Small extracellular vesicles derived from Nrf2-overexpressing human amniotic mesenchymal stem cells protect against lipopolysaccharide-induced acute lung injury by inhibiting NLRP3
Tóm tắt
Acute lung injury (ALI) is a major cause of respiratory failure in critically ill patients that results in significant morbidity and mortality. Recent studies indicate that cell-based therapies may be beneficial in the treatment of ALI. We recently demonstrated that Nrf2-overexpressing human amniotic mesenchymal stem cells (hAMSCs) reduce lung injury, fibrosis and inflammation in lipopolysaccharide (LPS)-challenged mice. Here we tested whether small extracellular vesicles (sEVs) derived from Nrf2-overexpressing hAMSCs (Nrf2-sEVs) could protect against ALI. sEVs were isolated from hAMSCs that overexpressed (Nrf2-sEVs) or silenced (siNrf2-sEVs) Nrf2. We examined the effects of sEVs treatment on lung inflammation in a mouse model of ALI, where LPS was administered intratracheally to mice, and lung tissues and bronchoalveolar lavage fluid (BALF) were analyzed 24 h later. Histological analysis, immunofluorescence microscopy, western blotting, RT-PCR and ELISA were used to measure the inflammatory response in the lungs and BALF. We found that sEVs from hAMSCs are protective in ALI and that Nrf2 overexpression promotes protection against lung disease. Nrf2-sEVs significantly reduced lung injury in LPS-challenged mice, which was associated with decreased apoptosis, reduced infiltration of neutrophils and macrophages, and inhibition of pro-inflammatory cytokine expression. We further show that Nrf2-sEVs act by inhibiting the activation of the NLRP3 inflammasome and promoting the polarization of M2 macrophages. Our data show that overexpression of Nrf2 protects against LPS-induced lung injury, and indicate that a novel therapeutic strategy using Nrf2-sEVs may be beneficial against ALI.
Tài liệu tham khảo
Ware LB, Matthay MA. The acute respiratory distress syndrome. N Engl J Med. 2000;342:1334–49.
Fanelli V, Ranieri VM. Mechanisms and clinical consequences of acute lung injury. Ann Am Thorac Soc. 2015;12(Suppl 1):3–8.
Johnson ER, Matthay MA. Acute lung injury: epidemiology, pathogenesis, and treatment. J Aerosol Med Pulm Drug Deliv. 2010;23:243–52.
Goss CH, Brower RG, Hudson LD, Rubenfeld GD. Incidence of acute lung injury in the United States. Crit Care Med. 2003;31:1607–11.
Rathbun KP, Bourgault AM, Sole MLJCCN. Oral microbes in hospital-acquired pneumonia: practice and research implications. Crit Care Nurse. 2022;42:47–54.
Chen H, Bai C, Wang X. The value of the lipopolysaccharide-induced acute lung injury model in respiratory medicine. Expert Rev Respir Med. 2010;4:773–83.
Sweeney RM, Griffiths M, McAuley D. Treatment of acute lung injury: current and emerging pharmacological therapies. Semin Respir Crit Care Med. 2013;34:487–98.
Gotts JE, Matthay MA. Mesenchymal stem cells and acute lung injury. Crit Care Clin. 2011;27:719–33.
Benayahu D. Db. Mesenchymal stem cell differentiation and usage for biotechnology applications: tissue engineering and food manufacturing. Biomater Transl. 2022;3:17–23.
Adak S, Mukherjee S, Sen D. Mesenchymal stem cell as a potential therapeutic for inflammatory bowel disease- myth or reality? Curr Stem Cell Res Therapy. 2017;12:644–57.
Kotton DN, Ma BY, Cardoso WV, Sanderson EA, Summer RS, Williams MC, et al. Bone marrow-derived cells as progenitors of lung alveolar epithelium. Development. 2001;128:5181–8.
McIntyre LA, Moher D, Fergusson DA, Sullivan KJ, Mei SH, Lalu M, et al. Efficacy of mesenchymal stromal cell therapy for acute lung Injury in preclinical animal models: a systematic review. PloS one. 2016;11:e0147170.
Jiang X, Jiang X, Qu C, Chang P, Zhang C, Qu Y, et al. Intravenous delivery of adipose-derived mesenchymal stromal cells attenuates acute radiation-induced lung injury in rats. Cytotherapy. 2015;17:560–70.
Xu Y, Xiang J, Zhao H, Liang H, Huang J, Li Y, et al. Human amniotic fluid stem cells labeled with up-conversion nanoparticles for imaging-monitored repairing of acute lung injury. Biomaterials. 2016;100:91–100.
Kim SW, Zhang HZ, Kim CE, Kim JM, Kim MH. Amniotic mesenchymal stem cells with robust chemotactic properties are effective in the treatment of a myocardial infarction model. Int J Cardiol. 2013;168:1062–9.
