Deleting fibroblast growth factor 2 in macrophages aggravates septic acute lung injury by increasing M1 polarization and inflammatory cytokine secretion.
Acute lung injury
Fibroblast growth factor 2
Inflammation
M1 macrophage
Sepsis
Journal
Molecular biomedicine
ISSN: 2662-8651
Titre abrégé: Mol Biomed
Pays: Singapore
ID NLM: 9918283581406676
Informations de publication
Date de publication:
22 Oct 2024
22 Oct 2024
Historique:
received:
11
05
2024
accepted:
22
08
2024
medline:
22
10
2024
pubmed:
22
10
2024
entrez:
22
10
2024
Statut:
epublish
Résumé
Septic lung injury is strongly associated with polarization of M1 macrophages and excessive cytokine release. Fibroblast growth factor (FGF) signaling plays a role in both processes. However, the impact of FGF2 deficiency on macrophage polarization and septic acute lung injury remains unclear. To investigate this, we obtained macrophages from FGF2 knockout mice and examined their polarization and inflammatory cytokine expression. We also eliminated endogenous macrophages using clodronate liposomes and administered FGF2 knockout or WT macrophages intravenously in conjunction with cecal ligation and puncture (CLP) surgery to induce sepsis. In vitro analysis by flow cytometry and real-time PCR analysis demonstrated that FGF2 deficiency resulted in increased expression of M1 markers (iNOS and CD86) and inflammatory cytokines (CXCL1, IL1β, and IL6), especially after LPS stimulation. Additionally, immunofluorescence demonstrated increased nuclear translocation of p65 NF-κB in FGF2 knockout macrophages and RNA-seq analysis showed enrichment of differentially expressed genes in the IL17 and TNFα inflammatory signaling pathways. Furthermore, in vivo experiments revealed that depletion of FGF2 in macrophages worsened sepsis-induced lung inflammation, lung vascular leak, and lung histological injury, accompanied by an increase in CD86-positive cells and apoptosis. Our study suggests that FGF2 deficiency in macrophages plays a critical role in the pathogenesis of septic ALI, possibly because of the enhanced M1 macrophage polarization and production of proinflammatory cytokines. These findings provide empirical evidence for potential therapeutic interventions targeting FGF2 signaling to modulate the polarization of M1 and M2 macrophages in the management of sepsis-induced acute lung injury.
Identifiants
pubmed: 39436561
doi: 10.1186/s43556-024-00203-0
pii: 10.1186/s43556-024-00203-0
doi:
Substances chimiques
Cytokines
0
Fibroblast Growth Factor 2
103107-01-3
Inflammation Mediators
0
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
50Subventions
Organisme : National Natural Science Foundation of China
ID : 82172401
Organisme : National Natural Science Foundation of China
ID : Grant no. 82202404
Informations de copyright
© 2024. The Author(s).
Références
Feng Q, Wei WQ, Chaugai S, Leon BGC, Mosley JD, Leon DAC, et al. Association between low-density lipoprotein cholesterol levels and risk for sepsis among patients admitted to the Hospital with infection. JAMA Netw Open. 2019;2(1):e187223. https://doi.org/10.1001/jamanetworkopen.2018.7223 .
doi: 10.1001/jamanetworkopen.2018.7223
pubmed: 30657536
pmcid: 6447031
Dumas G, Lavillegrand JR, Joffre J, Bige N, de-Moura EB, Baudel JL, et al. Mottling score is a strong predictor of 14-day mortality in septic patients whatever vasopressor doses and other tissue perfusion parameters. Crit Care. 2019;23(1):211. https://doi.org/10.1186/s13054-019-2496-4 .
doi: 10.1186/s13054-019-2496-4
pubmed: 31182133
pmcid: 6558704
Jones AE, Puskarich MA, Shapiro NI, Guirgis FW, Runyon M, Adams JY, et al. Effect of Levocarnitine vs Placebo as an adjunctive treatment for septic shock: the Rapid Administration of Carnitine in Sepsis (RACE) randomized clinical trial. JAMA Netw Open. 2018;1(8):e186076. https://doi.org/10.1001/jamanetworkopen.2018.6076 .
