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Lysophosphatidylinositol, an Endogenous Ligand for G Protein-Coupled Receptor 55, Has Anti-inflammatory Effects in Cultured Microglia

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Abstract

Lysophosphatidylinositol (LysoPI), an endogenous ligand for G protein-coupled receptor (GPR) 55, has been known to show various functions in several tissues and cells; however, its roles in the central nervous system (CNS) are not well known. In particular, the detailed effects of LysoPI on microglial inflammatory responses remain unknown. Microglia is the immune cell that has important functions in maintaining immune homeostasis of the CNS. In this study, we explored the effects of LysoPI on inflammatory responses using the mouse microglial cell line BV-2, which was stimulated with lipopolysaccharide (LPS), and some results were confirmed also in rat primary microglia. LysoPI was found to reduce LPS-induced nitric oxide (NO) production and inducible NO synthase protein expression without affecting cell viability in BV-2 cells. LysoPI also suppressed intracellular generation of reactive oxygen species both in BV-2 cells and primary microglia and cytokine release in BV-2 cells. In addition, LysoPI treatment decreased phagocytic activity of LPS-stimulated BV-2 cells and primary microglia. The GPR55 antagonist CID16020046 completely inhibited LysoPI-induced downregulation of phagocytosis in BV-2 microglia, but did not affect the LysoPI-induced decrease in NO production. Our results suggest that LysoPI suppresses microglial phagocytosis via a GPR55-dependent pathway and NO production via a GPR55-independent pathway. LysoPI may contribute to neuroprotection in pathological conditions such as brain injury or neurodegenerative diseases, through its suppressive role in the microglial inflammatory response.

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Abbreviations

CB2 :

Cannabinoid 2

DAN:

2,3-Diaminonaphthalene

DCF:

2′,7′-Dichlorofluorescein

DMEM:

Dulbecco’s modified Eagle medium

DMSO:

Dimethyl sulfoxide

ERK:

Extracellular signal-regulated kinase

FBS:

Fetal bovine serum

GPR:

G protein-coupled receptor

H2DCFDA:

2′,7′-Dichlorodihydrofluorescein diacetate

IL:

Interleukin

INF-γ:

Interferon-γ

iNOS:

Inducible nitric oxide synthase

LPLs:

Lysophospholipids

LPS:

Lipopolysaccharide

LysoPI:

Lysophosphatidylinositol

MA:

Methyl acetate

MTT:

3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-tetrazolium bromide

NF-κB:

Nuclear factor-kappa B

NO:

Nitric oxide

ROS:

Reactive oxygen species

TNF-α:

Tumor necrosis factor-α

References

  1. Kreutzberg, G.W. 1996. Microglia: a sensor for pathological events in the CNS. Trends in Neurosciences 19: 312–318. https://doi.org/10.1016/0166-2236(96)10049-7.

    Article  CAS  PubMed  Google Scholar 

  2. Nakamura, Y. 2002. Regulating factors for microglial activation. Biological and Pharmaceutical Bulletin 25: 945–953. https://doi.org/10.1248/bpb.25.945.

    Article  CAS  PubMed  Google Scholar 

  3. Block, M.L., L. Zecca, and J. Hong. 2007. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nature Reviews Neuroscience 8: 57–69. https://doi.org/10.1038/nrn2038.

    Article  CAS  PubMed  Google Scholar 

  4. Neniskyte, U., J.J. Neher, and G.C. Brown. 2011. Neuronal death induced by nanomolar amyloid β is mediated by primary phagocytosis of neurons by microglia. Journal of Biological Chemistry 286: 39904–39913. https://doi.org/10.1074/jbc.M111.267583.

    Article  CAS  PubMed  Google Scholar 

  5. Brown, G.C., and A. Vilalta. 2015. How microglia kill neurons. Brain Research 1628: 288–297. https://doi.org/10.1016/j.brainres.2015.08.031.

