POSSIBLE IMMUNOLOGICAL PATHOPHYSIOLOGY IN BIPOLAR DISORDER: REVERSE-TRANSLATIONAL RESEARCH USING INDUCED MICROGLIA-LIKE (IMG) CELLS

Abstract Background The pathophysiology of bipolar disorder remains unclear despite various biological research, including studies on pharmacological, genetical, brain imaging aspects1. It is a multifactorial disease with complex pathology, and there is a need for the accumulation and integration of multidimensional knowledge. Recently, the inflammation hypothesis has been proposed as one of the pathological mechanisms, supported by reports of elevated peripheral blood cytokine levels and activated microglia in bipolar disorder2-4. However, analyzing live microglia from patients has crucial technical and ethical issues. In 2014, we developed human induced microglia-like(iMG) cells and its utility has been reported from several groups5-7. In a pilot study of three bipolar disorder patients, we analyzed inflammation- related gene expression of iMG cells and identified CD206 as a potential state marker8. Aims & Objectives In order to validate the findings of the previous study and identify additional novel biomarkers, we expanded the sample size and conducted a comprehensive gene expression analysis in this study. Method This study was approved by the ethics committee of Kyushu University. Sixteen healthy subjects and fifteen bipolar disorder patients were recruited with written consent. Gene expression was analyzed by RNA sequencing in both groups of iMG cells and differentially expressed genes were identified. Correlation analysis between changes in mood symptom scores and gene expression of iMG cells was performed in a total of thirteen patients from whom blood samples were obtained at two time points. Results Twenty-two differentially expressed genes were identified and some of which were microglia- related genes. In pathway analysis, inflammation-related pathways were enriched. Several novel genes including GP*** were found to correlate with clinical symptoms. CD206 tended to be proportional to depressive symptoms but was not significant. Discussion & Conclusion iMG cells from bipolar patients showed an enrichment of inflammation and microglia related genes, indicating the involvement of microglia-mediated brain inflammation in the pathological background of bipolar disorder. Several genes that correlate with clinical symptoms might have possible utility as state biomarkers. However, further studies are essential to confirm these findings. *Novel gene names are masked for intellectual property protection References 1.MCINTYRE, R. S., BERK, M., BRIETZKE, E., GOLDSTEIN, B. I., LOPEZ-JARAMILLO, C., KESSING, L. V., MALHI, G. S., NIERENBERG, A. A., ROSENBLAT, J. D., MAJEED, A., VIETA, E., VINBERG, M., YOUNG, A. H. &MANSUR, R. B. 2020. Bipolar disorders. Lancet, 396, 1841-1856. 2.GOLDSMITH, D. R., RAPAPORT, M. H. &MILLER, B. J. 2016. A meta-analysis of blood cytokine network alterations in psychiatric patients: comparisons between schizophrenia, bipolar disorder and depression. Mol Psychiatry, 21, 1696-1709. 3.WOLF, S. A., BODDEKE, H. W. &KETTENMANN, H. 2017. Microglia in Physiology and Disease. Annu Rev Physiol, 79, 619-643. 4.HAARMAN, B. C., RIEMERSMA-VAN DER LEK, R. F., DE GROOT, J. C., RUHE, H. G., KLEIN, H. C., ZANDSTRA, T. E., BURGER, H., SCHOEVERS, R. A., DE VRIES, E. F., DREXHAGE, H. A., NOLEN, W. A. &DOORDUIN, J. 2014.Neuroinflammation in bipolar disorder - A [(11)C]-(R)-PK11195 positron emission tomography study. Brain Behav Immun, 40, 219-25. 5.SHIGENOBU, K., YOSHIDA, T., HAYAKAWA, K., SHIMOKAWA, N., MIURA, D., UTSUMI, H. &KANBA, S. 2014. Direct induction of ramified microglia-like cells from human monocytes: dynamic microglial dysfunction in Nasu-Hakola disease. Sci Rep, 4, 4957 6.SELLGREN, C. M., GRACIAS, J., WATMUFF, B., BIAG, J. D., THANOS, J. M., WHITTREDGE, P. B., FU, T., WORRINGER, K., BROWN, H. E., WANG, J., KAYKAS, A., KARMACHARYA, R., GOOLD, C. P., SHERIDAN, S. D. &PERLIS, R. H. 2019. Increased synapse elimination by microglia in schizophrenia patient-derived models of synaptic pruning. Nat Neurosci, 22, 374-385. 7.BANERJEE, A., LU, Y., DO, K., MIZE, T., WU, X., CHEN, X. &CHEN, J. 2021. Validation of Induced Microglia-Like Cells (iMG Cells) for Future Studies of Brain Diseases. Front Cell Neurosci, 15, 629279 8.OHGIDANI, M., KATO, T. A., HARAGUCHI, Y., MATSUSHIMA, T., MIZOGUCHI, Y., MURAKAWA-HIRACHI, T., SAGATA, N., MONJI, A. &KANBA, S. 2016. Microglial CD206 Gene Has Potential as a State Marker of Bipolar Disorder. Front Immunol, 7, 676.