Mesenchymal stem cells shift the pro-inflammatory phenotype of neutrophils to ameliorate acute lung injury.
Acute lung injury
Mesenchymal stem cell
Mouse model
Neutrophil
Single-cell RNA sequencing
Journal
Stem cell research & therapy
ISSN: 1757-6512
Titre abrégé: Stem Cell Res Ther
Pays: England
ID NLM: 101527581
Informations de publication
Date de publication:
08 08 2023
08 08 2023
Historique:
received:
18
10
2022
accepted:
31
07
2023
medline:
10
8
2023
pubmed:
9
8
2023
entrez:
8
8
2023
Statut:
epublish
Résumé
Mesenchymal stem cell (MSC) treatment plays a major role in the management of acute lung injury (ALI), and neutrophils are the initial line of defense against ALI. However, the effect of MSCs on neutrophils in ALI remains mostly unknown. We investigated the characteristics of neutrophils in lung tissue of ALI mice induced by lipopolysaccharide after treatment with MSCs using single-cell RNA sequencing. Neutrophils separated from lung tissue in ALI were co-cultured with MSCs, and then samples were collected for reverse transcription-polymerase chain reaction and flow cytometry. During inflammation, six clusters of neutrophils were identified, annotated as activated, aged, and circulatory neutrophils. Activated neutrophils had higher chemotaxis, reactive oxygen species (ROS) production, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase scores than aged neutrophils. Circulatory neutrophils occurred mainly in healthy tissue and were characterized by higher expression of Cxcr2 and Sell. Activated neutrophils tended to exhibit higher expression of Cxcl10 and Cd47, and lower expression of Cd24a, while aged neutrophils expressed a lower level of Cd47 and higher level of Cd24a. MSC treatment shifted activated neutrophils toward an aged neutrophil phenotype by upregulating the expression of CD24, thereby inhibiting inflammation by reducing chemotaxis, ROS production, and NADPH oxidase. We identified the immunosuppressive effects of MSCs on the subtype distribution of neutrophils and provided new insight into the therapeutic mechanism of MSC treatment in ALI.
Sections du résumé
BACKGROUND
Mesenchymal stem cell (MSC) treatment plays a major role in the management of acute lung injury (ALI), and neutrophils are the initial line of defense against ALI. However, the effect of MSCs on neutrophils in ALI remains mostly unknown.
METHODS
We investigated the characteristics of neutrophils in lung tissue of ALI mice induced by lipopolysaccharide after treatment with MSCs using single-cell RNA sequencing. Neutrophils separated from lung tissue in ALI were co-cultured with MSCs, and then samples were collected for reverse transcription-polymerase chain reaction and flow cytometry.
RESULTS
During inflammation, six clusters of neutrophils were identified, annotated as activated, aged, and circulatory neutrophils. Activated neutrophils had higher chemotaxis, reactive oxygen species (ROS) production, and nicotinamide adenine dinucleotide phosphate (NADPH) oxidase scores than aged neutrophils. Circulatory neutrophils occurred mainly in healthy tissue and were characterized by higher expression of Cxcr2 and Sell. Activated neutrophils tended to exhibit higher expression of Cxcl10 and Cd47, and lower expression of Cd24a, while aged neutrophils expressed a lower level of Cd47 and higher level of Cd24a. MSC treatment shifted activated neutrophils toward an aged neutrophil phenotype by upregulating the expression of CD24, thereby inhibiting inflammation by reducing chemotaxis, ROS production, and NADPH oxidase.
CONCLUSION
We identified the immunosuppressive effects of MSCs on the subtype distribution of neutrophils and provided new insight into the therapeutic mechanism of MSC treatment in ALI.
Identifiants
pubmed: 37553691
doi: 10.1186/s13287-023-03438-w
pii: 10.1186/s13287-023-03438-w
pmc: PMC10408228
doi:
Substances chimiques
CD47 Antigen
0
Reactive Oxygen Species
0
Lipopolysaccharides
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
197Informations de copyright
© 2023. BioMed Central Ltd., part of Springer Nature.