    Article  CAS  PubMed  Google Scholar 

  6. Aoki, J., Y. Nagai, H. Hosono, K. Inoue, and H. Arai. 2002. Structure and function of phosphatidylserine-specific phospholipase A1. Biochimica et Biophysica Acta 1582 (1–3): 26–32. https://doi.org/10.1016/s1388-1981(02)00134-8.

    Article  CAS  PubMed  Google Scholar 

  7. Alhouayek, M., J. Masquelier, and G.G. Muccioli. 2018. Lysophosphatidylinositols, from cell membrane constituents to GPR55 ligands. Trends in Pharmacological Sciences 39 (6): 586–604. https://doi.org/10.1016/j.tips.2018.02.011.

    Article  CAS  PubMed  Google Scholar 

  8. Grzelczyk, A., and E. Gendaszewska-Darmach. 2013. Novel bioactive glycerol-based lyosphospholipids: new data ― new insight into their function. Biochimie 95: 667–679. https://doi.org/10.1016/j.biochi.2012.10.009.

    Article  CAS  PubMed  Google Scholar 

  9. Kihara, Y., H. Mizuno, and J. Chun. 2015. Lysophospholipid receptors in drug discovery. Experimental Cell Research 333 (2): 171–177. https://doi.org/10.1016/j.yexcr.2014.11.020.

    Article  CAS  PubMed  Google Scholar 

  10. Zhao, C., M.J. Fernandes, G.D. Prestwich, M. Turgeon, J. Di Battista, T. Clair, P.E. Poubelle, and S.G. Bourgoin. 2008. Regulation of lysophosphatidic acid receptor expression and function in human synoviocytes: implications for rheumatoid arthritis? Molecular Pharmacology 73 (2): 587–600. https://doi.org/10.1124/mol.107.038216.

    Article  CAS  PubMed  Google Scholar 

  11. Bektas, M., M.L. Allende, B.G. Lee, W. Chen, M.J. Amar, A.T. Remaley, J.D. Saba, and R.L. Proia. 2010. Sphingosine 1-phosphate lyase deficiency disrupts lipid homeostasis in liver. Journal of Biological Chemistry 285 (14): 10880–10889. https://doi.org/10.1074/jbc.M109.081489.

    Article  CAS  PubMed  Google Scholar 

  12. Vladykovskaya, E., E. Ozhegov, J.D. Hoetker, Z. Xie, Y. Ahmed, J. Suttles, S. Srivastava, A. Bhatnagar, and O.A. Barski. 2011. Reductive metabolism increases the proinflammatory activity of aldehyde phospholipids. Journal of Lipid Research 52 (12): 2209–2225. https://doi.org/10.1194/jlr.M013854.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Hung, N.D., M.R. Kim, and D.E. Sok. 2011. 2-Polyunsaturated acyl lysophosphatidylethanolamine attenuates inflammatory response in zymosan A-induced peritonitis in mice. Lipids 46: 893–906. https://doi.org/10.1007/s11745-011-3589-2.

    Article  CAS  PubMed  Google Scholar 

  14. Nishikawa, M., M. Kurano, H. Ikeda, J. Aoki, and Y. Yatomi. 2015. Lysophosphatidylserine has bilateral effects on macrophages in the pathogenesis of atherosclerosis. Journal of Atherosclerosis and Thrombosis 22 (5): 518–526. https://doi.org/10.5551/jat.25650.

    Article  CAS  PubMed  Google Scholar 

  15. Henstridge, C.M., N.A. Balenga, L.A. Ford, R.A. Ross, M. Waldhoer, and A.J. Irving. 2009. The GPR55 ligand L-α-lysophosphatidylinositol promotes RhoA-dependent Ca2+ signaling and NFAT activation. FASEB Journal 23 (1): 183–193. https://doi.org/10.1096/fj.08-108670.

    Article  CAS  PubMed  Google Scholar 

  16. Anavi-Goffer, S., G. Baillie, A.J. Irving, J. Gertsch, I.R. Greig, R.G. Pertwee, and R.A. Ross. 2011. Modulation of L-α-lysophosphatidylinositol/GPR55 mitogen-activated protein kinase (MAPK) signaling by cannabinoids. Journal of Biological Chemistry 287 (1): 91–104. https://doi.org/10.1074/jbc.M111.296020.

