BMB Reports

Korean Society for Biochemistry and Molecular Biology (생화학분자생물학회)
권호 표지
DOI QR코드

DOI QR Code

Human umbilical cord mesenchymal stem cell-derived mitochondria (PN-101) attenuate LPS-induced inflammatory responses by inhibiting NFκB signaling pathway

  • Received : 2021.06.28
  • Accepted : 2021.08.09
  • Published : 2022.03.31
Download PDF
⟨ Previous Next ⟩

Abstract

Inflammation is one of the body's natural responses to injury and illness as part of the healing process. However, persistent inflammation can lead to chronic inflammatory diseases and multi-organ failure. Altered mitochondrial function has been implicated in several acute and chronic inflammatory diseases by inducing an abnormal inflammatory response. Therefore, treating inflammatory diseases by recovering mitochondrial function may be a potential therapeutic approach. Recently, mitochondrial transplantation has been proven to be beneficial in hyperinflammatory animal models. However, it is unclear how mitochondrial transplantation attenuates inflammatory responses induced by external stimuli. Here, we isolated mitochondria from umbilical cord-derived mesenchymal stem cells, referred as to PN-101. We found that PN-101 could significantly reduce LPS-induced mortality in mice. In addition, in phorbol 12-myristate 13-acetate (PMA)-treated THP-1 macrophages, PN-101 attenuated LPS-induced increase production of pro-inflammatory cytokines. Furthermore, the anti-inflammatory effect of PN-101 was mediated by blockade of phosphorylation, nuclear translocation, and trans-activity of NFκB. Taken together, our results demonstrate that PN-101 has therapeutic potential to attenuate pathological inflammatory responses.

Keywords

Acknowledgement

We would like to thank various Paean Biotechnology Inc. members who participated in the project. This work was supported by NRF-2016R1A2B4007640 grant (to C-H Kim).

