Generic placeholder image

CNS & Neurological Disorders - Drug Targets

Author(s): Zhiliang Guo, Guoli Xu, Jiaping Xu, Yaqian Huang, Chunfeng Liu and Yongjun Cao*

DOI: 10.2174/1871527322666230417112850

DownloadDownload PDF Flyer Cite As
Role of Lipocalin-2 in N1/N2 Neutrophil Polarization After Stroke

Page: [525 - 535] Pages: 11

  • * (Excluding Mailing and Handling)

Abstract

Background: Neutrophils and Lipocalin-2 (LCN2) play pivotal roles in cerebral ischemiareperfusion (I/R) injury. However, their contribution is not fully clarified.

Objective: This study aimed to explore the role of LCN2 and its association with neutrophil polarization in I/R injury.

Methods: A mouse model of middle cerebral artery occlusion (MCAO) was used to induce cerebral ischemia. LCN2mAb was administered 1 h and Anti-Ly6G was administered for 3d before MCAO. The role of LCN2 in the polarity transition of neutrophils was explored using an in vitro HL-60 cell model.

Results: LCN2mAb pretreatment had neuroprotective effects in mice. The expression of Ly6G was not significantly different, but the expression of N2 neutrophils was increased. In the in vitro study, LCN2mAb-treated N1-HL-60 cells induced N2-HL-60 polarization.

Conclusion: LCN2 may affect the prognosis of ischemic stroke by mediating neutrophil polarization.