    Article  CAS  PubMed  Google Scholar 

  17. Frasch, S.C., and D.L. Bratton. 2012. Emerging roles for lysophosphatidylserine in resolution of inflammation. Progress in Lipid Research 51 (3): 199–207. https://doi.org/10.1016/j.plipres.2012.03.001.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Kamat, S.S., K. Camara, W.H. Parsons, D.H. Chen, M.M. Dix, T.D. Bird, A.R. Howell, and B.F. Cravatt. 2015. Immunomodulatory lysophosphatidylserines are regulated by ABHD16A and ABHD12 interplay. Nature Chemical Biology 11 (2): 164–171. https://doi.org/10.1038/nchembio.1721.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Wang, X., Y.F. Li, G. Nanayakkara, Y. Shao, B. Liang, L. Cole, W.Y. Yang, X. Li, R. Cueto, J. Yu, H. Wang, and X.F. Yang. 2016. Lysophospholipid receptors, as novel conditional danger receptors and homeostatic receptors modulate inflammation-novel paradigm and therapeutic potential. Journal of Cardiovascular Translational Research 9 (4): 343–359. https://doi.org/10.1007/s12265-016-9700-6.

    Article  PubMed  PubMed Central  Google Scholar 

  20. Celorrio, M., E. Rojo-Bustamante, D. Fernández-Suárez, E. Sáez, A. Estella-Hermoso de Mendoza, C.E. Müller, M.J. Ramírez, J. Oyarzábal, R. Franco, and M.S. Aymerich. 2017. GPR55: a therapeutic target for Parkinson’s disease? Neuropharmacology 125: 319–332. https://doi.org/10.1016/j.neuropharm.2017.08.017.

    Article  CAS  PubMed  Google Scholar 

  21. Haque, M.E., I.S. Kim, M. Jakaria, M. Akther, and D.K. Choi. 2018. Importance of GPCR-mediated microglial activation in Alzheimer’s disease. Frontiers in Cellular Neuroscience 12: 258. https://doi.org/10.3389/fncel.2018.00258.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Oka, S., T. Toshida, K. Maruyama, K. Nakajima, A. Yamashita, and T. Sugiura. 2009. 2-Arachidonoyl-sn-glycero-3-phosphoinositol: a possible natural ligand for GPR55. Journal of Biochemistry 145 (1): 13–20. https://doi.org/10.1093/jb/mvn136.

    Article  CAS  PubMed  Google Scholar 

  23. Pietr, M., E. Kozela, R. Levy, N. Rimmerman, Y.H. Lin, N. Stella, Z. Vogel, and A. Juknat. 2009. Differential changes in GPR55 during microglial cell activation. FEBS Letters 583 (12): 2071–2076. https://doi.org/10.1016/j.febslet.2009.05.028.

    Article  CAS  PubMed  Google Scholar 

  24. Kallendrusch, S., S. Kremzow, M. Nowicki, U. Grabiec, R. Winkelmann, A. Benz, and M. Koch. 2013. The G protein-coupled receptor 55 ligand L-α-lysophosphatidylinositol exerts microglia-dependent neuroprotection after excitotoxic lesion. Glia 61 (11): 1822–1831. https://doi.org/10.1002/glia.22560.

    Article  PubMed  Google Scholar 

  25. Si, Q., Y. Nakamura, and K. Kataoka. 2000. A serum factor enhances production of nitric oxide and tumor necrosis factor-α from cultured microglia. Experimental Neurology 162 (1): 89–97. https://doi.org/10.1006/exnr.2000.7334.