Références
Bellani G, Laffey JG, Pham T, Fan E, Brochard L, Esteban A, et al. Epidemiology, patterns of care, and mortality for patients with acute respiratory distress syndrome in intensive care units in 50 countries. JAMA. 2016;315(8):788–800.
pubmed: 26903337
doi: 10.1001/jama.2016.0291
Park I, Kim M, Choe K, Song E, Seo H, Hwang Y, et al. Neutrophils disturb pulmonary microcirculation in sepsis-induced acute lung injury. Eur Respir J. 2019;53(3):1800786.
pubmed: 30635296
pmcid: 6437604
doi: 10.1183/13993003.00786-2018
Kapur R, Kasetty G, Rebetz J, Egesten A, Semple JW. Osteopontin mediates murine transfusion-related acute lung injury via stimulation of pulmonary neutrophil accumulation. Blood. 2019;134(1):74–84.
pubmed: 31076444
doi: 10.1182/blood.2019000972
Xu J, Guardado J, Hoffman R, Xu H, Namas R, Vodovotz Y, et al. IL33-mediated ILC2 activation and neutrophil IL5 production in the lung response after severe trauma: a reverse translation study from a human cohort to a mouse trauma model. PLoS Med. 2017;14(7):e1002365.
pubmed: 28742815
pmcid: 5526517
doi: 10.1371/journal.pmed.1002365
Lee WL, Downey GP. Neutrophil activation and acute lung injury. Curr Opin Crit Care. 2001;7(1):1–7.
pubmed: 11373504
doi: 10.1097/00075198-200102000-00001
Juss JK, House D, Amour A, Begg M, Herre J, Storisteanu DML, et al. Acute respiratory distress syndrome neutrophils have a distinct phenotype and are resistant to phosphoinositide 3-kinase inhibition. Am J Respir Crit Care Med. 2016;194(8):961–73.
pubmed: 27064380
pmcid: 5067816
doi: 10.1164/rccm.201509-1818OC
Zhang H, Liu J, Zhou Y, Qu M, Wang Y, Guo K, et al. Neutrophil extracellular traps mediate mA modification and regulates sepsis-associated acute lung injury by activating ferroptosis in alveolar epithelial cells. Int J Biol Sci. 2022;18(8):3337–57.
pubmed: 35637949
pmcid: 9134924
doi: 10.7150/ijbs.69141
Gill SE, Yamashita CM, Veldhuizen RAW. Lung remodeling associated with recovery from acute lung injury. Cell Tissue Res. 2017;367(3):495–509.
pubmed: 27796509
doi: 10.1007/s00441-016-2521-8
Abraham E, Carmody A, Shenkar R, Arcaroli J. Neutrophils as early immunologic effectors in hemorrhage- or endotoxemia-induced acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2000;279(6):L1137–45.
pubmed: 11076804
doi: 10.1152/ajplung.2000.279.6.L1137
Summers C. Chasing the “Holy Grail”: modulating neutrophils in inflammatory lung disease. Am J Respir Crit Care Med. 2019;200(2):131–2.
pubmed: 30865833
pmcid: 6635790
doi: 10.1164/rccm.201902-0333ED
Liu J, Feng B, Xu Y, Zhu J, Feng X, Chen W, et al. Immunomodulatory effect of mesenchymal stem cells in chemical-induced liver injury: a high-dimensional analysis. Stem Cell Res Ther. 2019;10(1):262.
pubmed: 31443686
pmcid: 6708172
doi: 10.1186/s13287-019-1379-6
Wang R, Yao Q, Chen W, Gao F, Li P, Wu J, et al. Stem cell therapy for Crohn’s disease: systematic review and meta-analysis of preclinical and clinical studies. Stem Cell Res Ther. 2021;12(1):463.
pubmed: 34407875
pmcid: 8375136
doi: 10.1186/s13287-021-02533-0
Matthay MA, Calfee CS, Zhuo H, Thompson BT, Wilson JG, Levitt JE, et al. Treatment with allogeneic mesenchymal stromal cells for moderate to severe acute respiratory distress syndrome (START study): a randomised phase 2a safety trial. Lancet Respir Med. 2019;7(2):154–62.
pubmed: 30455077
doi: 10.1016/S2213-2600(18)30418-1
Simonson OE, Mougiakakos D, Heldring N, Bassi G, Johansson HJ, Dalen M, et al. In vivo effects of mesenchymal stromal cells in two patients with severe acute respiratory distress syndrome. Stem Cells Transl Med. 2015;4(10):1199–213.
pubmed: 26285659
pmcid: 4572899
doi: 10.5966/sctm.2015-0021
Wilson JG, Liu KD, Zhuo H, Caballero L, McMillan M, Fang X, et al. Mesenchymal stem (stromal) cells for treatment of ARDS: a phase 1 clinical trial. Lancet Respir Med. 2015;3(1):24–32.
pubmed: 25529339
doi: 10.1016/S2213-2600(14)70291-7
Yudhawati R, Amin M, Rantam FA, Prasetya RR, Dewantari JR, Nastri AM, et al. Bone marrow-derived mesenchymal stem cells attenuate pulmonary inflammation and lung damage caused by highly pathogenic avian influenza A/H5N1 virus in BALB/c mice. BMC Infect Dis. 2020;20(1):823.
