91
Views
0
CrossRef citations to date
0
Altmetric
ORIGINAL RESEARCH

Actives from the Micro-Immunotherapy Medicine 2LMIREG® Reduce the Expression of Cytokines and Immune-Related Markers Including Interleukin-2 and HLA-II While Modulating Oxidative Stress and Mitochondrial Function

ORCID Icon, , & ORCID Icon
Pages 1161-1181 | Received 03 Nov 2023, Accepted 13 Feb 2024, Published online: 20 Feb 2024

References

  • Pagano G, Aiello talamanca A, Castello G, et al. Oxidative stress and mitochondrial dysfunction across broad-ranging pathologies: toward mitochondria-targeted clinical strategies. Oxid Med Cell Longev. 2014;2014:e541230. doi:10.1155/2014/541230
  • Wallace DC. A mitochondrial paradigm of metabolic and degenerative diseases, aging, and cancer: a Dawn for evolutionary medicine. Annu Rev Genet. 2005;39:359–407. doi:10.1146/annurev.genet.39.110304.095751
  • Hill S, Van Remmen H. Mitochondrial stress signaling in longevity: a new role for mitochondrial function in aging. Redox Biol. 2014;2:936–944. doi:10.1016/j.redox.2014.07.005
  • Vaamonde-García C, Riveiro‐Naveira RR, Valcárcel‐Ares MN, et al. Mitochondrial dysfunction increases inflammatory responsiveness to cytokines in normal human chondrocytes. Arthritis Rheum. 2012;64:2927–2936. doi:10.1002/art.34508
  • López-Armada MJ, Riveiro-Naveira RR, Vaamonde-García C, Valcárcel-Ares MN. Mitochondrial dysfunction and the inflammatory response. Mitochondrion. 2013;13:106–118.
  • Bouhamida E, Morciano G, Perrone M, et al. The interplay of hypoxia signaling on mitochondrial dysfunction and inflammation in cardiovascular diseases and cancer: from molecular mechanisms to therapeutic approaches. Biology. 2022;11:300. doi:10.3390/biology11020300
  • Jacques C, Chatelais M, Fekir K, Brulefert A, Floris I. The unitary micro-immunotherapy medicine interferon-γ (4 CH) displays similar immunostimulatory and immunomodulatory effects than those of biologically active human interferon-γ on various cell types. Int J Mol Sci. 2022;23:2314. doi:10.3390/ijms23042314
  • Jacques C, Chatelais M, Fekir K, et al. The micro-immunotherapy medicine 2LEID exhibits an immunostimulant effect by boosting both innate and adaptive immune responses. Int J Mol Sci. 2021;23:110. doi:10.3390/ijms23010110
  • Floris I, et al. Pro-inflammatory cytokines at ultra-low dose exert anti-inflammatory effect in vitro: a possible mode of action involving sub-micron particles? Dose-Response Publ Int Hormesis Soc. 2020;18:1559325820961723.
  • Floris I, Appel K, Rose T, Lejeune B. 2LARTH®, a micro-immunotherapy medicine, exerts anti-inflammatory effects in vitro and reduces TNF-α and IL-1β secretion. J Inflamm Res. 2018;11:397–405. doi:10.2147/JIR.S174326
  • Floris I, García-González V, Palomares B, Appel K, Lejeune B. The micro-immunotherapy medicine 2LARTH® reduces inflammation and symptoms of rheumatoid arthritis in vivo. Int J Rheumatol. 2020;2020:1594573. doi:10.1155/2020/1594573
  • Jacques C, Floris I, Lejeune B. Ultra-low dose cytokines in rheumatoid arthritis, three birds with one stone as the rationale of the 2LARTH® Micro-immunotherapy treatment. Int J Mol Sci. 2021;22:6717. doi:10.3390/ijms22136717
  • Jacques C, Floris I. Special focus on the cellular anti-inflammatory effects of several micro-immunotherapy formulations: considerations regarding intestinal-, immune-axis-related- and neuronal-inflammation contexts. J Inflamm Res. 2022;15:6695–6717. doi:10.2147/JIR.S389614
  • Floris I, Chenuet P, Togbe D, Volteau C, Lejeune B. Potential role of the micro-immunotherapy medicine 2LALERG in the treatment of pollen-induced allergic inflammation. Dose-Response Publ Int Hormesis Soc. 2020;18:1559325820914092.