    Article  CAS  PubMed  Google Scholar 

  26. Horvath, R.J., N. Nutile-McMenemy, M.S. Alkaitis, and J.A. Deleo. 2008. Differential migration, LPS-induced cytokine, chemokine, and NO expression in immortalized BV-2 and HAPI cell lines and primary microglial cultures. Journal of Neurochemistry 107 (2): 557–569. https://doi.org/10.1111/j.1471-4159.2008.05633.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. de Jong, E.K., A.H. de Haas, N. Brouwer, H.R. van Weering, M. Hensens, I. Bechmann, P. Pratley, E. Wesseling, H.W. Boddeke, and K. Biber. 2008. Expression of CXCL4 in microglia in vitro and in vivo and its possible signaling through CXCR3. Journal of Neurochemistry 105 (5): 1726–1736. https://doi.org/10.1111/j.1471-4159.2008.05267.x.

    Article  CAS  PubMed  Google Scholar 

  28. Kim, Y.L., Y.J. Im, N.C. Ha, and D.S. Im. 2006. Albumin inhibits cytotoxic activity of lysophosphatidylcholine by direct binding. Prostaglandins & Other Lipid Mediators 83 (1-2): 130–138. https://doi.org/10.1016/j.prostaglandins.2006.10.006.

    Article  CAS  Google Scholar 

  29. Takano, K., K. Sugita, M. Moriyama, K. Hashida, S. Hibino, T. Choshi, R. Murakami, M. Yamada, H. Suzuki, O. Hori, and Y. Nakamura. 2011. A dibenzoylmethane derivative protects against hydrogen peroxide-induced cell death and inhibits lipopolysaccharide-induced nitric oxide production in cultured rat astrocytes. Journal of Neuroscience Research 89: 955–965. https://doi.org/10.1002/jnr.22617.

    Article  CAS  PubMed  Google Scholar 

  30. Bradford, M.M. 1976. A rapid and sensitive method for the quantitation of microgram quantities of protein utilizing the principle of protein-dye binding. Analytical Biochemistry 72 (1–2): 248–254. https://doi.org/10.1006/abio.1976.9999.

    Article  CAS  PubMed  Google Scholar 

  31. Koyama, Y., Y. Kimura, Y. Yoshioka, D. Wakamatsu, R. Kozaki, H. Hashimoto, T. Matsuda, and A. Baba. 2000. Serum-deprivation induces cell death of rat cultured microglia accompanied with expression of Bax protein. Japanese Journal of Pharmacology 83 (4): 351–354. https://doi.org/10.1254/jjp.83.351.

    Article  CAS  PubMed  Google Scholar 

  32. Hsieh, H.L., and C.M. Yang. 2013. Role of redox signaling in neuroinflammation and neurodegenerative diseases. BioMed Research International 2013: 484613–484618. https://doi.org/10.1155/2013/484613.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  33. Mittal, M., M.R. Siddiqui, K. Tran, S.P. Reddy, and A.B. Malik. 2014. Reactive oxygen species in inflammation and tissue injury. Antioxidants & Redox Signaling 20 (7): 1126–1167. https://doi.org/10.1089/ars.2012.5149.

    Article  CAS  Google Scholar 

  34. Qin, L., Y. Liu, T. Wang, S.J. Wei, M.L. Block, B. Wilson, B. Liu, and J.S. Hong. 2004. NADPH oxidase mediates lipopolysaccharide-induced neurotoxicity and proinflammatory gene expression in activated microglia. Journal of Biological Chemistry 279 (2): 1415–1421. https://doi.org/10.1074/jbc.M307657200.

    Article  CAS  PubMed  Google Scholar 

  35. Li, B., K. Bedard, S. Sorce, B. Hinz, M. Dubois-Dauphin, and K.H. Krause. 2009. NOX4 expression in human microglia leads to constitutive generation of reactive oxygen species and to constitutive IL-6 expression. Journal of Innate Immunity 1 (6): 570–581. https://doi.org/10.1159/000235563.