References

  1. Giorgi C, Marchi S and Pinton P (2018) The machineries, regulation and cellular functions of mitochondrial calcium. Nat Rev Mol Cell Biol 19, 713-730 https://doi.org/10.1038/s41580-018-0052-8
  2. Nunnari J and Suomalainen A (2012) Mitochondria: in sickness and in health. Cell 148, 1145-1159 https://doi.org/10.1016/j.cell.2012.02.035
  3. Suomalainen A and Battersby BJ (2018) Mitochondrial diseases: the contribution of organelle stress responses to pathology. Nat Rev Mol Cell Biol 19, 77-92 https://doi.org/10.1038/nrm.2017.66
  4. Lopez-Armada MJ, Riveiro-Naveira RR, Vaamonde-Garcia C and Valcarcel-Ares MN (2013) Mitochondrial dysfunction and the inflammatory response. Mitochondrion 13, 106-118 https://doi.org/10.1016/j.mito.2013.01.003
  5. Kim TH, Yoon HJ, Lim CM, Kim EK, Kim MJ and Koh Y (2005) The role of endogenous histamine on the pathogenesis of the lipopolysaccharide (LPS)-induced, acute lung injury: a pilot study. Inflammation 29, 72-80 https://doi.org/10.1007/s10753-006-9001-3
  6. Brigham KL and Meyrick B (1986) Endotoxin and lung injury. Am Rev Respir Dis 133, 913-927
  7. Kawai T and Akira S (2007) Signaling to NF-kappaB by Toll-like receptors. Trends Mol Med 13, 460-469 https://doi.org/10.1016/j.molmed.2007.09.002
  8. Hayden MS, West AP and Ghosh S (2006) NF-kappaB and the immune response. Oncogene 25, 6758-6780 https://doi.org/10.1038/sj.onc.1209943
  9. Gollihue JL and Rabchevsky AG (2017) Prospects for therapeutic mitochondrial transplantation. Mitochondrion 35, 70-79 https://doi.org/10.1016/j.mito.2017.05.007
  10. McCully JD, Cowan DB, Emani SM and Del Nido PJ (2017) Mitochondrial transplantation: from animal models to clinical use in humans. Mitochondrion 34, 127-134 https://doi.org/10.1016/j.mito.2017.03.004
  11. McCully JD, Levitsky S, Del Nido PJ and Cowan DB (2016) Mitochondrial transplantation for therapeutic use. Clin Transl Med 5, 16 https://doi.org/10.1186/s40169-016-0095-4
  12. Jabbari H, Roushandeh AM, Rostami MK et al (2020) Mitochondrial transplantation ameliorates ischemia/reperfusion-induced kidney injury in rat. Biochim Biophys Acta Mol Basis Dis 1866, 165809 https://doi.org/10.1016/j.bbadis.2020.165809
  13. Katrangi E, D'Souza G, Boddapati SV et al (2007) Xenogenic transfer of isolated murine mitochondria into human rho0 cells can improve respiratory function. Rejuvenation Res 10, 561-570 https://doi.org/10.1089/rej.2007.0575
  14. Kitani T, Kami D, Kawasaki T, Nakata M, Matoba S and Gojo S (2014) Direct human mitochondrial transfer: a novel concept based on the endosymbiotic theory. Transplant Proc 46, 1233-1236 https://doi.org/10.1016/j.transproceed.2013.11.133
  15. Kesner EE, Saada-Reich A and Lorberboum-Galski H (2016) Characteristics of mitochondrial transformation into human cells. Sci Rep 6, 26057 https://doi.org/10.1038/srep26057
  16. Kim MJ, Hwang JW, Yun CK, Lee Y and Choi YS (2018) Delivery of exogenous mitochondria via centrifugation enhances cellular metabolic function. Sci Rep 8, 3330 https://doi.org/10.1038/s41598-018-21539-y
  17. Cowan DB, Yao R, Akurathi V et al (2016) Intracoronary delivery of mitochondria to the ischemic heart for cardioprotection. PLoS One 11, e0160889 https://doi.org/10.1371/journal.pone.0160889
  18. Shi X, Zhao M, Fu C and Fu A (2017) Intravenous administration of mitochondria for treating experimental Parkinson's disease. Mitochondrion 34, 91-100 https://doi.org/10.1016/j.mito.2017.02.005
  19. Fu A, Shi X, Zhang H and Fu B (2017) Mitotherapy for fatty liver by intravenous administration of exogenous mitochondria in male mice. Front Pharmacol 8, 241 https://doi.org/10.3389/fphar.2017.00241
  20. Spinazzi M, Casarin A, Pertegato V, Salviati L and Angelini C (2012) Assessment of mitochondrial respiratory chain enzymatic activities on tissues and cultured cells. Nat Protoc 7, 1235-1246 https://doi.org/10.1038/nprot.2012.058
  21. Yamamoto Y, Harashima A, Saito H et al (2011) Septic shock is associated with receptor for advanced glycation end products ligation of LPS. J Immunol 186, 3248-3257 https://doi.org/10.4049/jimmunol.1002253
  22. Kany S, Vollrath JT and Relja B (2019) Cytokines in inflammatory disease. Int J Mol Sci 20, 6008-6038 https://doi.org/10.3390/ijms20236008
  23. Bonizzi G and Karin M (2004) The two NF-kappaB activation pathways and their role in innate and adaptive immunity. Trends Immunol 25, 280-288 https://doi.org/10.1016/j.it.2004.03.008
  24. Iwai K (2012) Diverse ubiquitin signaling in NF-kappaB activation. Trends Cell Biol 22, 355-364 https://doi.org/10.1016/j.tcb.2012.04.001
  25. Kandasamy K, Bezavada L, Escue RB and Parthasarathi K (2013) Lipopolysaccharide induces endoplasmic store Ca2+-dependent inflammatory responses in lung microvessels. PLoS One 8, e63465 https://doi.org/10.1371/journal.pone.0063465
  26. Berry CT, May MJ and Freedman BD (2018) STIM- and Orai-mediated calcium entry controls NF-kappaB activity and function in lymphocytes. Cell Calcium 74, 131-143 https://doi.org/10.1016/j.ceca.2018.07.003
  27. Gewirtz AT, Rao AS, Simon PO Jr et al (2000) Salmonella typhimurium induces epithelial IL-8 expression via Ca(2+)-mediated activation of the NF-kappaB pathway. J Clin Invest 105, 79-92 https://doi.org/10.1172/JCI8066
  28. Sandhir R, Halder A and Sunkaria A (2017) Mitochondria as a centrally positioned hub in the innate immune response. Biochim Biophys Acta Mol Basis Dis 1863, 1090-1097 https://doi.org/10.1016/j.bbadis.2016.10.020
  29. Wang Y, Ni J, Gao C et al (2019) Mitochondrial transplantation attenuates lipopolysaccharide- induced depression-like behaviors. Prog Neuropsychopharmacol Biol Psychiatry 93, 240-249 https://doi.org/10.1016/j.pnpbp.2019.04.010
  30. Hwang JW, Lee MJ, Chung TN et al (2021) The immune modulatory effects of mitochondrial transplantation on cecal slurry model in rat. Crit Care 25, 20 https://doi.org/10.1186/s13054-020-03436-x
  31. Liu T, Zhang L, Joo D and Sun SC (2017) NF-kappaB signaling in inflammation. Signal Transduct Target Ther 2, e17023
  32. Lee YK, Yi EY, Park SY et al (2018) Mitochondrial dysfunction suppresses p53 expression via calcium-mediated nuclear factor-kB signaling in HCT116 human colorectal carcinoma cells. BMB Rep 51, 296-301 https://doi.org/10.5483/BMBRep.2018.51.6.232
  33. Ryan DG, Murphy MP, Frezza C et al (2019) Coupling Krebs cycle metabolites to signalling in immunity and cancer. Nat Metab 1, 16-33 https://doi.org/10.1038/s42255-018-0014-7
  34. Thapa B and Lee K (2019) Metabolic influence on macrophage polarization and pathogenesis. BMB Rep 52, 360-372 https://doi.org/10.5483/bmbrep.2019.52.6.140
  35. Mills EL, Kelly B, Logan A et al (2016) Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages. Cell 167, 457-470 e413 https://doi.org/10.1016/j.cell.2016.08.064
  36. Lampropoulou V, Sergushichev A, Bambouskova M et al (2016) Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation. Cell Metab 24, 158-166 https://doi.org/10.1016/j.cmet.2016.06.004
  37. Sciacovelli M, Goncalves E, Johnson TI et al (2016) Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition. Nature 537, 544-547 https://doi.org/10.1038/nature19353
  38. Kristian T, Hopkins IB, McKenna MC and Fiskum G (2006) Isolation of mitochondria with high respiratory control from primary cultures of neurons and astrocytes using nitrogen cavitation. J Neurosci Methods 152, 136-143 https://doi.org/10.1016/j.jneumeth.2005.08.018