  • Jacques C, Marchesi I, Fiorentino FP, et al. A micro-immunotherapy sequential medicine mim-seq displays immunomodulatory effects on human macrophages and anti-tumor properties towards in vitro 2D and 3D models of colon carcinoma and in an in vivo subcutaneous xenograft colon carcinoma model. Int J Mol Sci. 2022;23:6059. doi:10.3390/ijms23116059
  • Ji D, Yin J-Y, Li D-F, et al. Effects of inflammatory and anti-inflammatory environments on the macrophage mitochondrial function. Sci Rep. 2020;10:20324. doi:10.1038/s41598-020-77370-x
  • Watanabe T, Tanigawa T, Nadatani Y, et al. Mitochondrial disorders in NSAIDs-induced small bowel injury. J Clin Biochem Nutr. 2011;48:117–121. doi:10.3164/jcbn.10-73
  • Vaux DL. Research methods: know when your numbers are significant. Nature. 2012;492:180–181. doi:10.1038/492180a
  • Amersfoort J, Eelen G, Carmeliet P. Immunomodulation by endothelial cells — partnering up with the immune system? Nat Rev Immunol. 2022;22:576–588. doi:10.1038/s41577-022-00694-4
  • Maenaka A, Kenta I, Ota A, et al. Interferon-γ-induced HLA Class II expression on endothelial cells is decreased by inhibition of mTOR and HMG-CoA reductase. FEBS Open Bio. 2020;10:927–936. doi:10.1002/2211-5463.12854
  • Ferrà-Cañellas MDM, Munar‐Bestard M, Garcia‐Sureda L, et al. BMP4 micro-immunotherapy increases collagen deposition and reduces PGE2 release in human gingival fibroblasts and increases tissue viability of engineered 3D gingiva under inflammatory conditions. J Periodontol. 2021;92:1448–1459. doi:10.1002/JPER.20-0552
  • Ansari MY, Khan NM, Ahmad I, Haqqi TM. Parkin clearance of dysfunctional mitochondria regulates ROS levels and increases survival of human chondrocytes. Osteoarthritis Cartilage. 2018;26:1087–1097. doi:10.1016/j.joca.2017.07.020
  • Yang D, Elner SG, Bian Z-M, et al. Pro-inflammatory cytokines increase reactive oxygen species through mitochondria and NADPH oxidase in cultured RPE cells. Exp Eye Res. 2007;85:462–472. doi:10.1016/j.exer.2007.06.013
  • Akkaya B. Increased mitochondrial biogenesis and ROS production accompany prolonged CD4+ T cell activation. J Immunol. 2018;201:3294–3306.