    Article  CAS  PubMed  Google Scholar 

  36. Balenga, N.A., E. Aflaki, J. Kargl, W. Platzer, R. Schröder, S. Blättermann, E. Kostenis, A.J. Brown, A. Heinemann, and M. Waldhoer. 2011. GPR55 regulates cannabinoid 2 receptor-mediated responses in human neutrophils. Cell Research 21 (10): 1452–1469. https://doi.org/10.1038/cr.2011.60.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Li, X., L. Wang, P. Fang, Y. Sun, X. Jiang, H. Wang, and X.F. Yang. 2018. Lysophospholipids induce innate immune transdifferentiation of endothelial cells, resulting in prolonged endothelial activation. Journal of Biological Chemistry 293 (28): 11033–11045. https://doi.org/10.1074/jbc.RA118.002752.

    Article  CAS  PubMed  Google Scholar 

  38. Ginsburg, I., P.A. Ward, and J. Varani. 1989. Lysophosphatides enhance superoxide responses of stimulated human neutrophils. Inflammation 13 (2): 163–174. https://doi.org/10.1007/bf00924787.

    Article  CAS  PubMed  Google Scholar 

  39. Ojala, P.J., T.E. Hirvonen, M. Hermansson, P. Somerharju, and J. Parkkinen. 2007. Acyl chain-dependent effect of lysophosphatidylcholine on human neutrophils. Journal of Leukocyte Biology 82 (6): 1501–1509. https://doi.org/10.1189/jlb.0507292.

    Article  CAS  PubMed  Google Scholar 

  40. Brkić, L., M. Riederer, W.F. Graier, R. Malli, and S. Frank. 2012. Acyl chain-dependent effect of lysophosphatidylcholine on cyclooxygenase (COX)-2 expression in endothelial cells. Atherosclerosis 224 (2): 348–354. https://doi.org/10.1016/j.atherosclerosis.2012.07.038.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Rao, S.P., M. Riederer, M. Lechleitner, M. Hermansson, G. Desoye, S. Hallström, W.F. Graier, and S. Frank. 2013. Acyl chain-dependent effect of lysophosphatidylcholine on endothelium-dependent vasorelaxation. PLoS One 8 (5): e65155. https://doi.org/10.1371/journal.pone.0065155.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Tokizane, K., H. Konishi, K. Makide, H. Kawana, S. Nakamuta, K. Kaibuchi, T. Ohwada, J. Aoki, and H. Kiyama. 2017. Phospholipid localization implies microglial morphology and function via Cdc42 in vitro. Glia 65 (5): 740–755. https://doi.org/10.1002/glia.23123.

    Article  PubMed  Google Scholar 

  43. Ailte, I., A.B. Lingelem, A.S. Kvalvaag, S. Kavaliauskiene, A. Brech, G. Koster, P.G. Dommersnes, J. Bergan, T. Skotland, and K. Sandvig. 2017. Exogenous lysophospholipids with large head groups perturb clathrin-mediated endocytosis. Traffic 18 (3): 176–191. https://doi.org/10.1111/tra.12468.

    Article  CAS  PubMed  Google Scholar 

  44. Amorós, I., A. Barana, R. Caballero, R. Gómez, L. Osuna, M.P. Lillo, J. Tamargo, and E. Delpón. 2010. Endocannabinoids and cannabinoid analogues block human cardiac Kv4.3 channels in a receptor-independent manner. Journal of Molecular and Cellular Cardiology 48 (1): 201–210. https://doi.org/10.1016/j.yjmcc.2009.07.011.

    Article  CAS  PubMed  Google Scholar 

  45. Bondarenko, A., M. Waldeck-Weiermair, S. Naghdi, M. Poteser, R. Malli, and W.F. Graier. 2010. GPR55-dependent and -independent ion signalling in response to lysophosphatidylinositol in endothelial cells. British Journal of Pharmacology 161 (2): 308–320. https://doi.org/10.1111/j.1476-5381.2010.00744.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Bondarenko, A.I., R. Malli, and W.F. Graier. 2011. The GPR55 agonist lysophosphatidylinositol directly activates intermediate-conductance Ca2+-activated K+ channels. Pflügers Archiv: European Journal of Physiology 462 (2): 245–255. https://doi.org/10.1007/s00424-011-0977-7.

