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S1P1 Regulates M1/M2 Polarization toward Brain Injury after Transient Focal Cerebral Ischemia

  • Gaire, Bhakta Prasad (College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University) ;
  • Bae, Young Joo (College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University) ;
  • Choi, Ji Woong (College of Pharmacy and Gachon Institute of Pharmaceutical Sciences, Gachon University)
  • Received : 2019.01.10
  • Accepted : 2019.04.09
  • Published : 2019.11.01

Abstract

M1/M2 polarization of immune cells including microglia has been well characterized. It mediates detrimental or beneficial roles in neuroinflammatory disorders including cerebral ischemia. We have previously found that sphingosine 1-phospate receptor subtype 1 ($S1P_1$) in post-ischemic brain following transient middle cerebral artery occlusion (tMCAO) can trigger microglial activation, leading to brain damage. Although the link between $S1P_1$ and microglial activation as a pathogenesis in cerebral ischemia had been clearly demonstrated, whether the pathogenic role of $S1P_1$ is associated with its regulation of M1/M2 polarization remains unclear. Thus, this study aimed to determine whether $S1P_1$ was associated with regulation of M1/M2 polarization in post-ischemic brain. Suppressing $S1P_1$ activity with its functional antagonist, AUY954 (5 mg/kg, p.o.), attenuated mRNA upregulation of M1 polarization markers in post-ischemic brain at 1 day and 3 days after tMCAO challenge. Similarly, suppressing $S1P_1$ activity with AUY954 administration inhibited M1-polarizatioin-relevant $NF-{\kappa}B$ activation in post-ischemic brain. Particularly, $NF-{\kappa}B$ activation was observed in activated microglia of post-ischemic brain and markedly attenuated by AUY954, indicating that M1 polarization through $S1P_1$ in post-ischemic brain mainly occurred in activated microglia. Suppressing $S1P_1$ activity with AUY954 also increased mRNA expression levels of M2 polarization markers in post-ischemic brain, further indicating that $S1P_1$ could also influence M2 polarization in post-ischemic brain. Finally, suppressing $S1P_1$ activity decreased phosphorylation of M1-relevant ERK1/2, p38, and JNK MAPKs, but increased phosphorylation of M2-relevant Akt, all of which were downstream pathways following $S1P_1$ activation. Overall, these results revealed $S1P_1$-regulated M1/M2 polarization toward brain damage as a pathogenesis of cerebral ischemia.