doi: 10.1001/jamanetworkopen.2018.6076
pubmed: 30646314
pmcid: 6324339
Rudd KE, Johnson SC, Agesa KM, Shackelford KA, Tsoi D, Kievlan DR, et al. Global, regional, and national sepsis incidence and mortality, 1990–2017: analysis for the global burden of Disease Study. Lancet. 2020;395(10219):200–11. https://doi.org/10.1016/S0140-6736(19)32989-7 .
doi: 10.1016/S0140-6736(19)32989-7
pubmed: 31954465
pmcid: 6970225
Xia L, Zhang C, Lv N, Liang Z, Ma T, Cheng H, et al. AdMSC-derived exosomes alleviate acute lung injury via transferring mitochondrial component to improve homeostasis of alveolar macrophages. Theranostics. 2022;12(6):2928–47. https://doi.org/10.7150/thno.69533 .
doi: 10.7150/thno.69533
pubmed: 35401830
pmcid: 8965475
Yang HH, Duan JX, Liu SK, Xiong JB, Guan XX, Zhong WJ, et al. A COX-2/sEH dual inhibitor PTUPB alleviates lipopolysaccharide-induced acute lung injury in mice by inhibiting NLRP3 inflammasome activation. Theranostics. 2020;10(11):4749–61. https://doi.org/10.7150/thno.43108 .
doi: 10.7150/thno.43108
pubmed: 32308747
pmcid: 7163435
Zhu X, Huang B, Zhao F, Lian J, He L, Zhang Y, et al. p38-mediated FOXN3 phosphorylation modulates lung inflammation and injury through the NF-kappaB signaling pathway. Nucleic Acids Res. 2023;51(5):2195–214. https://doi.org/10.1093/nar/gkad057 .
doi: 10.1093/nar/gkad057
pubmed: 36794705
pmcid: 10018351
Kumar V. Targeting macrophage immunometabolism: dawn in the darkness of sepsis. Int Immunopharmacol. 2018;58:173–85. https://doi.org/10.1016/j.intimp.2018.03.005 .
doi: 10.1016/j.intimp.2018.03.005
pubmed: 29625385
Wang Z, Wang Z. The role of macrophages polarization in sepsis-induced acute lung injury. Front Immunol. 2023;14:1209438. https://doi.org/10.3389/fimmu.2023.1209438 .
doi: 10.3389/fimmu.2023.1209438
pubmed: 37691951
pmcid: 10483837
Pan X, Xu S, Zhou Z, Wang F, Mao L, Li H, et al. Fibroblast growth factor-2 alleviates the capillary leakage and inflammation in sepsis. Mol Med. 2020;26(1):108. https://doi.org/10.1186/s10020-020-00221-y .
doi: 10.1186/s10020-020-00221-y
pubmed: 33187467
pmcid: 7662026
Sun Y, Ye F, Li D, Yang H, Xu T, Zhong X, et al. Fibroblast growth factor 2 (FGF2) ameliorates the coagulation abnormalities in sepsis. Toxicol Appl Pharmacol. 2023;460:116364. https://doi.org/10.1016/j.taap.2023.116364 .
doi: 10.1016/j.taap.2023.116364
pubmed: 36621722
Tan Y, Qiao Y, Chen Z, Liu J, Guo Y, Tran T, et al. FGF2, an Immunomodulatory factor in Asthma and Chronic Obstructive Pulmonary Disease (COPD). Front Cell Dev Biol. 2020;8:223. https://doi.org/10.3389/fcell.2020.00223 .