Zhou H, Zhang H, Yan Z, Xu R. Transplantation of human amniotic mesenchymal stem cells promotes neurological recovery in an intracerebral hemorrhage rat model. Biochem Biophys Res Commun. 2016;475:202–8.
Zhou HL, Zhang XJ, Zhang MY, Yan ZJ, Xu ZM, Xu RX. Transplantation of human amniotic mesenchymal stem cells promotes functional recovery in a rat model of traumatic spinal cord Injury. Neurochem Res. 2016;41:2708–18.
Kim KS, Kim HS, Park JM, Kim HW, Park MK, Lee HS, et al. Long-term immunomodulatory effect of amniotic stem cells in an Alzheimer’s disease model. Neurobiol Aging. 2013;34:2408–20.
Zhang S, Jiang W, Ma L, Liu Y, Zhang X, Wang S. Nrf2 transfection enhances the efficacy of human amniotic mesenchymal stem cells to repair lung injury induced by lipopolysaccharide. J Cell Biochem. 2018;119:1627–36.
Ren K. Exosomes in perspective: a potential surrogate for stem cell therapy. Odontology. 2019;107:271–84.
Phinney DG, Pittenger MF. Concise review: MSC-derived exosomes for cell-free therapy. Stem Cells. 2017;35:851–8.
Zubarev I, Vladimirtsev D, Vorontsova M, Blatov I, Shevchenko K, Zvereva S, et al. Viral membrane Fusion Proteins and RNA sorting mechanisms for the molecular delivery by exosomes. Cells. 2021;10:3043.
Lässer C, Eldh M, Lötvall J. Isolation and characterization of RNA-containing exosomes. J Vis Exp JoVE. 2012;59:e3037.
Kalluri R, LeBleu VS. The biology, function, and biomedical applications of exosomes. 367. New York: Science; 2020.
Wang X, Zhou G, Zhou W, Wang X, Wang X, Miao C. Exosomes as a new delivery vehicle in inflammatory bowel sisease. Pharmaceutics. 2021;13:1644.
Kojima M, Gimenes-Junior JA, Chan TW, Eliceiri BP, Baird A, Costantini TW, et al. Exosomes in postshock mesenteric lymph are key mediators of acute lung injury triggering the macrophage activation via toll-like receptor 4. FASEB J Off Publ Fed Am Soc Exp Biol. 2018;32:97–110.
Yi X, Wei X, Lv H, An Y, Li L, Lu P, et al. Exosomes derived from microRNA-30b-3p-overexpressing mesenchymal stem cells protect against lipopolysaccharide-induced acute lung injury by inhibiting SAA3. Exp Cell Res. 2019;383:111454.
Jiang K, Yang J, Guo S, Zhao G, Wu H, Deng G. Peripheral circulating exosome-mediated delivery of miR-155 as a novel mechanism for acute lung inflammation. Mol Ther J Am Soc Gene Ther. 2019;27:1758–71.
Xu B, Chen SS, Liu MZ, Gan CX, Li JQ, Guo GH. Stem cell derived exosomes-based therapy for acute lung injury and acute respiratory distress syndrome: a novel therapeutic strategy. Life Sci. 2020;254:117766.
Li J, Deng X, Ji X, Shi X, Ying Z, Shen K, et al. Mesenchymal stem cell exosomes reverse acute lung injury through Nrf-2/ARE and NF-κB signaling pathways. PeerJ. 2020;8:e9928.
Nguyen T, Nioi P, Pickett CB. The Nrf2-antioxidant response element signaling pathway and its activation by oxidative stress. J Biol Chem. 2009;284:13291–5.
Saha S, Buttari B, Panieri E, Profumo E, Saso L. An overview of Nrf2 signaling pathway and its role in inflammation. Molecules (Basel, Switzerland). 2020;25:5474.
Panieri E, Saso L. Potential applications of NRF2 inhibitors in cancer therapy. Oxid Med Cell Longev. 2019;2019:8592348.
Cheng L, Zhang H, Wu F, Liu Z, Cheng Y, Wang C. Role of Nrf2 and its activators in cardiocerebral vascular disease. Oxidative Med Cell Longev. 2020;2020:4683943.
Johnson DA, Johnson JA. Nrf2–a therapeutic target for the treatment of neurodegenerative diseases. Free Radic Biol Med. 2015;88:253–67.
Carlson J, Price L, Deng H. Nrf2 and the Nrf2-interacting network in respiratory inflammation and diseases. Nrf2 and its Modulation in Inflammation. Vol 85. Springer, Cham, 2020; pp. 51–76.