Keywords

References

  1. Aoki, M., Aoki, H., Ramanathan, R., Hait, N. C. and Takabe, K. (2016) Corrigendum to "sphingosine-1-phosphate signaling in immune cells and inflammation: roles and therapeutic potential". Mediators Inflamm. 2016, 2856829.
  2. Block, M. L., Zecca, L. and Hong, J. S. (2007) Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat. Rev. Neurosci. 8, 57-69. https://doi.org/10.1038/nrn2038
  3. Butovsky, O., Ziv, Y., Schwartz, A., Landa, G., Talpalar, A. E., Pluchino, S., Martino, G. and Schwartz, M. (2006) Microglia activated by IL-4 or IFN-gamma differentially induce neurogenesis and oligodendrogenesis from adult stem/progenitor cells. Mol. Cell. Neurosci. 31, 149-160. https://doi.org/10.1016/j.mcn.2005.10.006
  4. Byles, V., Covarrubias, A. J., Ben-Sahra, I., Lamming, D. W., Sabatini, D. M., Manning, B. D. and Horng, T. (2013) The TSC-mTOR pathway regulates macrophage polarization. Nat. Commun. 4, 2834. https://doi.org/10.1038/ncomms3834
  5. Cherry, J. D., Olschowka, J. A. and O'Banion, M. K. (2014) Neuroinflammation and M2 microglia: the good, the bad, and the inflamed. J. Neuroinflammation 11, 98. https://doi.org/10.1186/1742-2094-11-98
  6. Chi, H. (2011) Sphingosine-1-phosphate and immune regulation: trafficking and beyond. Trends. Pharmacol. Sci. 32, 16-24. https://doi.org/10.1016/j.tips.2010.11.002
  7. Choi, J. W. and Chun, J. (2013) Lysophospholipids and their receptors in the central nervous system. Biochim. Biophys. Acta 1831, 20-32. https://doi.org/10.1016/j.bbalip.2012.07.015
  8. Cyster, J. G. and Schwab, S. R. (2012) Sphingosine-1-phosphate and lymphocyte egress from lymphoid organs. Annu. Rev. Immunol. 30, 69-94. https://doi.org/10.1146/annurev-immunol-020711-075011
  9. Czech, B., Pfeilschifter, W., Mazaheri-Omrani, N., Strobel, M. A., Kahles, T., Neumann-Haefelin, T., Rami, A., Huwiler, A. and Pfeilschifter, J. (2009) The immunomodulatory sphingosine 1-phosphate analog FTY720 reduces lesion size and improves neurological outcome in a mouse model of cerebral ischemia. Biochem. Biophys. Res. Commun. 389, 251-256. https://doi.org/10.1016/j.bbrc.2009.08.142
  10. Doll, D. N., Barr, T. L. and Simpkins, J. W. (2014) Cytokines: their role in stroke and potential use as biomarkers and therapeutic targets. Aging Dis. 5, 294-306. https://doi.org/10.14336/AD.2014.0500294
  11. Fu, Y., Hao, J., Zhang, N., Ren, L., Sun, N., Li, Y. J., Yan, Y., Huang, D., Yu, C. and Shi, F. D. (2014) Fingolimod for the treatment of intracerebral hemorrhage: a 2-arm proof-of-concept study. JAMA Neurol. 71, 1092-1101. https://doi.org/10.1001/jamaneurol.2014.1065
  12. Gabriel, C., Justicia, C., Camins, A. and Planas, A. M. (1999) Activation of nuclear factor-kappaB in the rat brain after transient focal ischemia. Brain Res. Mol. Brain Res. 65, 61-69. https://doi.org/10.1016/S0169-328X(98)00330-1
  13. Gaire, B. P., Kwon, O. W., Park, S. H., Chun, K. H., Kim, S. Y., Shin, D. Y. and Choi, J. W. (2015) Neuroprotective effect of 6-paradol in focal cerebral ischemia involves the attenuation of neuroinflammatory responses in activated microglia. PLoS ONE 10, e0120203. https://doi.org/10.1371/journal.pone.0120203
  14. Gaire, B. P., Lee, C. H., Sapkota, A., Lee, S. Y., Chun, J., Cho, H. J., Nam, T. G. and Choi, J. W. (2018a) Identification of sphingosine 1-phosphate receptor subtype 1 (S1P1) as a pathogenic factor in transient focal cerebral ischemia. Mol. Neurobiol. 55, 2320-2332. https://doi.org/10.1007/s12035-017-0468-8
  15. Gaire, B. P., Song, M. R. and Choi, J. W. (2018b) Sphingosine 1-phosphate receptor subtype 3 (S1P3) contributes to brain injury after transient focal cerebral ischemia via modulating microglial activation and their M1 polarization. J. Neuroinflammation 15, 284. https://doi.org/10.1186/s12974-018-1323-1
  16. Gu, L., Huang, B., Shen, W., Gao, L., Ding, Z., Wu, H. and Guo, J. (2013) Early activation of nSMase2/ceramide pathway in astrocytes is involved in ischemia-associated neuronal damage via inflammation in rat hippocampi. J. Neuroinflammation 10, 109.
  17. Harari, O. A. and Liao, J. K. (2010) NF-kappaB and innate immunity in ischemic stroke. Ann. N. Y. Acad. Sci. 1207, 32-40. https://doi.org/10.1111/j.1749-6632.2010.05735.x