doi: 10.3389/fcell.2020.00223
pubmed: 32300593
pmcid: 7142218
Im JH, Buzzelli JN, Jones K, Franchini F, Gordon-Weeks A, Markelc B, et al. FGF2 alters macrophage polarization, tumour immunity and growth and can be targeted during radiotherapy. Nat Commun. 2020;11(1):4064. https://doi.org/10.1038/s41467-020-17914-x .
doi: 10.1038/s41467-020-17914-x
pubmed: 32792542
pmcid: 7426415
Zhao YN, Liu ZD, Yan T, Xu TX, Jin TY, Jiang YS, et al. Macrophage-specific FGFR1 deletion alleviates high-fat-diet-induced liver inflammation by inhibiting the MAPKs/TNF pathways. Acta Pharmacol Sin. 2024. https://doi.org/10.1038/s41401-024-01226-7 .
doi: 10.1038/s41401-024-01226-7
pubmed: 39349767
pmcid: 11130324
Kuang L, Wu J, Su N, Qi H, Chen H, Zhou S, et al. FGFR3 deficiency enhances CXCL12-dependent chemotaxis of macrophages via upregulating CXCR7 and aggravates joint destruction in mice. Ann Rheum Dis. 2020;79(1):112–22. https://doi.org/10.1136/annrheumdis-2019-215696 .
doi: 10.1136/annrheumdis-2019-215696
pubmed: 31662319
Tong Y, Yu Z, Chen Z, Zhang R, Ding X, Yang X, et al. The HIV protease inhibitor saquinavir attenuates sepsis-induced acute lung injury and promotes M2 macrophage polarization via targeting matrix metalloproteinase-9. Cell Death Dis. 2021;12(1):67. https://doi.org/10.1038/s41419-020-03320-0 .
doi: 10.1038/s41419-020-03320-0
pubmed: 33431821
pmcid: 7798387
Nguyen T, Du J, Li YC. A protocol for macrophage depletion and reconstitution in a mouse model of sepsis. STAR Protoc. 2021;2(4):101004. https://doi.org/10.1016/j.xpro.2021.101004 .
doi: 10.1016/j.xpro.2021.101004
pubmed: 34917981
pmcid: 8669096
Shen L, Li Y, Zhao H. Fibroblast growth factor signaling in macrophage polarization: impact on health and diseases. Front Immunol. 2024;15:1390453. https://doi.org/10.3389/fimmu.2024.1390453 .
doi: 10.3389/fimmu.2024.1390453
pubmed: 38962005
pmcid: 11219802
Li Y, Shi Y, Zhang X, Li P, Ma L, Hu P, et al. FGFR2 upregulates PAI-1 via JAK2/STAT3 signaling to induce M2 polarization of macrophages in colorectal cancer. Biochim Biophys Acta Mol Basis Dis. 2023;1869(4):166665. https://doi.org/10.1016/j.bbadis.2023.166665 .
doi: 10.1016/j.bbadis.2023.166665
pubmed: 36781088
Cai X, Tao W, Li L. Glioma cell-derived FGF20 suppresses macrophage function by activating beta-catenin. Cell Signal. 2022;89:110181. https://doi.org/10.1016/j.cellsig.2021.110181 .
doi: 10.1016/j.cellsig.2021.110181
pubmed: 34757019
Wang Y, Sun Q, Ye Y, Sun X, Xie S, Zhan Y, et al. FGF-2 signaling in nasopharyngeal carcinoma modulates pericyte-macrophage crosstalk and metastasis. JCI Insight. 2022;7(10):e157874. https://doi.org/10.1172/jci.insight.157874 .
doi: 10.1172/jci.insight.157874
pubmed: 35439170
pmcid: 9220856
Shao X, Chen S, Yang D, Cao M, Yao Y, Wu Z, et al. FGF2 cooperates with IL-17 to promote autoimmune inflammation. Sci Rep. 2017;7(1):7024. https://doi.org/10.1038/s41598-017-07597-8 .