pubmed: 33176722
pmcid: 7656227
doi: 10.1186/s12879-020-05525-2
Zhu R, Yan T, Feng Y, Liu Y, Cao H, Peng G, et al. Mesenchymal stem cell treatment improves outcome of COVID-19 patients via multiple immunomodulatory mechanisms. Cell Res. 2021;31(12):1244–62.
pubmed: 34702946
pmcid: 8546390
doi: 10.1038/s41422-021-00573-y
Shi L, Huang H, Lu X, Yan X, Jiang X, Xu R, et al. Effect of human umbilical cord-derived mesenchymal stem cells on lung damage in severe COVID-19 patients: a randomized, double-blind, placebo-controlled phase 2 trial. Signal Transduct Target Ther. 2021;6(1):58.
pubmed: 33568628
pmcid: 7873662
doi: 10.1038/s41392-021-00488-5
Lanzoni G, Linetsky E, Correa D, Messinger Cayetano S, Alvarez RA, Kouroupis D, et al. Umbilical cord mesenchymal stem cells for COVID-19 acute respiratory distress syndrome: a double-blind, phase 1/2a, randomized controlled trial. Stem Cells Transl Med. 2021;10(5):660–73.
pubmed: 33400390
pmcid: 8046040
doi: 10.1002/sctm.20-0472
Liu J, Li P, Zhu J, Lin F, Zhou J, Feng B, et al. Mesenchymal stem cell-mediated immunomodulation of recruited mononuclear phagocytes during acute lung injury: a high-dimensional analysis study. Theranostics. 2021;11(5):2232–46.
pubmed: 33500722
pmcid: 7797670
doi: 10.7150/thno.52514
Silva JD, Lopes-Pacheco M, de Castro LL, Kitoko JZ, Trivelin SA, Amorim NR, et al. Eicosapentaenoic acid potentiates the therapeutic effects of adipose tissue-derived mesenchymal stromal cells on lung and distal organ injury in experimental sepsis. Stem Cell Res Ther. 2019;10(1):264.
pubmed: 31443678
pmcid: 6708232
doi: 10.1186/s13287-019-1365-z
Huang Q, Cheng X, Luo C, Yang S, Li S, Wang B, et al. Placental chorionic plate-derived mesenchymal stem cells ameliorate severe acute pancreatitis by regulating macrophage polarization via secreting TSG-6. Stem Cell Res Ther. 2021;12(1):337.
pubmed: 34112260
pmcid: 8193892
doi: 10.1186/s13287-021-02411-9
Ionescu L, Byrne RN, van Haaften T, Vadivel A, Alphonse RS, Rey-Parra GJ, et al. Stem cell conditioned medium improves acute lung injury in mice: in vivo evidence for stem cell paracrine action. Am J Physiol Lung Cell Mol Physiol. 2012;303(11):L967–77.
pubmed: 23023971
pmcid: 3532523
doi: 10.1152/ajplung.00144.2011
Su VY-F, Lin C-S, Hung S-C, Yang K-Y. Mesenchymal stem cell-conditioned medium induces neutrophil apoptosis associated with inhibition of the NF-κB pathway in endotoxin-induced acute lung injury. Int J Mol Sci. 2019;20(9):2208.
pubmed: 31060326
pmcid: 6540353
doi: 10.3390/ijms20092208
Kwon M-Y, Ghanta S, Ng J, Tsoyi K, Lederer JA, Bronson RT, et al. Expression of stromal cell-derived factor-1 by mesenchymal stromal cells impacts neutrophil function during sepsis. Crit Care Med. 2020;48(5):e409–17.
pubmed: 32167490
pmcid: 7556326
doi: 10.1097/CCM.0000000000004244
Taghavi-Farahabadi M, Mahmoudi M, Rezaei N, Hashemi SM. Wharton’s jelly mesenchymal stem cells exosomes and conditioned media increased neutrophil lifespan and phagocytosis capacity. Immunol Invest. 2021;50(8):1042–57.
pubmed: 32777963
doi: 10.1080/08820139.2020.1801720
Dagvadorj J, Shimada K, Chen S, Jones HD, Tumurkhuu G, Zhang W, et al. Lipopolysaccharide induces alveolar macrophage necrosis via CD14 and the P2X7 receptor leading to interleukin-1α release. Immunity. 2015;42(4):640–53.
