Human umbilical cord mesenchymal stem cell-derived mitochondria (PN-101) attenuate LPS-induced inflammatory responses by inhibiting NFκB signaling pathway
2
조회
0
다운로드
1
인용
0
참고문헌
키워드
초록
Inflammation is one of the body’s natural responses to injuryand illness as part of the healing process. However, persistentinflammation can lead to chronic inflammatory diseases andmulti-organ failure. Altered mitochondrial function has beenimplicated in several acute and chronic inflammatory diseasesby inducing an abnormal inflammatory response. Therefore,treating inflammatory diseases by recovering mitochondrialfunction may be a potential therapeutic approach. Recently,mitochondrial transplantation has been proven to be beneficialin hyperinflammatory animal models. However, it is unclearhow mitochondrial transplantation attenuates inflammatoryresponses induced by external stimuli. Here, we isolated mitochondriafrom umbilical cord-derived mesenchymal stem cells,referred as to PN-101. We found that PN-101 could significantlyreduce LPS-induced mortality in mice. In addition, inphorbol 12-myristate 13-acetate (PMA)-treated THP-1 macrophages,PN-101 attenuated LPS-induced increase productionof pro-inflammatory cytokines. Furthermore, the anti-inflammatoryeffect of PN-101 was mediated by blockade of phosphorylation,nuclear translocation, and trans-activity of NFκB. Takentogether, our results demonstrate that PN-101 has therapeuticpotential to attenuate pathological inflammatory responses.
Abstract
Inflammation is one of the body’s natural responses to injuryand illness as part of the healing process. However, persistentinflammation can lead to chronic inflammatory diseases andmulti-organ failure. Altered mitochondrial function has beenimplicated in several acute and chronic inflammatory diseasesby inducing an abnormal inflammatory response. Therefore,treating inflammatory diseases by recovering mitochondrialfunction may be a potential therapeutic approach. Recently,mitochondrial transplantation has been proven to be beneficialin hyperinflammatory animal models. However, it is unclearhow mitochondrial transplantation attenuates inflammatoryresponses induced by external stimuli. Here, we isolated mitochondriafrom umbilical cord-derived mesenchymal stem cells,referred as to PN-101. We found that PN-101 could significantlyreduce LPS-induced mortality in mice. In addition, inphorbol 12-myristate 13-acetate (PMA)-treated THP-1 macrophages,PN-101 attenuated LPS-induced increase productionof pro-inflammatory cytokines. Furthermore, the anti-inflammatoryeffect of PN-101 was mediated by blockade of phosphorylation,nuclear translocation, and trans-activity of NFκB. Takentogether, our results demonstrate that PN-101 has therapeuticpotential to attenuate pathological inflammatory responses.
참고문헌 (38)
- Giorgi C, "The machineries, regulation and cellular functions of mitochondrial calcium", Nat Rev Mol Cell Biol, 19, pp.713~730 (2018)
- Nunnari J, "Mitochondria : in sickness and in health", Cell, 148, pp.1145~1159 (2012)
- Suomalainen A, "Mitochondrial diseases : the contribution of organelle stress responses to pathology", Nat Rev Mol Cell Biol, 19, pp.77~92 (2018)
- Lopez-Armada MJ, "Mitochondrial dysfunction and the inflammatory response", Mitochondrion, 13, pp.106~118 (2013)
- Kim TH, "The role of endogenous histamine on the patho-genesis of the lipopolysaccharide(LPS)-induced, acute lung injury : a pilot study", Inflammation, 29, pp.72~80 (2005)
- Brigham KL, "Endotoxin and lung injury", Am Rev Respir Dis, 133, pp.913~927 (1986)
- Kawai T, "Signaling to NF-kappaB by Toll-like receptors", Trends Mol Med, 13, pp.460~469 (2007)
- Hayden MS, "NF-kappaB and the immune response", Oncogene, 25, pp.6758~6780 (2006)
- Gollihue JL, "Prospects for therapeutic mitochondrial transplantation", Mitochondrion, 35, pp.70~79 (2017)
- McCully JD, "Mitochondrial transplantation : from animal models to clinical use in humans", Mitochondrion, 34, pp.127~134 (2017)