doi: 10.1038/s41598-017-07597-8
pubmed: 28765647
pmcid: 5539112
Pan RL, Xiang LX, Wang P, Liu XY, Nie L, Huang W, et al. Low-molecular-weight fibroblast growth factor 2 attenuates hepatic fibrosis by epigenetic down-regulation of Delta-like1. Hepatology. 2015;61(5):1708–20. https://doi.org/10.1002/hep.27649 .
doi: 10.1002/hep.27649
pubmed: 25501710
Burt PM, Xiao L, Doetschman T, Hurley MM. Ablation of low-molecular-weight FGF2 isoform accelerates murine osteoarthritis while loss of high-molecular-weight FGF2 isoforms offers protection. J Cell Physiol. 2019;234(4):4418–31. https://doi.org/10.1002/jcp.27230 .
doi: 10.1002/jcp.27230
pubmed: 30144364
Motozawa K, Motoyoshi M, Saiki A, Sasaki H, Shimizu N, Asano M. Functional comparison of high and low molecular weight basic fibroblast growth factors. J Cell Biochem. 2018;119(9):7818–26. https://doi.org/10.1002/jcb.27179 .
doi: 10.1002/jcb.27179
pubmed: 29923210
Chen X, Liu Y, Gao Y, Shou S, Chai Y. The roles of macrophage polarization in the host immune response to sepsis. Int Immunopharmacol. 2021;96:107791. https://doi.org/10.1016/j.intimp.2021.107791 .
doi: 10.1016/j.intimp.2021.107791
pubmed: 34162154
Wang A, Kang X, Wang J, Zhang S. IFIH1/IRF1/STAT1 promotes sepsis associated inflammatory lung injury via activating macrophage M1 polarization. Int Immunopharmacol. 2023;114:109478. https://doi.org/10.1016/j.intimp.2022.109478 .
doi: 10.1016/j.intimp.2022.109478
pubmed: 36462334
Zhou S, Zhao T, Chen X, Zhang W, Zou X, Yang Y, et al. Runx1 Deficiency promotes M2 macrophage polarization through enhancing STAT6 phosphorylation. Inflammation. 2023;46(6):2241–53. https://doi.org/10.1007/s10753-023-01874-7 .
doi: 10.1007/s10753-023-01874-7
pubmed: 37530929
Liu CP, Zhang X, Tan QL, Xu WX, Zhou CY, Luo M, et al. NF-kappaB pathways are involved in M1 polarization of RAW 264.7 macrophage by polyporus polysaccharide in the tumor microenvironment. PLoS ONE. 2017;12(11):e0188317. https://doi.org/10.1371/journal.pone.0188317 .
doi: 10.1371/journal.pone.0188317
pubmed: 29155869
pmcid: 5695768
Wu X, Wang Z, Shi J, Yu X, Li C, Liu J, et al. Macrophage polarization toward M1 phenotype through NF-kappaB signaling in patients with Behcet’s disease. Arthritis Res Ther. 2022;24(1):249. https://doi.org/10.1186/s13075-022-02938-z .
doi: 10.1186/s13075-022-02938-z
pubmed: 36333776
pmcid: 9635113
Yabluchanskiy A, Ma Y, DeLeon-Pennell KY, Altara R, Halade GV, Voorhees AP, et al. Myocardial infarction superimposed on aging: MMP-9 deletion promotes M2 macrophage polarization. J Gerontol Biol Sci Med Sci. 2016;71(4):475–83. https://doi.org/10.1093/gerona/glv034 .
doi: 10.1093/gerona/glv034
Gong Y, Hart E, Shchurin A, Hoover-Plow J. Inflammatory macrophage migration requires MMP-9 activation by plasminogen in mice. J Clin Invest. 2008;118(9):3012–24. https://doi.org/10.1172/JCI32750 .