Wei J, Chen G, Shi X, Zhou H, Liu M, Chen Y, et al. Nrf2 activation protects against intratracheal LPS induced mouse/murine acute respiratory distress syndrome by regulating macrophage polarization. Biochem Biophys Res Commun. 2018;500:790–6.
Hennig P, Garstkiewicz M, Grossi S, Di Filippo M, French LE, Beer HD. The crosstalk between Nrf2 and inflammasomes. Int J Mol Sci. 2018;19:562.
Liu X, Zhang X, Ding Y, Zhou W, Tao L, Lu P, et al. Nuclear factor E2-Related Factor-2 negatively regulates NLRP3 inflammasome activity by inhibiting reactive oxygen species-induced NLRP3 priming. Antioxid Redox Signal. 2017;26:28–43.
Dhar R, Zhang L, Li Y, Rana MN, Hu Z, Li Z, et al. Electroacupuncture ameliorates cardiopulmonary bypass induced apoptosis in lung via ROS/Nrf2/NLRP3 inflammasome pathway. Life Sci. 2019;238:116962.
Jones HD, Crother TR, Gonzalez-Villalobos RA, Jupelli M, Chen S, Dagvadorj J, et al. The NLRP3 inflammasome is required for the development of hypoxemia in LPS/mechanical ventilation acute lung injury. Am J Respir Cell Mol Biol. 2014;50:270–80.
Grailer JJ, Canning BA, Kalbitz M, Haggadone MD, Dhond RM, Andjelkovic AV, et al. Critical role for the NLRP3 inflammasome during acute lung injury. J Immunol (Baltimore, Md: 1950). 2014;192:5974-83.
Du Z, Wang Q, Ma G, Jiao J, Jiang D, Zheng X, et al. Inhibition of Nrf2 promotes the antitumor effect of Pinelliae rhizome in papillary thyroid cancer. J Cell Physiol. 2019;234:13867–77.
Zhang C, Guo F, Chang M, Zhou Z, Yi L, Gao C, et al. Exosome-delivered syndecan-1 rescues acute lung injury via a FAK/p190RhoGAP/RhoA/ROCK/NF-κB signaling axis and glycocalyx enhancement. Exp Cell Res. 2019;384:111596.
Kowal J, Arras G, Colombo M, Jouve M, Morath JP, Primdal-Bengtson B, et al. Proteomic comparison defines novel markers to characterize heterogeneous populations of extracellular vesicle subtypes. Proc Natl Acad Sci USA. 2016;113:E968-77.
Zheng W, Huang W, Chen J, Zhou J, Xu X, Xu G, et al. Identification of colorectal cell exosomes by Raman spectral analysis. 2018;11:12991–3002.
Peng Y, Wu Q, Tang H, Chen J, Wu Q, Yuan X, et al. NLRP3 regulated CXCL12 expression in acute neutrophilic lung Injury. J Inflamm Res. 2020;13:377–86.
Domscheit H, Hegeman MA, Carvalho N, Spieth PM. Molecular dynamics of lipopolysaccharide-induced lung injury in rodents. Front Physiol. 2020;11:36.
Kim J, Cha YN, Surh YJ. A protective role of nuclear factor-erythroid 2-related factor-2 (Nrf2) in inflammatory disorders. Mutat Res. 2010;690:12–23.
Naito Y, Takagi T, Higashimura Y. Heme oxygenase-1 and anti-inflammatory M2 macrophages. Arch Biochem Biophys. 2014;564:83–8.
Atabai K, Matthay MA. The pulmonary physician in critical care. 5: Acute lung injury and the acute respiratory distress syndrome: definitions and epidemiology. Thorax. 2002;57:452–8.
Gao S, Chen T, Hao Y, Zhang F, Tang X, Wang D, et al. Exosomal miR-135a derived from human amnion mesenchymal stem cells promotes cutaneous wound healing in rats and fibroblast migration by directly inhibiting LATS2 expression. Stem Cell Res Ther. 2020;11:56.
Mosser DM, Edwards JP. Exploring the full spectrum of macrophage activation. Nat Rev Immunol. 2008;8:958–69.
Johnston LK, Rims CR, Gill SE, McGuire JK, Manicone AM. Pulmonary macrophage subpopulations in the induction and resolution of acute lung injury. Am J Respir Cell Mol Biol. 2012;47:417–26.
Luo YH, Cheng HJ, Tsai FY, Tsou TC, Lin SY, Lin P. Primary amine modified gold nanodots regulate macrophage function and antioxidant response: potential therapeutics targeting of Nrf2. Int J Nanomedicine. 2020;15:8411–26.
Pang Z, Xu Y, Zhu Q. Early growth response 1 suppresses macrophage phagocytosis by inhibiting NRF2 activation through upregulation of autophagy during pseudomonas aeruginosa infection. Front Cell Infect Microbiol. 2021;11:773665.