Graphical Abstract

[1]
Stoll G, Nieswandt B. Thrombo-inflammation in acute ischaemic stroke-implications for treatment. Nat Rev Neurol 2019; 15(8): 473-81.
[http://dx.doi.org/10.1038/s41582-019-0221-1] [PMID: 31263257]
[2]
Powers WJ, Rabinstein AA, Ackerson T, et al. 2018 Guidelines for the early management of patients with acute ischemic stroke: A guideline for healthcare professionals from the American Heart Association/American stroke association. Stroke 2018; 49(3): e46-e110.
[http://dx.doi.org/10.1161/STR.0000000000000158] [PMID: 29367334]
[3]
Gauberti M, Lapergue B, Martinez de Lizarrondo S, et al. Ischemia-reperfusion injury after endovascular thrombectomy for ischemic stroke. Stroke 2018; 49(12): 3071-4.
[http://dx.doi.org/10.1161/STROKEAHA.118.022015] [PMID: 30571423]
[4]
Mizuma A, You JS, Yenari MA. Targeting reperfusion injury in the age of mechanical thrombectomy. Stroke 2018; 49(7): 1796-802.
[http://dx.doi.org/10.1161/STROKEAHA.117.017286] [PMID: 29760275]
[5]
Mizuma A, Yenari MA. Anti-inflammatory targets for the treatment of reperfusion injury in stroke. Front Neurol 2017; 8: 467.
[http://dx.doi.org/10.3389/fneur.2017.00467] [PMID: 28936196]
[6]
Németh T, Mócsai A. Feedback amplification of neutrophil function. Trends Immunol 2016; 37(6): 412-24.
[http://dx.doi.org/10.1016/j.it.2016.04.002] [PMID: 27157638]
[7]
Jickling GC, Liu D, Ander BP, Stamova B, Zhan X, Sharp FR. Targeting neutrophils in ischemic stroke: Translational insights from experimental studies. J Cereb Blood Flow Metab 2015; 35(6): 888-901.
[http://dx.doi.org/10.1038/jcbfm.2015.45] [PMID: 25806703]
[8]
Zhang X, Shi H, Yuan X, Jiang P, Qian H, Xu W. Tumor-derived exosomes induce N2 polarization of neutrophils to promote gastric cancer cell migration. Mol Cancer 2018; 17(1): 146.
[http://dx.doi.org/10.1186/s12943-018-0898-6] [PMID: 30292233]
[9]
Fridlender ZG, Sun J, Kim S, et al. Polarization of tumor-associated neutrophil phenotype by TGF-beta: “N1” versus “N2” TAN. Cancer Cell 2009; 16(3): 183-94.
[http://dx.doi.org/10.1016/j.ccr.2009.06.017] [PMID: 19732719]
[10]
Cuartero MI, Ballesteros I, Moraga A, et al. N2 neutrophils, novel players in brain inflammation after stroke: modulation by the PPARγ agonist rosiglitazone. Stroke 2013; 44(12): 3498-508.
[http://dx.doi.org/10.1161/STROKEAHA.113.002470] [PMID: 24135932]
[11]
Ferreira AC, Dá Mesquita S, Sousa JC, et al. From the periphery to the brain: Lipocalin-2, a friend or foe? Prog Neurobiol 2015; 131: 120-36.
[http://dx.doi.org/10.1016/j.pneurobio.2015.06.005] [PMID: 26159707]
[12]
Jha MK, Lee S, Park DH, et al. Diverse functional roles of lipocalin-2 in the central nervous system. Neurosci Biobehav Rev 2015; 49: 135-56.
[http://dx.doi.org/10.1016/j.neubiorev.2014.12.006] [PMID: 25511817]
[13]
Luo C, Zhou S, Yin S, et al. Lipocalin-2 and cerebral stroke. Front Mol Neurosci 2022; 15: 850849.
[http://dx.doi.org/10.3389/fnmol.2022.850849] [PMID: 35493318]
[14]
Jin M, Kim JH, Jang E, et al. Lipocalin-2 deficiency attenuates neuroinflammation and brain injury after transient middle cerebral artery occlusion in mice. J Cereb Blood Flow Metab 2014; 34(8): 1306-14.
[http://dx.doi.org/10.1038/jcbfm.2014.83] [PMID: 24780901]
[15]
Wang G, Weng YC, Chiang IC, et al. Neutralization of lipocalin-2 diminishes stroke-reperfusion injury. Int J Mol Sci 2020; 21(17): 6253.
[http://dx.doi.org/10.3390/ijms21176253] [PMID: 32872405]
[16]
Cheng L, Xing H, Mao X, Li L, Li X, Li Q. Lipocalin-2 promotes m1 macrophages polarization in a mouse cardiac ischaemiareperfusion injury model. Scand J Immunol 2015; 81(1): 31-8.
[http://dx.doi.org/10.1111/sji.12245] [PMID: 25359467]
[17]
Vinuesa E, Sola A, Jung M, Alfaro V, Hotter G. Lipocalin-2-induced renal regeneration depends on cytokines. Am J Physiol Renal Physiol 2008; 295(5): F1554-62.
[http://dx.doi.org/10.1152/ajprenal.90250.2008] [PMID: 18815220]
[18]
Madhi R, Rahman M, Mörgelin M, Thorlacius H. c-Abl kinase regulates neutrophil extracellular trap formation, inflammation, and tissue damage in severe acute pancreatitis. J Leukoc Biol 2019; 106(2): 455-66.
[http://dx.doi.org/10.1002/JLB.3A0618-222RR] [PMID: 30861207]
[19]
Daley JM, Thomay AA, Connolly MD, Reichner JS, Albina JE. Use of Ly6G-specific monoclonal antibody to deplete neutrophils in mice. J Leukoc Biol 2008; 83(1): 64-70.
[http://dx.doi.org/10.1189/jlb.0407247] [PMID: 17884993]
[20]
Cai W, Wang J, Hu M, et al. All trans-retinoic acid protects against acute ischemic stroke by modulating neutrophil functions through STAT1 signaling. J Neuroinflammation 2019; 16(1): 175.
[http://dx.doi.org/10.1186/s12974-019-1557-6] [PMID: 31472680]
[21]
Zhang S, Zhou L, Zhang M, et al. Berberine maintains the neutrophil N1 phenotype to reverse cancer cell resistance to Doxorubicin. Front Pharmacol 2020; 10: 1658.