    Article  CAS  PubMed  Google Scholar 

  47. Karpińska, O., M. Baranowska-Kuczko, B. Malinowska, M. Kloza, M. Kusaczuk, A. Gęgotek, P. Golec, I. Kasacka, and H. Kozłowska. 2018. Mechanisms of L-alpha-lysophosphatidylinositol-induced relaxation in human pulmonary arteries. Life Sciences 192: 38–45. https://doi.org/10.1016/j.lfs.2017.11.020.

    Article  CAS  PubMed  Google Scholar 

  48. Kaushal, V., P.D. Koeberle, Y. Wang, and L.C. Schlichter. 2007. The Ca2+-activated K+ channel KCNN4/KCa3.1 contributes to microglia activation and nitric oxide-dependent neurodegeneration. The Journal of Neuroscience 27 (1): 234–244. https://doi.org/10.1523/JNEUROSCI.3593-06.2007.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Nguyen, H.M., E.M. Grössinger, M. Horiuchi, K.W. Davis, L.W. Jin, I. Maezawa, and H. Wulff. 2017. Differential Kv1.3, KCa3.1, and Kir2.1 expression in “classically” and “alternatively” activated microglia. Glia 65 (1): 106–121. https://doi.org/10.1002/glia.23078.

    Article  PubMed  Google Scholar 

  50. Malek, N., K. Popiolek-Barczyk, J. Mika, B. Przewlocka, and K. Starowicz. 2015. Anandamide, acting via CB2 receptors, alleviates LPS-induced neuroinflammation in rat primary microglial cultures. Neural Plasticity 2015: 130639–130610. https://doi.org/10.1155/2015/130639.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  51. Saliba, S.W., H. Jauch, B. Gargouri, A. Keil, T. Hurrle, N. Volz, F. Mohr, M. van der Stelt, S. Bräse, and B.L. Fiebich. 2018. Anti-neuroinflammatory effects of GPR55 antagonists in LPS-activated primary microglial cells. Journal of Neuroinflammation 15 (1): 322. https://doi.org/10.1186/s12974-018-1362-7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  52. Lieb, K., S. Engels, and B.L. Fiebich. 2003. Inhibition of LPS-induced iNOS and NO synthesis in primary rat microglial cells. Neurochemistry International 42: 131–137. https://doi.org/10.1016/s0197-0186(02)00076-1.

    Article  CAS  PubMed  Google Scholar 

  53. McHugh, D. 2012. GPR18 in microglia: Implications for the CNS and endocannabinoid system signaling. British Journal of Pharmacology 167 (8): 1575–1582. https://doi.org/10.1111/j.1476-5381.2012.02019.x.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  54. Reyes-Resina, I., G. Navarro, D. Aguinaga, E.I. Canela, C.T. Schoeder, M. Załuski, K. Kieć-Kononowicz, C.A. Saura, C.E. Müller, and R. Franco. 2018. Molecular and functional interaction between GPR18 and cannabinoid CB2 G-protein-coupled receptors. Relevance in neurodegenerative diseases. Biochemical Pharmacology 157: 169–179. https://doi.org/10.1016/j.bcp.2018.06.001.

    Article  CAS  PubMed  Google Scholar 

  55. Fu, R., Q. Shen, P. Xu, J.J. Luo, and Y. Tang. 2014. Phagocytosis of microglia in the central nervous system diseases. Molecular Neurobiology 49 (3): 1422–1434. https://doi.org/10.1007/s12035-013-8620-6.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  56. Rinne, P., R. Guillamat-Prats, M. Rami, L. Bindila, L. Ring, L.P. Lyytikäinen, E. Raitoharju, N. Oksala, T. Lehtimäki, C. Weber, E.P.C. van der Vorst, and S. Steffens. 2018. Palmitoylethanolamide promotes a proresolving macrophage phenotype and attenuates atherosclerotic plaque formation. Arteriosclerosis, Thrombosis, and Vascular Biology 38 (11): 2562–2575. https://doi.org/10.1161/ATVBAHA.118.311185.

