https://doi.org/10.4081/ejh.2023.3528
Decreased VEGFA alleviates the symptoms of LPS-induced sepsis in a mouse model by inhibiting glycolysis and thereby regulating the polarization of macrophages
Submitted: 12 August 2022
Accepted: 1 December 2022
Published: 22 December 2022
Accepted: 1 December 2022
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Supplementary: 66
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All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article or claim that may be made by its manufacturer is not guaranteed or endorsed by the publisher.
Authors
The immune imbalance caused by excessive inflammatory reactions is the primary cause of sepsis. Macrophages with M1 and M2 polarization states are important immune cells that regulate the balance of the inflammatory response in sepsis. Encouraging the conversion of macrophages from the M1 to the M2 type is an important strategy for relieving sepsis. Here, we demonstrated the upregulation of vascular endothelial growth factor A (VEGFA) in a mouse model of sepsis. Then, siRNA technology was applied to inhibit the expression of VEGFA in macrophages. Flow cytometry and RT‒qPCR results showed that low expression of VEGFA inhibited LPS-induced M1 polarization of macrophages. Decreased VEGFA was also proven to lower TNF-α, IL-1β, and IL-6 secretion by LPS-induced macrophages. In addition, the effects of knocking down VEGFA on the energy metabolism pattern of macrophages were investigated by glycolysis pressure tests and mitochondrial pressure tests, and VEGFA knockdown reversed the induction of glycolysis in macrophages by LPS. The mitochondrial content and ATP content results also confirmed this finding. After the tail vein of septic mice was injected with macrophages transfected with si-VEGFA, the liver and kidney damage and the pathological conditions of the lung were alleviated. The secretion of TNF-α and IL-6 was decreased, while IL-10 was increased in their serum. Immunohistochemical staining revealed decreased expression of CD86 and increased expression of CD206 in the si-VEGFA group. This study demonstrates that decreased VEGFA inhibits glycolysis and thus inhibits LPS-induced M1 polarization of macrophages, ultimately relieving sepsis.
Cecconi M, Evans L, Levy M, Rhodes A. Sepsis and septic shock. Lancet 2018;392:75-87.
DOI: https://doi.org/10.1016/S0140-6736(18)30696-2
Rhee C, Klompas M. Sepsis trends: increasing incidence and decreasing mortality, or changing denominator? J Thorac Dis 2020;12:S89-S100.
DOI: https://doi.org/10.21037/jtd.2019.12.51
Huang M, Cai S, Su J. The pathogenesis of sepsis and potential therapeutic targets. Int J Mol Sci 2019;20:5376.
DOI: https://doi.org/10.3390/ijms20215376
Novotny AR, Reim D, Assfalg V, Altmayr F, Friess HM, Emmanuel K, et al. Mixed antagonist response and sepsis severity-dependent dysbalance of pro- and anti-inflammatory responses at the onset of postoperative sepsis. Immunobiology 2012;217:616-21.
DOI: https://doi.org/10.1016/j.imbio.2011.10.019
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.
DOI: https://doi.org/10.1016/j.intimp.2021.107791
Italiani P, Boraschi D. From monocytes to M1/M2 macrophages: Phenotypical vs. functional differentiation. Front Immunol 2014;5:514.
DOI: https://doi.org/10.3389/fimmu.2014.00514
Verdeguer F, Aouadi M. Macrophage heterogeneity and energy metabolism. Exp Cell Res 2017;360:35-40.
DOI: https://doi.org/10.1016/j.yexcr.2017.03.043
Wang T, Liu H, Lian G, Zhang SY, Wang X, Jiang C. HIF1alpha-induced glycolysis metabolism is essential to the activation of inflammatory macrophages. Mediators Inflamm 2017;2017:9029327.
DOI: https://doi.org/10.1155/2017/9029327
Gao L, Yang J, Li Y, Liu K, Sun H, Tang J, et al. Long noncoding RNA SCIRT promotes HUVEC angiogenesis via stabilizing VEGFA mRNA induced by hypoxia. Oxid Med Cell Longev 2022;2022:9102978.
DOI: https://doi.org/10.1155/2022/9102978
Wan X, Xie MK, Xu H, Wei ZW, Yao HJ, Wang Z, et al. Hypoxia-preconditioned adipose-derived stem cells combined with scaffold promote urethral reconstruction by upregulation of angiogenesis and glycolysis. Stem Cell Res Ther 2020;11:535.
DOI: https://doi.org/10.1186/s13287-020-02052-4
Azuma M, Shi M, Danenberg KD, Gardner H, Barrett C, Jacques CJ, et al. Serum lactate dehydrogenase levels and glycolysis significantly correlate with tumor VEGFA and VEGFR expression in metastatic CRC patients. Pharmacogenomics 2007;8:1705-13.
DOI: https://doi.org/10.2217/14622416.8.12.1705
Ren Z, Liang H, Galbo PM, Jr., Dharmaratne M, Kulkarni AS, Fard AT, et al. Redox signaling by glutathione peroxidase 2 links vascular modulation to metabolic plasticity of breast cancer. Proc Natl Acad Sci USA 2022;119:e2107266119.