[http://dx.doi.org/10.3389/fphar.2019.01658] [PMID: 32063859]
[22]
Li Z, Lin Y, Zhang S, et al. Emodin regulates neutrophil phenotypes to prevent hypercoagulation and lung carcinogenesis. J Transl Med 2019; 17(1): 90.
[http://dx.doi.org/10.1186/s12967-019-1838-y] [PMID: 30885207]
[23]
Cai W, Liu S, Hu M, et al. Functional dynamics of neutrophils after ischemic stroke. Transl Stroke Res 2020; 11(1): 108-21.
[http://dx.doi.org/10.1007/s12975-019-00694-y] [PMID: 30847778]
[24]
Ip JPK, Noçon AL, Hofer MJ, Lim SL, Müller M, Campbell IL. Lipocalin 2 in the central nervous system host response to systemic lipopolysaccharide administration. J Neuroinflammation 2011; 8(1): 124.
[http://dx.doi.org/10.1186/1742-2094-8-124] [PMID: 21943033]
[25]
Bi F, Huang C, Tong J, et al. Reactive astrocytes secrete lcn2 to promote neuron death. Proc Natl Acad Sci USA 2013; 110(10): 4069-74.
[http://dx.doi.org/10.1073/pnas.1218497110] [PMID: 23431168]
[26]
Suk K. Lipocalin-2 as a therapeutic target for brain injury: An astrocentric perspective. Prog Neurobiol 2016; 144: 158-72.
[http://dx.doi.org/10.1016/j.pneurobio.2016.08.001] [PMID: 27498195]
[27]
Zhao N, Xu X, Jiang Y, et al. Lipocalin-2 may produce damaging effect after cerebral ischemia by inducing astrocytes classical activation. J Neuroinflammation 2019; 16(1): 168.
[http://dx.doi.org/10.1186/s12974-019-1556-7] [PMID: 31426811]
[28]
Chen X, Qiu F, Zhao X, et al. Astrocyte-derived lipocalin-2 is involved in mitochondrion-related neuronal apoptosis induced by methamphetamine. ACS Chem Neurosci 2020; 11(8): 1102-16.
[http://dx.doi.org/10.1021/acschemneuro.9b00559] [PMID: 32186847]
[29]
Asimakopoulou A, Borkham-Kamphorst E, Tacke F, Weiskirchen R. Lipocalin-2 (NGAL/LCN2), a “help-me” signal in organ inflammation. Hepatology 2016; 63(2): 669-71.
[http://dx.doi.org/10.1002/hep.27930] [PMID: 26054053]
[30]
Ye D, Yang K, Zang S, et al. Lipocalin-2 mediates non-alcoholic steatohepatitis by promoting neutrophil-macrophage crosstalk via the induction of CXCR2. J Hepatol 2016; 65(5): 988-97.
[http://dx.doi.org/10.1016/j.jhep.2016.05.041] [PMID: 27266617]
[31]
Wang Q, Li S, Tang X, Liang L, Wang F, Du H. Lipocalin 2 protects against Escherichia coli infection by modulating neutrophil and macrophage function. Front Immunol 2019; 10: 2594.
[http://dx.doi.org/10.3389/fimmu.2019.02594] [PMID: 31781104]
[32]
Shao S, Cao T, Jin L, et al. Increased lipocalin-2 contributes to the pathogenesis of psoriasis by modulating neutrophil chemotaxis and cytokine secretion. J Invest Dermatol 2016; 136(7): 1418-28.
[http://dx.doi.org/10.1016/j.jid.2016.03.002] [PMID: 26979478]
[33]
Zhang SR, Phan TG, Sobey CG. Targeting the immune system for ischemic stroke. Trends Pharmacol Sci 2021; 42(2): 96-105.
[http://dx.doi.org/10.1016/j.tips.2020.11.010] [PMID: 33341247]
[34]
Mao S, Xi G, Keep RF, Hua Y. Role of lipocalin-2 in thrombin-induced brain injury. Stroke 2016; 47(4): 1078-84.
[http://dx.doi.org/10.1161/STROKEAHA.115.012153] [PMID: 26869387]
[35]
Wang G, Weng YC, Han X, Whaley JD, McCrae KR, Chou WH. Lipocalin-2 released in response to cerebral ischaemia mediates reperfusion injury in mice. J Cell Mol Med 2015; 19(7): 1637-45.
[http://dx.doi.org/10.1111/jcmm.12538] [PMID: 25702801]
[36]
García-Culebras A, Durán-Laforet V, Peña-Martínez C, et al. Role of TLR4 (Toll-Like Receptor 4) in N1/N2 neutrophil programming after stroke. Stroke 2019; 50(10): 2922-32.
[http://dx.doi.org/10.1161/STROKEAHA.119.025085] [PMID: 31451099]
[37]
Chen Q, Yin H, Liu S, et al. Prognostic value of tumorassociated N1/N2 neutrophil plasticity in patients following radical resection of pancreas ductal adenocarcinoma. J Immunother Cancer 2022; 10(12): e005798.
[http://dx.doi.org/10.1136/jitc-2022-005798] [PMID: 36600557]
[38]
Ma Y, Yabluchanskiy A, Iyer RP, et al. Temporal neutrophil polarization following myocardial infarction. Cardiovasc Res 2016; 110(1): 51-61.
[http://dx.doi.org/10.1093/cvr/cvw024] [PMID: 26825554]
[39]
Hsieh SW, Huang LC, Chang YP, Hung CH, Yang YH. M2b macrophage subset decrement as an indicator of cognitive function in Alzheimer’s disease. Psychiatry Clin Neurosci 2020; 74(7): 383-91.
[http://dx.doi.org/10.1111/pcn.13000] [PMID: 32170772]
[40]
Xie M, Hao Y, Feng L, et al. Neutrophil heterogeneity and its roles in the inflammatory network after ischemic stroke. Curr Neuropharmacol 2023; 21(3): 621-50.
[http://dx.doi.org/10.2174/1570159X20666220706115957] [PMID: 35794770]
[41]
Certo M, Endo Y, Ohta K, Sakurada S, Bagetta G, Amantea D. Activation of RXR/PPARγ- underlies neuroprotection by bexarotene in ischemic stroke. Pharmacol Res 2015; 102: 298-307.
[http://dx.doi.org/10.1016/j.phrs.2015.10.009] [PMID: 26546745]