    Article  CAS  PubMed  Google Scholar 

  57. Balenga, N.A., E. Martínez-Pinilla, J. Kargl, R. Schröder, M. Peinhaupt, W. Platzer, Z. Bálint, M. Zamarbide, I.G. Dopeso-Reyes, A. Ricobaraza, J.M. Pérez-Ortiz, E. Kostenis, M. Waldhoer, A. Heinemann, and R. Franco. 2014. Heteromerization of GPR55 and cannabinoid CB2 receptors modulates signalling. British Journal of Pharmacology 171 (23): 5387–5406. https://doi.org/10.1111/bph.12850.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Moreno, E., C. Andradas, M. Medrano, M.M. Caffarel, E. Pérez-Gómez, S. Blasco-Benito, M. Gómez-Cañas, M.R. Pazos, A.J. Irving, C. Lluís, E.I. Canela, J. Fernández-Ruiz, M. Guzmán, P.J. McCormick, and C. Sánchez. 2014. Targeting CB2-GPR55 receptor heteromers modulates cancer cell signaling. Journal of Biological Chemistry 289 (32): 21960–21972. https://doi.org/10.1074/jbc.M114.561761.

    Article  CAS  PubMed  Google Scholar 

  59. Stella, N. 2009. Endocannabinoid signaling in microglial cells. Neuropharmacology 56 Suppl 1: 244–253. https://doi.org/10.1016/j.neuropharm.2008.07.037.

    Article  CAS  PubMed  Google Scholar 

  60. Mecha, M., F.J. Carrillo-Salinas, A. Feliú, L. Mestre, and C. Guaza. 2016. Microglia activation states and cannabinoid system: therapeutic implications. Pharmacology and Therapeutics 166: 40–55. https://doi.org/10.1016/j.pharmthera.2016.06.011.

    Article  CAS  PubMed  Google Scholar 

  61. Hassan, S., K. Eldeeb, P.J. Millns, A.J. Bennett, S.P. Alexander, and D.A. Kendall. 2014. Cannabidiol enhances microglial phagocytosis via transient receptor potential (TRP) channel activation. British Journal of Pharmacology 171 (9): 2426–2439. https://doi.org/10.1111/bph.12615.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  62. Marichal-Cancino, B.A., A. Fajardo-Valdez, A.E. Ruiz-Contreras, M. Mendez-Díaz, and O. Prospero-García. 2017. Advances in the physiology of GPR55 in the central nervous system. Current Neuropharmacology 15 (5): 771–778. https://doi.org/10.2174/1570159X14666160729155441.

    Article  CAS  PubMed  Google Scholar 

  63. Cooper, C.L., G.H. Jeohn, P. Tobias, and J.S. Hong. 2002. Serum-dependence of LPS-induced neurotoxicity in rat cortical neurons. Annals of the New York Academy of Sciences 962: 306–317. https://doi.org/10.1111/j.1749-6632.2002.tb04076.x.

    Article  CAS  PubMed  Google Scholar 

  64. McHugh, D., S.S. Hu, N. Rimmerman, A. Juknat, Z. Vogel, J.M. Walker, and H.B. Bradshaw. 2010. N-Arachidonoyl glycine, an abundant endogenous lipid, potently drives directed cellular migration through GPR18, the putative abnormal cannabidiol receptor. BMC Neuroscience 11: 44. https://doi.org/10.1186/1471-2202-11-44.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  65. Plastira, I., E. Bernhart, M. Goeritzer, H. Reicher, V.B. Kumble, N. Kogelnik, A. Wintersperger, A. Hammer, S. Schlager, K. Jandl, A. Heinemann, D. Kratky, E. Malle, and W. Sattler. 2016. 1-Oleyl-lysophosphatidic acid (LPA) promotes polarization of BV-2 and primary murine microglia towards an M1-like phenotype. Journal of Neuroinflammation 13 (1): 205. https://doi.org/10.1186/s12974-016-0701-9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Hill, J.D., V. Zuluaga-Ramirez, S. Gajghate, M. Winfield, and Y. Persidsky. 2018. Activation of GPR55 increases neural stem cell proliferation and promotes early adult hippocampal neurogenesis. British Journal of Pharmacology 175 (16): 3407–3421. https://doi.org/10.1111/bph.14387.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Hill, J.D., V. Zuluaga-Ramirez, S. Gajghate, M. Winfield, U. Sriram, S. Rom, and Y. Persidsky. 2019. Activation of GPR55 induces neuroprotection of hippocampal neurogenesis and immune responses of neural stem cells following chronic, systemic inflammation. Brain, Behavior, and Immunity 76: 165–181. https://doi.org/10.1016/j.bbi.2018.11.017.