DOI: https://doi.org/10.1073/pnas.2107266119
Varney ML, Olsen KJ, Mosley RL, Singh RK. Paracrine regulation of vascular endothelial growth factor-a expression during macrophage-melanoma cell interaction: role of monocyte chemotactic protein-1 and macrophage colony-stimulating factor. J Interferon Cytokine Res 2005;25:674-83.
DOI: https://doi.org/10.1089/jir.2005.25.674
Yang N, Li X. Epigallocatechin gallate relieves asthmatic symptoms in mice by suppressing HIF-1α/VEGFA-mediated M2 skewing of macrophages. Biochem Pharmacol 2022;202:115112.
DOI: https://doi.org/10.1016/j.bcp.2022.115112
Li JL, Li G, Jing XZ, Li YF, Ye QY, Jia HH, et al. Assessment of clinical sepsis-associated biomarkers in a septic mouse model. J Int Med Res 2018;46:2410-22.
DOI: https://doi.org/10.1177/0300060518764717
Plitzko B, Loesgen S. Measurement of oxygen consumption rate (OCR) and extracellular acidification rate (ECAR) in culture cells for assessment of the energy metabolism. Bio Protoc 2018;8:e2850.
DOI: https://doi.org/10.21769/BioProtoc.2850
Karlsson S, Pettila V, Tenhunen J, Lund V, Hovilehto S, Ruokonen E, et al. Vascular endothelial growth factor in severe sepsis and septic shock. Anesth Analg 2008;106:1820-6.
DOI: https://doi.org/10.1213/ane.0b013e31816a643f
Kikuchi R, Stevens M, Harada K, Oltean S, Murohara T. Anti-angiogenic isoform of vascular endothelial growth factor-A in cardiovascular and renal disease. Adv Clin Chem 2019;88:1-33.
DOI: https://doi.org/10.1016/bs.acc.2018.10.001
Alves BE, Montalvao SA, Aranha FJ, Lorand-Metze I, De Souza CA, Annichino-Bizzacchi JM, et al. Time-course of sFlt-1 and VEGF-A release in neutropenic patients with sepsis and septic shock: a prospective study. J Transl Med 2011;9:23.
DOI: https://doi.org/10.1186/1479-5876-9-23
van der Flier M, van Leeuwen HJ, van Kessel KP, Kimpen JL, Hoepelman AI, Geelen SP. Plasma vascular endothelial growth factor in severe sepsis. Shock 2005;23:35-8.
DOI: https://doi.org/10.1097/01.shk.0000150728.91155.41
Linde N, Lederle W, Depner S, van Rooijen N, Gutschalk CM, Mueller MM. Vascular endothelial growth factor-induced skin carcinogenesis depends on recruitment and alternative activation of macrophages. J Pathol 2012;227:17-28.
DOI: https://doi.org/10.1002/path.3989
Wheeler KC, Jena MK, Pradhan BS, Nayak N, Das S, Hsu CD, et al. VEGF may contribute to macrophage recruitment and M2 polarization in the decidua. PLoS One 2018;13:e0191040.
DOI: https://doi.org/10.1371/journal.pone.0191040
Luo YY, Yang ZQ, Lin XF, Zhao FL, Tu HT, Wang LJ, et al. Knockdown of lncRNA PVT1 attenuated macrophage M1 polarization and relieved sepsis induced myocardial injury via miR-29a/HMGB1 axis. Cytokine 2021;143:155509.
DOI: https://doi.org/10.1016/j.cyto.2021.155509
Xing L, Zhongqian L, Chunmei S, Pingfa C, Lei H, Qin J, et al. Activation of M1 macrophages in sepsis-induced acute kidney injury in response to heparin-binding protein. PLoS One 2018;13:e0196423.
DOI: https://doi.org/10.1371/journal.pone.0196423
Thapa B, Lee K. Metabolic influence on macrophage polarization and pathogenesis. BMB Rep 2019;52:360-72.
DOI: https://doi.org/10.5483/BMBRep.2019.52.6.140
Soto-Heredero G, Gomez de Las Heras MM, Gabande-Rodriguez E, Oller J, Mittelbrunn M. Glycolysis - a key player in the inflammatory response. FEBS J 2020;287:3350-69.
DOI: https://doi.org/10.1111/febs.15327
Zheng D, Huang X, Peng J, Zhuang Y, Li Y, Qu J, et al. CircMYOF triggers progression and facilitates glycolysis via the VEGFA/PI3K/AKT axis by absorbing miR-4739 in pancreatic ductal adenocarcinoma. Cell Death Discov 2021;7:362.
DOI: https://doi.org/10.1038/s41420-021-00759-8
Shi S, Xu J, Zhang B, Ji S, Xu W, Liu J, et al. VEGF promotes glycolysis in pancreatic cancer via HIF1α up-regulation. Curr Mol Med 2016;16:394-403.
DOI: https://doi.org/10.2174/1566524016666160316153623
How to Cite
Lin, J., Jiang, L., Guo, K., & Feng, N. (2022). Decreased VEGFA alleviates the symptoms of LPS-induced sepsis in a mouse model by inhibiting glycolysis and thereby regulating the polarization of macrophages. European Journal of Histochemistry, 67(1). https://doi.org/10.4081/ejh.2023.3528
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