  • Krstić J, Trivanović D, Mojsilović S, Santibanez JF. Transforming growth factor-beta and oxidative stress interplay: implications in tumorigenesis and cancer progression. Oxid Med Cell Longev. 2015;2015:654594. doi:10.1155/2015/654594
  • Jacques C, Floris I. How an immune-factor-based formulation of micro-immunotherapy could interfere with the physiological processes involved in the atopic march. Int J Mol Sci. 2023;24:1483. doi:10.3390/ijms24021483
  • Ferrà-Cañellas MDM, Munar-Bestard M, Floris I, et al. A sequential micro-immunotherapy medicine increases collagen deposition in human gingival fibroblasts and in an engineered 3D gingival model under inflammatory conditions. Int J Mol Sci. 2023;24:10484. doi:10.3390/ijms241310484
  • Zhang H, Wang L, Chu Y. Reactive oxygen species: the signal regulator of B cell. Free Radic Biol Med. 2019;142:16–22. doi:10.1016/j.freeradbiomed.2019.06.004
  • Bystrom J, Taher TE, Henson SM, Gould DJ, Mageed RA. Metabolic requirements of Th17 cells and of B cells: regulation and defects in health and in inflammatory diseases. Front Immunol. 2022;13:990794. doi:10.3389/fimmu.2022.990794
  • Vené R, Delfino L, Castellani P, et al. Redox remodeling allows and controls B-cell activation and differentiation. Antioxid Redox Signal. 2010;13:1145–1155. doi:10.1089/ars.2009.3078
  • Bertolotti M, Yim SH, Garcia-Manteiga JM, et al. B- to plasma-cell terminal differentiation entails oxidative stress and profound reshaping of the antioxidant responses. Antioxid Redox Signal. 2010;13:1133–1144. doi:10.1089/ars.2009.3079
  • Winterbourn CC, Kettle AJ, Hampton MB. Reactive oxygen species and neutrophil function. Annu Rev Biochem. 2016;85:765–792.
  • Vorobjeva N, Prikhodko A, Galkin I, et al. Mitochondrial reactive oxygen species are involved in chemoattractant-induced oxidative burst and degranulation of human neutrophils in vitro. Eur J Cell Biol. 2017;96:254–265. doi:10.1016/j.ejcb.2017.03.003
  • Chen Y, Junger WG. Measurement of oxidative burst in neutrophils. Methods Mol Biol Clifton NJ. 2012;844:115–124.
  • Matsuyama S, Reed JC. Mitochondria-dependent apoptosis and cellular pH regulation. Cell Death Differ. 2000;7:1155–1165. doi:10.1038/sj.cdd.4400779
  • Donaghy L, Kraffe E, Le Goïc N, et al. Reactive oxygen species in unstimulated hemocytes of the pacific oyster Crassostrea gigas: a mitochondrial involvement. PLoS One. 2012;7:e46594. doi:10.1371/journal.pone.0046594
  • Jacques C, Marchand F, Chatelais M, Brulefert A, Floris I. Understanding the mode of action of a micro-immunotherapy formulation: pre-clinical evidence from the study of 2LEBV® active ingredients. Life Basel Switz. 2024;14:102.
  • Moussion C, Ortega N, Girard J-P. The IL-1-like cytokine IL-33 is constitutively expressed in the nucleus of endothelial cells and epithelial cells in vivo: a novel ‘alarmin’? PLoS One. 2008;3:e3331. doi:10.1371/journal.pone.0003331
  • Schmitz J, Owyang A, Oldham E, et al. IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines. Immunity. 2005;23:479–490. doi:10.1016/j.immuni.2005.09.015
  • Guo L, Wei G, Zhu J, et al. IL-1 family members and STAT activators induce cytokine production by Th2, Th17, and Th1 cells. Proc Natl Acad Sci U S A. 2009;106:13463–13468. doi:10.1073/pnas.0906988106
  • Paul WE, Zhu J. How are TH2-type immune responses initiated and amplified? Nat Rev Immunol. 2010;10:225–235. doi:10.1038/nri2735
  • Mai J, Virtue A, Shen J, Wang H, Yang X-F. An evolving new paradigm: endothelial cells – conditional innate immune cells. J Hematol Oncol. 2013;6:61.
  • Austrup F, Vestweber D, Borges E, et al. P- and E-selectin mediate recruitment of T-helper-1 but not T-helper-2 cells into inflamed tissues. Nature. 1997;385:81–83. doi:10.1038/385081a0
  • Cho KW, Morris D, DelProposto J, et al. An MHC II-dependent activation loop between adipose tissue macrophages and CD4+ T cells controls obesity-induced inflammation. Cell Rep. 2014;9:605–617. doi:10.1016/j.celrep.2014.09.004
  • Morris DL, Cho KW, DelProposto JL, et al. Adipose tissue macrophages function as antigen-presenting cells and regulate adipose tissue CD4+ T cells in mice. Diabetes. 2013;62:2762–2772. doi:10.2337/db12-1404
  • Sena LA, Li S, Jairaman A, et al. Mitochondria are required for antigen-specific T cell activation through reactive oxygen species signaling. Immunity. 2013;38:225–236. doi:10.1016/j.immuni.2012.10.020
  • Yang Z-Z, Grote DM, Ziesmer SC, et al. Soluble and membrane-bound TGF-β-mediated regulation of intratumoral T cell differentiation and function in B-cell non-Hodgkin lymphoma. PLoS One. 2013;8:e59456.
