, Abdulkareem BO, et al. NLRP12 is an innate immune checkpoint for repressing IFN signatures and attenuating lupus nephritis progression. J Clin Invest. 2023;133(3):e157272. [View at Publisher] [DOI] [PMID] [Google Scholar]
38. Sharma BR, Karki R, Rajesh Y, Kanneganti TD. Immune regulator IRF1 contributes to ZBP1-, AIM2-, RIPK1-, and NLRP12-PANoptosome activation and inflammatory cell death (PANoptosis). J Biol Chem. 2023;299(9):105141. [View at Publisher] [DOI] [PMID] [Google Scholar]
39. Ataide MA, Andrade WA, Zamboni DS, Wang D, Souza Mdo C, Franklin BS, et al. Malaria-induced NLRP12/NLRP3-dependent caspase-1 activation mediates inflammation and hypersensitivity to bacterial superinfection. PLoS Pathog .2014;10(1):e1003885. [View at Publisher] [DOI] [PMID] [Google Scholar]
40. Zaki MH, Man SM, Vogel P, Lamkanfi M, Kanneganti TD. Salmonella exploits NLRP12-dependent innate immune signaling to suppress host defenses during infection. Proc Natl Acad Sci U S A. 2014;111(1):385-90. [View at Publisher] [DOI] [PMID] [Google Scholar]
41. Radulovic K, Ayata CK, Mak'Anyengo R, Lechner K, Wuggenig P, Kaya B, et al. NLRP6 deficiency in CD4 T cells decreases T cell survival associated with increased cell death. J Immunol. 2019;203(2):544-56. [View at Publisher] [DOI] [PMID] [Google Scholar]
42. Nahumi A , Pirdel L, Asadi A, Abdolmaleki A. Evaluation of NLR Family CARD Domain Containing 3 and NLR Family CARD Domain Containing 5 Gene Expression in Interferon Gamma-Treated Mesenchymal Stem Cells from Wharton's Jelly of Human Umbilical Cord. Gene Cell Tissue. 2022;9(2):e118882. [View at Publisher] [DOI] [Google Scholar]
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