    Article  CAS  PubMed  Google Scholar 

  68. Stančić, A., K. Jandl, C. Hasenöhrl, F. Reichmann, G. Marsche, R. Schuligoi, A. Heinemann, M. Storr, and R. Schicho. 2015. The GPR55 antagonist CID16020046 protects against intestinal inflammation. Neurogastroenterology and Motility 27 (10): 1432–1445. https://doi.org/10.1111/nmo.12639.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Brown, A.J., I. Castellano-Pellicena, C.P. Haslam, P.L. Nichols, and S.J. Dowell. 2018. Structure-activity relationship of the GPR55 antagonist, CID16020046. Pharmacology 102 (5–6): 324–331. https://doi.org/10.1159/000493490.

    Article  CAS  PubMed  Google Scholar 

  70. Janefjord, E., J.L. Mååg, B.S. Harvey, and S.D. Smid. 2014. Cannabinoid effects on β amyloid fibril and aggregate formation, neuronal and microglial-activated neurotoxicity in vitro. Cellular and Molecular Neurobiology 34 (1): 31–42. https://doi.org/10.1007/s10571-013-9984-x.

    Article  CAS  PubMed  Google Scholar 

  71. Li, K., J.Y. Feng, Y.Y. Li, B. Yuece, X.H. Lin, L.Y. Yu, Y.N. Li, Y.J. Feng, and M. Storr. 2013. Anti-inflammatory role of cannabidiol and O-1602 in cerulein-induced acute pancreatitis in mice. Pancreas 42 (1): 123–129. https://doi.org/10.1097/MPA.0b013e318259f6f0.

    Article  CAS  PubMed  Google Scholar 

  72. Wei, D., H. Wang, J. Yang, Z. Dai, R. Yang, S. Meng, Y. Li, and X. Lin. 2020. Effects of O-1602 and CBD on TNBS-induced colonic disturbances. Neurogastroenterology and Motility 32 (3): e13756. https://doi.org/10.1111/nmo.13756.

    Article  CAS  PubMed  Google Scholar 

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Funding

This work was funded in part by JSPS KAKENHI Grant No. JP18K05999 to Y.N., JP17K15390 to K.T., and JP17K08127 to M.M.

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Authors and Affiliations

  1. Laboratory of Integrative Physiology in Veterinary Sciences, Osaka Prefecture University, 1-58 Rinku Ourai Kita, Izumisano, Osaka, 598-8531, Japan

    Tomoki Minamihata, Katsura Takano, Mitsuaki Moriyama & Yoichi Nakamura

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  1. Tomoki Minamihata
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  2. Katsura Takano
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  3. Mitsuaki Moriyama
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  4. Yoichi Nakamura
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Contributions

T.M. and M.M. contributed to the study concept and design, analysis, and drafting of the manuscript. K.T. participated in the data analysis and drafting of the manuscript. Y.N. provided helpful discussion, data interpretation, and manuscript review. All of the authors edited the manuscript and approved the final version.

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Correspondence to Mitsuaki Moriyama.

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Minamihata, T., Takano, K., Moriyama, M. et al. Lysophosphatidylinositol, an Endogenous Ligand for G Protein-Coupled Receptor 55, Has Anti-inflammatory Effects in Cultured Microglia. Inflammation 43, 1971–1987 (2020). https://doi.org/10.1007/s10753-020-01271-4

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