  • Kimura A, Kishimoto T. IL-6: regulator of Treg/Th17 balance. Eur J Immunol. 2010;40:1830–1835.
  • Tau GZ, Von der Weid T, Lu B, et al. Interferon γ signaling alters the function of T helper type 1 cells. J Exp Med. 2000;192:977–986. doi:10.1084/jem.192.7.977
  • Laouini D, Alenius H, Bryce P, et al. IL-10 is critical for Th2 responses in a murine model of allergic dermatitis. J Clin Invest. 2003;112:1058–1066.
  • Ross SH, Cantrell DA. Signaling and function of interleukin-2 in T lymphocytes. Annu Rev Immunol. 2018;36:411–433. doi:10.1146/annurev-immunol-042617-053352
  • Laurence A, Tato CM, Davidson TS, et al. Interleukin-2 signaling via STAT5 constrains T helper 17 cell generation. Immunity. 2007;26:371–381. doi:10.1016/j.immuni.2007.02.009
  • Noster R, de Koning H, Sallusto F, Zielinski C. Two types of human Th17 cells with pro- and anti-inflammatory properties and distinct roles in autoinflammation. Pediatr Rheumatol Online J. 2015;13:O49. doi:10.1186/1546-0096-13-S1-O49
  • McBride HM, Neuspiel M, Wasiak S. Mitochondria: more than just a powerhouse. Curr Biol CB. 2006;16:R551–560.
  • Mills EL, Kelly B, O’Neill LAJ. Mitochondria are the powerhouses of immunity. Nat Immunol. 2017;18:488–498. doi:10.1038/ni.3704
  • Missiroli S, Genovese I, Perrone M, et al. The role of mitochondria in inflammation: from cancer to neurodegenerative disorders. J Clin Med. 2020;9:740. doi:10.3390/jcm9030740
  • Mohanty A, Tiwari-Pandey R, Pandey NR. Mitochondria: the indispensable players in innate immunity and guardians of the inflammatory response. J Cell Commun Signal. 2019;13:303–318. doi:10.1007/s12079-019-00507-9
  • Cao Z, Zhao M, Sun H, et al. Roles of mitochondria in neutrophils. Front Immunol. 2022;13:934444. doi:10.3389/fimmu.2022.934444
  • Wang Y, Li N, Zhang X, Horng T. Mitochondrial metabolism regulates macrophage biology. J Biol Chem. 2021;297:100904. doi:10.1016/j.jbc.2021.100904
  • Sandoval H, Kodali S, Wang J. Regulation of B cell fate, survival, and function by mitochondria and autophagy. Mitochondrion. 2018;41:58–65. doi:10.1016/j.mito.2017.11.005
  • Kolaczkowska E, Kubes P. Neutrophil recruitment and function in health and inflammation. Nat Rev Immunol. 2013;13:159–175. doi:10.1038/nri3399
  • Kuwabara WMT, Zhang L, Schuiki I, et al. NADPH oxidase-dependent production of reactive oxygen species induces endoplasmatic reticulum stress in neutrophil-like HL60 cells. PLoS One. 2015;10:e0116410. doi:10.1371/journal.pone.0116410
  • Yang Y, Bazhin AV, Werner J, Karakhanova S. Reactive oxygen species in the immune system. Int Rev Immunol. 2013;32:249–270. doi:10.3109/08830185.2012.755176
  • West AP, Brodsky IE, Rahner C, et al. TLR signalling augments macrophage bactericidal activity through mitochondrial ROS. Nature. 2011;472:476–480.