  18. Hu, X., Leak, R. K., Shi, Y., Suenaga, J., Gao, Y., Zheng, P. and Chen, J. (2015) Microglial and macrophage polarization-new prospects for brain repair. Nat. Rev. Neurol. 11, 56-64. https://doi.org/10.1038/nrneurol.2014.207
  19. Hu, X., Li, P., Guo, Y., Wang, H., Leak, R. K., Chen, S., Gao, Y. and Chen, J. (2012) Microglia/macrophage polarization dynamics reveal novel mechanism of injury expansion after focal cerebral ischemia. Stroke 43, 3063-3070. https://doi.org/10.1161/STROKEAHA.112.659656
  20. Jiang, B., Brecher, P. and Cohen, R. A. (2001) Persistent activation of nuclear factor-kappaB by interleukin-1beta and subsequent inducible NO synthase expression requires extracellular signal-regulated kinase. Arterioscler. Thromb. Vasc. Biol. 21, 1915-1920. https://doi.org/10.1161/hq1201.099424
  21. Kim, G. S., Yang, L., Zhang, G., Zhao, H., Selim, M., McCullough, L. D., Kluk, M. J. and Sanchez, T. (2015) Critical role of sphingosine- 1-phosphate receptor-2 in the disruption of cerebrovascular integrity in experimental stroke. Nat. Commun. 6, 7893. https://doi.org/10.1038/ncomms8893
  22. Kraft, P., Gob, E., Schuhmann, M. K., Gobel, K., Deppermann, C., Thielmann, I., Herrmann, A. M., Lorenz, K., Brede, M., Stoll, G., Meuth, S. G., Nieswandt, B., Pfeilschifter, W. and Kleinschnitz, C. (2013) FTY720 ameliorates acute ischemic stroke in mice by reducing thrombo-inflammation but not by direct neuroprotection. Stroke 44, 3202-3210. https://doi.org/10.1161/STROKEAHA.113.002880
  23. Lan, X., Han, X., Li, Q., Yang, Q. W. and Wang, J. (2017) Modulators of microglial activation and polarization after intracerebral haemorrhage. Nat. Rev. Neurol. 13, 420-433. https://doi.org/10.1038/nrneurol.2017.69
  24. Mattson, M. P. and Camandola, S. (2001) NF-kappaB in neuronal plasticity and neurodegenerative disorders. J. Clin. Invest. 107, 247-254. https://doi.org/10.1172/JCI11916
  25. Mirendil, H., Thomas, E. A., De Loera, C., Okada, K., Inomata, Y. and Chun, J. (2015) LPA signaling initiates schizophrenia-like brain and behavioral changes in a mouse model of prenatal brain hemorrhage. Translational. Psychiatry 5, e541. https://doi.org/10.1038/tp.2015.33
  26. Moon, E., Han, J. E., Jeon, S., Ryu, J. H., Choi, J. W. and Chun, J. (2015) Exogenous S1P exposure potentiates ischemic stroke damage that is reduced possibly by inhibiting S1P receptor signaling. Mediators Inflamm. 2015, 492659.
  27. Nayak, D., Huo, Y., Kwang, W. X., Pushparaj, P. N., Kumar, S. D., Ling, E. A. and Dheen, S. T. (2010) Sphingosine kinase 1 regulates the expression of proinflammatory cytokines and nitric oxide in activated microglia. Neuroscience 166, 132-144. https://doi.org/10.1016/j.neuroscience.2009.12.020
  28. Nazari, M., Keshavarz, S., Rafati, A., Namavar, M. R. and Haghani, M. (2016) Fingolimod (FTY720) improves hippocampal synaptic plasticity and memory deficit in rats following focal cerebral ischemia. Brain Res. Bull. 124, 95-102. https://doi.org/10.1016/j.brainresbull.2016.04.004
  29. Noda, H., Takeuchi, H., Mizuno, T. and Suzumura, A. (2013) Fingolimod phosphate promotes the neuroprotective effects of microglia. J. Neuroimmunol. 256, 13-18. https://doi.org/10.1016/j.jneuroim.2012.12.005
  30. Olson, C. M., Hedrick, M. N., Izadi, H., Bates, T. C., Olivera, E. R. and Anguita, J. (2007) p38 mitogen-activated protein kinase controls NF-kappaB transcriptional activation and tumor necrosis factor alpha production through RelA phosphorylation mediated by mitogen- and stress-activated protein kinase 1 in response to Borrelia burgdorferi antigens. Infect. Immun. 75, 270-277. https://doi.org/10.1128/IAI.01412-06
  31. Pan, Y., Zhang, X., Wang, Y., Cai, L., Ren, L., Tang, L., Wang, J., Zhao, Y., Wang, Y., Liu, Q., Li, X. and Liang, G. (2013) Targeting JNK by a new curcumin analog to inhibit NF-kB${\kappa}B$-mediated expression of cell adhesion molecules attenuates renal macrophage infiltration and injury in diabetic mice. PLoS ONE 8, e79084. https://doi.org/10.1371/journal.pone.0079084
  32. Patel, A. R., Ritzel, R., McCullough, L. D. and Liu, F. (2013) Microglia and ischemic stroke: a double-edged sword. Int. J. Physiol. Pathophysiol. Pharmacol. 5, 73-90.