pubmed: 25862090
pmcid: 4423803
doi: 10.1016/j.immuni.2015.03.007
Lv H, Yu Z, Zheng Y, Wang L, Qin X, Cheng G, et al. Isovitexin exerts anti-inflammatory and anti-oxidant activities on lipopolysaccharide-induced acute lung injury by inhibiting MAPK and NF-κB and activating HO-1/Nrf2 pathways. Int J Biol Sci. 2016;12(1):72–86.
pubmed: 26722219
pmcid: 4679400
doi: 10.7150/ijbs.13188
Lee JW, Fang X, Gupta N, Serikov V, Matthay MA. Allogeneic human mesenchymal stem cells for treatment of E. coli endotoxin-induced acute lung injury in the ex vivo perfused human lung. Proc Natl Acad Sci U S A. 2009;106(38):16357–62.
pubmed: 19721001
pmcid: 2735560
doi: 10.1073/pnas.0907996106
Zhu J, Feng B, Xu Y, Chen W, Sheng X, Feng X, et al. Mesenchymal stem cells alleviate LPS-induced acute lung injury by inhibiting the proinflammatory function of Ly6C CD8 T cells. Cell Death Dis. 2020;11(10):829.
pubmed: 33024074
pmcid: 7538431
doi: 10.1038/s41419-020-03036-1
Feng X-D, Zhou J-H, Chen J-Y, Feng B, Hu R-T, Wu J, et al. Long non-coding RNA SNHG16 promotes human placenta-derived mesenchymal stem cell proliferation capacity through the PI3K/AKT pathway under hypoxia. World J Stem Cells. 2022;14(9):714–28.
pubmed: 36188116
pmcid: 9516465
doi: 10.4252/wjsc.v14.i9.714
Martin C, Burdon PCE, Bridger G, Gutierrez-Ramos JC, Williams TJ, Rankin SM. Chemokines acting via CXCR2 and CXCR4 control the release of neutrophils from the bone marrow and their return following senescence. Immunity. 2003;19(4):583–93.
pubmed: 14563322
doi: 10.1016/S1074-7613(03)00263-2
Xie X, Shi Q, Wu P, Zhang X, Kambara H, Su J, et al. Single-cell transcriptome profiling reveals neutrophil heterogeneity in homeostasis and infection. Nat Immunol. 2020;21(9):1119–33.
pubmed: 32719519
pmcid: 7442692
doi: 10.1038/s41590-020-0736-z
Dömer D, Walther T, Möller S, Behnen M, Laskay T. Neutrophil extracellular traps activate proinflammatory functions of human neutrophils. Front Immunol. 2021;12:636954.
pubmed: 34168641
pmcid: 8217666
doi: 10.3389/fimmu.2021.636954
Gibson PG, Qin L, Puah SH. COVID-19 acute respiratory distress syndrome (ARDS): clinical features and differences from typical pre-COVID-19 ARDS. Med J Aust. 2020;213(2):54-56.e1.
pubmed: 32572965
pmcid: 7361309
doi: 10.5694/mja2.50674
Wu C, Chen X, Cai Y, Xia J, Zhou X, Xu S, et al. Risk factors associated with acute respiratory distress syndrome and death in patients with coronavirus disease 2019 pneumonia in Wuhan, China. JAMA Intern Med. 2020;180(7):934–43.
pubmed: 32167524
doi: 10.1001/jamainternmed.2020.0994
Zhang D, Song D, Shi L, Sun X, Zheng Y, Zeng Y, et al. Mechanisms of interactions between lung-origin telocytes and mesenchymal stem cells to treat experimental acute lung injury. Clin Transl Med. 2020;10(8):e231.
pubmed: 33377639
pmcid: 7724099
doi: 10.1002/ctm2.231
Dos Santos CC, Amatullah H, Vaswani CM, Maron-Gutierrez T, Kim M, Mei SHJ, et al. Mesenchymal stromal (stem) cell therapy modulates miR-193b-5p expression to attenuate sepsis-induced acute lung injury. Eur Respir J. 2022;59(1):2004216.
pubmed: 34112731
doi: 10.1183/13993003.04216-2020
Wick KD, Leligdowicz A, Zhuo H, Ware LB, Matthay MA. Mesenchymal stromal cells reduce evidence of lung injury in patients with ARDS. JCI Insight. 2021;6(12):e148983.
pubmed: 33974564
pmcid: 8262503
doi: 10.1172/jci.insight.148983
Al-Ani B, ShamsEldeen AM, Kamar SS, Haidara MA, Al-Hashem F, Alshahrani MY, et al. Lipopolysaccharide induces acute lung injury and alveolar haemorrhage in association with the cytokine storm, coagulopathy and AT1R/JAK/STAT augmentation in a rat model that mimics moderate and severe Covid-19 pathology. Clin Exp Pharmacol Physiol. 2022;49(4):483–91.