  • Ganeshan K, Chawla A. Metabolic regulation of immune responses. Annu Rev Immunol. 2014;32:609–634. doi:10.1146/annurev-immunol-032713-120236
  • Kaminski MM, Sauer SW, Klemke CD, et al. Mitochondrial reactive oxygen species control T cell activation by regulating IL-2 and IL-4 expression: mechanism of ciprofloxacin-mediated immunosuppression. J Immunol. 2010;184:4827–4841.
  • Palacios R. HLA-DR antigens render interleukin-2-producer T lymphocytes sensitive to interleukin-1. Scand J Immunol. 1981;14:321–326. doi:10.1111/j.1365-3083.1981.tb00571.x
  • Salgado FJ, Lojo J, Fernández‐Alonso CM, et al. Interleukin-dependent modulation of HLA-DR expression on CD4 and CD8 activated T cells. Immunol Cell Biol. 2002;80:138–147. doi:10.1046/j.1440-1711.2002.01055.x
  • Abdel-Salam BKA-H. Comparing effects of interleukin-2 and interleukin-4 on the expression of MHC class II, CD80 and CD86 on polymorphonuclear neutrophils. Egypt J Med Hum Genet. 2010;11:115–120. doi:10.1016/j.ejmhg.2010.05.002
  • Liu R-M, Desai LP. Reciprocal regulation of TGF-β and reactive oxygen species: a perverse cycle for fibrosis. Redox Biol. 2015;6:565–577. doi:10.1016/j.redox.2015.09.009
  • Younes N, Alsahan BS, Al-Mesaifri AJ, et al. JC-10 probe as a novel method for analyzing the mitochondrial membrane potential and cell stress in whole zebrafish embryos. Toxicol Res. 2022;11:77–87. doi:10.1093/toxres/tfab114
  • Koshiba T, Yasukawa K, Yanagi Y, Kawabata S. Mitochondrial membrane potential is required for MAVS-mediated antiviral signaling. Sci Signal. 2011;4:ra7. doi:10.1126/scisignal.2001147
  • Devadas S, Zaritskaya L, Rhee SG, Oberley L, Williams MS. Discrete generation of superoxide and hydrogen peroxide by T cell receptor stimulation: selective regulation of mitogen-activated protein kinase activation and fas ligand expression. J Exp Med. 2002;195:59–70. doi:10.1084/jem.20010659
  • Miranda D, Jara C, Ibañez J, et al. PGC-1 α -dependent mitochondrial adaptation is necessary to sustain IL-2-induced activities in human NK cells. Mediators Inflamm. 2016;2016:9605253. doi:10.1155/2016/9605253
  • Abe Y, Sakairi T, Beeson C, Kopp JB. TGF-β1 stimulates mitochondrial oxidative phosphorylation and generation of reactive oxygen species in cultured mouse podocytes, mediated in part by the mTOR pathway. Am J Physiol - Ren Physiol. 2013;305:F1477–F1490. doi:10.1152/ajprenal.00182.2013
  • Morris G, Gevezova M, Sarafian V, Maes M. Redox regulation of the immune response. Cell Mol Immunol. 2022;19:1079–1101. doi:10.1038/s41423-022-00902-0
  • Bettonville M, d’Aria S, Weatherly K, et al. Long-term antigen exposure irreversibly modifies metabolic requirements for T cell function. eLife. 2018;7:e30938. doi:10.7554/eLife.30938
  • Yarosz EL, Chang C-H. The role of reactive oxygen species in regulating T cell-mediated immunity and disease. Immune Netw. 2018;18:e14. doi:10.4110/in.2018.18.e14
  • Tavassolifar MJ, Vodjgani M, Salehi Z, Izad M. The influence of reactive oxygen species in the immune system and pathogenesis of multiple sclerosis. Autoimmune Dis. 2020;2020:5793817. doi:10.1155/2020/5793817