- McCully JD, "Mitochondrial transplantation for therapeutic use", Clin Transl Med, 5, pp.16~ (2016)
- Jabbari H, "Mitochondrial transplantation ameliorates ischemia", reperfusion-induced kidney injury in rat, 2020, pp.1866, 165809~
- Katrangi E, "Xenogenic transfer of isolated murine mitochondria into human rho0 cells can improve respiratory function", Rejuvenation Res, 10, pp.561~570 (2007)
- Kitani T, "Direct human mitochondrial transfer : a novel concept based on the endosymbiotic theory", Transplant Proc, 46, pp.1233~1236 (2014)
- Kesner EE, "Characteristics of mitochondrial transformation into human cells", Sci Rep, 6, pp.26057~ (2016)
- Kim MJ, "Delivery of exogenous mitochondria via centrifugation enhances cellular metabolic function", Sci Rep, 8, pp.3330~ (2018)
- Cowan DB, "Intracoronary delivery of mitochondria to the ischemic heart for cardioprotection", PLoS One, 11, pp.e0160889~ (2016)
- Shi X, "Intravenous administration of mitochondria for treating experimental Parkinson’s disease", Mitochondrion, 34, pp.91~100 (2017)
- Fu A, "Mitotherapy for fatty liver by intravenous administration of exogenous mitochondria in male mice", Front Pharmacol, 8, pp.241~ (2017)
- Spinazzi M, "Assessment of mitochondrial respiratory chain enzymatic activities on tissues and cultured cells", Nat Protoc, 7, pp.1235~1246 (2012)
- Yamamoto Y, "Septic shock is associated with receptor for advanced glycation end products ligation of LPS", J Immunol, 186, pp.3248~3257 (2011)
- Kany S, "Cytokines in inflammatory disease", Int J Mol Sci, 20, pp.6008~6038 (2019)
- Bonizzi G, "The two NF-kappaB activation pathways and their role in innate and adaptive immunity", Trends Immunol, 25, pp.280~288 (2004)
- Iwai K, "Diverse ubiquitin signaling in NF-kappaB activation", Trends Cell Biol, 22, pp.355~364 (2012)
- Kandasamy K, "Lipopolysaccharide induces endoplasmic store Ca2+-dependent inflammatory responses in lung microvessels", PLoS One, 8, pp.e63465~ (2013)
- Berry CT, "STIM-and Orai-mediated calcium entry controls NF-kappaB activity and function in lymphocytes", Cell Calcium, 74, pp.131~143 (2018)
- Gewirtz AT, "Salmonella typhimurium induces epithelial IL-8 expression via Ca(2+)-mediated activation of the NF-kappaB pathway", J Clin Invest, 105, pp.79~92 (2000)
- Sandhir R, "Mitochondria as a centrally positioned hub in the innate immune response", Biochim Biophys Acta Mol Basis Dis, 1863, pp.1090~1097 (2017)
- Wang Y, "Mitochondrial transplantation attenuates lipopolysaccharide-induced depression-like behaviors", Prog Neuropsychopharmacol Biol Psychiatry, 93, pp.240~249 (2019)
- Hwang JW, "The immune modulatory effects of mitochondrial transplantation on cecal slurry model in rat", Crit Care, 25, pp.20~ (2021)
- Liu T, "NF-kappaB signaling in inflammation", Signal Transduct Target Ther, 2, pp.e17023~ (2017)
- 이영경, "Mitochondrial dysfunction suppresses p53 expression via calcium-mediated nuclear factor-kB signaling in HCT116 human colorectal carcinoma cells", BMB Reports, 51(6), pp.296~301 (2018), 생화학분자생물학회
- Ryan DG, "Coupling Krebs cycle metabolites to signalling in immunity and cancer", Nat Metab, 1, pp.16~33 (2019)
- Bikash Thapa, "Metabolic influence on macrophage polarization and pathogenesis", BMB Reports, 52(6), pp.360~372 (2019), 생화학분자생물학회[DOI]
- Mills EL, "Succinate dehydrogenase supports metabolic repurposing of mitochondria to drive inflammatory macrophages", Cell, 167, pp.457~470 (2016)
- Lampropoulou V, "Itaconate links inhibition of succinate dehydrogenase with macrophage metabolic remodeling and regulation of inflammation", Cell Metab, 24, pp.158~166 (2016)
- Sciacovelli M, "Fumarate is an epigenetic modifier that elicits epithelial-to-mesenchymal transition", Nature, 537, pp.544~547 (2016)
- Kristian T, "Isolation of mitochondria with high respiratory control from primary cultures of neurons and astrocytes using nitrogen cavitation", J Neurosci Methods, 152, pp.136~143 (2006)