pubmed: 35066912
doi: 10.1111/1440-1681.13620
Hind LE, Ingram PN, Beebe DJ, Huttenlocher A. Interaction with an endothelial lumen increases neutrophil lifetime and motility in response to P. aeruginosa. Blood. 2018;132(17):1818–28.
pubmed: 30143504
pmcid: 6202912
doi: 10.1182/blood-2018-05-848465
Korbecki J, Barczak K, Gutowska I, Chlubek D, Baranowska-Bosiacka I. CXCL1: gene, promoter, regulation of expression, mRNA stability, regulation of activity in the intercellular space. Int J Mol Sci. 2022;23(2):792.
pubmed: 35054978
pmcid: 8776070
doi: 10.3390/ijms23020792
Evrard M, Kwok IWH, Chong SZ, Teng KWW, Becht E, Chen J, et al. Developmental analysis of bone marrow neutrophils reveals populations specialized in expansion, trafficking, and effector functions. Immunity. 2018;48(2):364-379.e8.
pubmed: 29466759
doi: 10.1016/j.immuni.2018.02.002
Paris AJ, Liu Y, Mei J, Dai N, Guo L, Spruce LA, et al. Neutrophils promote alveolar epithelial regeneration by enhancing type II pneumocyte proliferation in a model of acid-induced acute lung injury. Am J Physiol Lung Cell Mol Physiol. 2016;311(6):L1062–75.
pubmed: 27694472
pmcid: 5206401
doi: 10.1152/ajplung.00327.2016
Yan H, Zhou H-F, Akk A, Hu Y, Springer LE, Ennis TL, et al. Neutrophil proteases promote experimental abdominal aortic aneurysm via extracellular trap release and plasmacytoid dendritic cell activation. Arterioscler Thromb Vasc Biol. 2016;36(8):1660–9.
pubmed: 27283739
pmcid: 4965335
doi: 10.1161/ATVBAHA.116.307786
Yang P, Li Y, Xie Y, Liu Y. Different faces for different places: heterogeneity of neutrophil phenotype and function. J Immunol Res. 2019;2019:8016254.
pubmed: 30944838
pmcid: 6421822
doi: 10.1155/2019/8016254
Gandhirajan RK, Meng S, Chandramoorthy HC, Mallilankaraman K, Mancarella S, Gao H, et al. Blockade of NOX2 and STIM1 signaling limits lipopolysaccharide-induced vascular inflammation. J Clin Invest. 2013;123(2):887–902.
pubmed: 23348743
pmcid: 3561818
Chen G-Y, Tang J, Zheng P, Liu Y. CD24 and Siglec-10 selectively repress tissue damage-induced immune responses. Science. 2009;323(5922):1722–5.
pubmed: 19264983
pmcid: 2765686
doi: 10.1126/science.1168988
Parlato M, Souza-Fonseca-Guimaraes F, Philippart F, Misset B, Adib-Conquy M, Cavaillon J-M. CD24-triggered caspase-dependent apoptosis via mitochondrial membrane depolarization and reactive oxygen species production of human neutrophils is impaired in sepsis. J Immunol. 2014;192(5):2449–59.
pubmed: 24501201
doi: 10.4049/jimmunol.1301055
Wang J-F, Wang Y-P, Xie J, Zhao Z-Z, Gupta S, Guo Y, et al. Upregulated PD-L1 delays human neutrophil apoptosis and promotes lung injury in an experimental mouse model of sepsis. Blood. 2021;138(9):806–10.
pubmed: 34473230
doi: 10.1182/blood.2020009417
Langereis JD, Pickkers P, de Kleijn S, Gerretsen J, de Jonge MI, Kox M. Spleen-derived IFN-γ induces generation of PD-L1-suppressive neutrophils during endotoxemia. J Leukoc Biol. 2017;102(6):1401–9.
pubmed: 28974543
doi: 10.1189/jlb.3A0217-051RR
Deng Y, Zheng Y, Li D, Hong Q, Zhang M, Li Q, et al. Expression characteristics of interferon-stimulated genes and possible regulatory mechanisms in lupus patients using transcriptomics analyses. EBioMedicine. 2021;70:103477.
pubmed: 34284174
pmcid: 8318865
doi: 10.1016/j.ebiom.2021.103477
Suratt BT, Petty JM, Young SK, Malcolm KC, Lieber JG, Nick JA, et al. Role of the CXCR4/SDF-1 chemokine axis in circulating neutrophil homeostasis. Blood. 2004;104(2):565–71.
pubmed: 15054039
doi: 10.1182/blood-2003-10-3638