  33. Qin, C., Fan, W. H., Liu, Q., Shang, K., Murugan, M., Wu, L. J., Wang, W. and Tian, D. S. (2017) Fingolimod protects against ischemic white matter damage by modulating microglia toward M2 polarization via STAT3 pathway. Stroke 48, 3336-3346. https://doi.org/10.1161/STROKEAHA.117.018505
  34. Rothhammer, V., Kenison, J. E., Tjon, E., Takenaka, M. C., de Lima, K. A., Borucki, D. M., Chao, C. C., Wilz, A., Blain, M., Healy, L., Antel, J. and Quintana, F. J. (2017) Sphingosine 1-phosphate receptor modulation suppresses pathogenic astrocyte activation and chronic progressive CNS inflammation. Proc. Natl. Acad. Sci. U.S A. 114, 2012-2017.
  35. Sapkota, A., Gaire, B. P., Cho, K. S., Jeon, S. J., Kwon, O. W., Jang, D. S., Kim, S. Y., Ryu, J. H. and Choi, J. W. (2017) Eupatilin exerts neuroprotective effects in mice with transient focal cerebral ischemia by reducing microglial activation. PLoS ONE 12, e0171479. https://doi.org/10.1371/journal.pone.0171479
  36. Tam, W. Y. and Ma, C. H. (2014) Bipolar/rod-shaped microglia are proliferating microglia with distinct M1/M2 phenotypes. Sci. Rep. 4, 7279. https://doi.org/10.1038/srep07279
  37. Thored, P., Heldmann, U., Gomes-Leal, W., Gisler, R., Darsalia, V., Taneera, J., Nygren, J. M., Jacobsen, S. E., Ekdahl, C. T., Kokaia, Z. and Lindvall, O. (2009) Long-term accumulation of microglia with proneurogenic phenotype concomitant with persistent neurogenesis in adult subventricular zone after stroke. Glia 57, 835-849. https://doi.org/10.1002/glia.20810
  38. Tsai, H. C. and Han, M. H. (2016) Sphingosine-1-phosphate (S1P) and S1P signaling pathway: therapeutic targets in autoimmunity and inflammation. Drugs 76, 1067-1079. https://doi.org/10.1007/s40265-016-0603-2
  39. Vergadi, E., Ieronymaki, E., Lyroni, K., Vaporidi, K. and Tsatsanis, C. (2017) Akt signaling pathway in macrophage activation and M1/M2 polarization. J. Immunol. 198, 1006-1014. https://doi.org/10.4049/jimmunol.1601515
  40. Walker, D. G. and Lue, L. F. (2015) Immune phenotypes of microglia in human neurodegenerative disease: challenges to detecting microglial polarization in human brains. Alzheimers Res. Ther. 7, 56. https://doi.org/10.1186/s13195-015-0139-9
  41. Wang, P., He, Y., Li, D., Han, R., Liu, G., Kong, D. and Hao, J. (2016) Class I PI3K inhibitor ZSTK474 mediates a shift in microglial/macrophage phenotype and inhibits inflammatory response in mice with cerebral ischemia/reperfusion injury. J. Neuroinflammation 13, 192. https://doi.org/10.1186/s12974-016-0660-1
  42. Xia, C. Y., Zhang, S., Gao, Y., Wang, Z. Z. and Chen, N. H. (2015) Selective modulation of microglia polarization to M2 phenotype for stroke treatment. Int. Immunopharmacol. 25, 377-382. https://doi.org/10.1016/j.intimp.2015.02.019
  43. Xiong, X. Y., Liu, L. and Yang, Q. W. (2016) Functions and mechanisms of microglia/macrophages in neuroinflammation and neurogenesis after stroke. Prog. Neurobiol. 142, 23-44. https://doi.org/10.1016/j.pneurobio.2016.05.001
  44. Zhang, C., Zhu, Y., Wang, S., Zachory Wei, Z., Jiang, M. Q., Zhang, Y., Pan, Y., Tao, S., Li, J. and Wei, L. (2018) Temporal gene expression profiles after focal cerebral ischemia in mice. Aging Dis. 9, 249-261. https://doi.org/10.14336/AD.2017.0424
  45. Zhang, G., Yang, L., Kim, G. S., Ryan, K., Lu, S., O'Donnell, R. K., Spokes, K., Shapiro, N., Aird, W. C., Kluk, M. J., Yano, K. and Sanchez, T. (2013) Critical role of sphingosine-1-phosphate receptor 2 (S1PR2) in acute vascular inflammation. Blood 122, 443-455.
  46. Zhou, S., Zhu, W., Zhang, Y., Pan, S. and Bao, J. (2018) S100B promotes microglia M1 polarization and migration to aggravate cerebral ischemia. Inflamm. Res. 67, 937-949. https://doi.org/10.1007/s00011-018-1187-y
  47. Zhu, Z., Fu, Y., Tian, D., Sun, N., Han, W., Chang, G., Dong, Y., Xu, X., Liu, Q., Huang, D., and Shi, F. D. (2015) Combination of the immune modulator fingolimod with alteplase in acute ischemic stroke: a pilot trial. Circulation 132, 1104-1112. https://doi.org/10.1161/CIRCULATIONAHA.115.016371

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