doi: 10.1172/JCI32750
pubmed: 18677407
pmcid: 2491456
Chen W, Wang Y, Zhou Y, Xu Y, Bo X, Wu J. M1 macrophages increase endothelial permeability and enhance p38 phosphorylation via PPAR-gamma/CXCL13-CXCR5 in Sepsis. Int Arch Allergy Immunol. 2022;183(9):997–1006. https://doi.org/10.1159/000524272 .
doi: 10.1159/000524272
pubmed: 35526523
Zittermann SI, Issekutz AC. Endothelial growth factors VEGF and bFGF differentially enhance monocyte and neutrophil recruitment to inflammation. J Leukoc Biol. 2006;80(2):247–57. https://doi.org/10.1189/jlb.1205718 .
doi: 10.1189/jlb.1205718
pubmed: 16818728
Huang S, Xue Y, Chen W, Xue M, Miao L, Dong L, et al. Fibroblast growth factor 10 alleviates acute lung injury by inhibiting excessive autophagy via Nrf2. J Endocrinol. 2023;259(1):e230095. https://doi.org/10.1530/JOE-23-0095 .
doi: 10.1530/JOE-23-0095
pubmed: 37417397
Dhlamini Q, Wang W, Feng G, Chen A, Chong L, Li X, et al. FGF1 alleviates LPS-induced acute lung injury via suppression of inflammation and oxidative stress. Mol Med. 2022;28(1):73. https://doi.org/10.1186/s10020-022-00502-8 .
doi: 10.1186/s10020-022-00502-8
pubmed: 35764933
pmcid: 9238076
Wang X, Zhou L, Ye S, Liu S, Chen L, Cheng Z, et al. rFGF4 alleviates lipopolysaccharide-induced acute lung injury by inhibiting the TLR4/NF-kappaB signaling pathway. Int Immunopharmacol. 2023;117:109923. https://doi.org/10.1016/j.intimp.2023.109923 .
doi: 10.1016/j.intimp.2023.109923
pubmed: 36842235
Cai M, Ye H, Zhu X, Li X, Cai L, Jin J, et al. Fibroblast growth factor 21 relieves Lipopolysaccharide-Induced Acute Lung Injury by suppressing JAK2/STAT3 signaling pathway. Inflammation. 2024;47(1):209–26. https://doi.org/10.1007/s10753-023-01905-3 .
doi: 10.1007/s10753-023-01905-3
pubmed: 37864659
Meng Q, Wang X, Guo D, Shi C, Gu R, Ma J, et al. Nano-chemically modified Tetracycline-3 (nCMT-3) attenuates acute lung injury via blocking sTREM-1 release and NLRP3 inflammasome activation. Shock. 2022;57(5):749–58. https://doi.org/10.1097/SHK.0000000000001927 .
doi: 10.1097/SHK.0000000000001927
pubmed: 35583915
Qin A, Wang XJ, Fu J, Shen A, Huang X, Chen Z, et al. hMSCs treatment attenuates murine herpesvirus-68 (MHV-68) pneumonia through altering innate immune response via ROS/NLRP3 signaling pathway. Mol Biomed. 2023;4(1):27. https://doi.org/10.1186/s43556-023-00137-z .
doi: 10.1186/s43556-023-00137-z
pubmed: 37704783
pmcid: 10499773
Yi L, Weng T, Nie P, Zhu L, Gao M, Jia H, et al. Overexpression of interleukin-10 in engineered macrophages protects endothelial cells against LPS-induced injury in vitro. FEBS Open Bio. 2022;12(3):605–15. https://doi.org/10.1002/2211-5463.13365 .
doi: 10.1002/2211-5463.13365
pubmed: 35015384
pmcid: 8886523
Zhong J, Zheng C, Chen Z, Yue H, Gao H, Jiang Y, et al. Phosphopeptides P140 cause oxidative burst responses of pulmonary macrophages in an imiquimod-induced lupus model. Mol Biomed. 2023;4(1):38. https://doi.org/10.1186/s43556-023-00149-9 .
doi: 10.1186/s43556-023-00149-9
pubmed: 37922035
pmcid: 10624795