Abstract
Central nervous system tuberculosis (CNS-TB) is caused by infection with Mycobacterium tuberculosis (Mtb). The inflammatory response following CNS-TB involves the activation of resident microglia and the infiltration of macrophages. However, it has not been clarified whether microglia can be polarized into the classically activated proinflammatory M1 phenotype or the alternatively activated anti-inflammatory M2 phenotype after Mtb infection. In this study, we found that BV2 treated with conditioned media from cultures of macrophages infected with Mycobacterium marinum (Mm) induced the expression of M1 phenotypic genes including iNOS, TNF-α, IL-1β, IL-6, CCL2, and CXCL10 but reduced that of M2 phenotypic genes such as Arginase 1, Ym1, and CD163. These results suggest that polarization of microglia is partly mediated through macrophage-microglia interactions as a priming signal. Overall, these results provide new insights into the modulatory mechanisms of microglial polarization, thereby possibly facilitating the development of new therapies for CNS-TB infection via the regulation of microglial polarization through signalling derived from macrophages infected with mycobacteria.



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Kingkaew, N., B. Sangtong, W. Amnuaiphon, J. Jongpaibulpatana, W. Mankatittham, S. Akksilp, C. Sirinak, S. Nateniyom, C. Burapat, W. Kittikraisak, P. Monkongdee, and J.K. Varma. 2009. HIV-associated extrapulmonary tuberculosis in Thailand: epidemiology and risk factors for death. International Journal of Infectious Diseases 13: 722–729.
DeLance, A.R., M. Safaee, M.C. Oh, A.J. Clark, G. Kaur, M.Z. Sun, A.W. Bollen, J.J. Phillips, and A.T. Parsa. 2013. Tuberculoma of the central nervous system. Journal of Clinical Neuropsychology 20: 1333–1341.
Donald, P.R., H.S. Schaaf, and J.F. Schoeman. 2005. Tuberculous meningitis and miliary tuberculosis: the rich focus revisited. The Journal of Infection 50: 193–195.
Jain, S.K., M. Paul-Satyaseela, G. Lamichhane, K.S. Kim, and W.R. Bishai. 2006. Mycobacterium tuberculosis invasion and traversal across an in vitro human blood–brain barrier as a pathogenic mechanism for central nervous system tuberculosis. The Journal of Infectious Diseases 193: 1287–1295.
van Leeuwen, L. M., M. van der Kuip, S. A. Youssef, A. de Bruin, W. Bitter, A. M. van Furth, and A. M. van der Sar. 2014. Modelling tuberculous meningitis in zebrafish using Mycobacterium marinum. Dis Model Mech.
Mosser, D.M., and J.P. Edwards. 2008. Exploring the full spectrum of macrophage activation. Nature Reviews Immunology 8: 958–969.
Benoit, M., B. Desnues, and J.L. Mege. 2008. Macrophage polarization in bacterial infections. Journal of Immunology 181: 3733–3739.
Taylor, P.R., L. Martinez-Pomares, M. Stacey, H.H. Lin, G.D. Brown, and S. Gordon. 2005. Macrophage receptors and immune recognition. Annual Review of Immunology 23: 901–944.
MacMicking, J., Q.W. Xie, and C. Nathan. 1997. Nitric oxide and macrophage function. Annual Review of Immunology 15: 323–350.
Rock, R.B., S. Hu, G. Gekker, W.S. Sheng, B. May, V. Kapur, and P.K. Peterson. 2005. Mycobacterium tuberculosis-induced cytokine and chemokine expression by human microglia and astrocytes: effects of dexamethasone. The Journal of Infectious Diseases 192: 2054–2058.
Rock, R.B., M. Olin, C.A. Baker, T.W. Molitor, and P.K. Peterson. 2008. Central nervous system tuberculosis: pathogenesis and clinical aspects. Clinical Microbiology Reviews 21: 243–261.
Mills, C.D., K. Kincaid, J.M. Alt, M.J. Heilman, and A.M. Hill. 2000. M-1/M-2 macrophages and the Th1/Th2 paradigm. Journal of Immunology 164: 6166–6173.
Lacy-Hulbert, A., and K.J. Moore. 2006. Designer macrophages: oxidative metabolism fuels inflammation repair. Cell Metabolism 4: 7–8.
Durafourt, B.A., C.S. Moore, D.A. Zammit, T.A. Johnson, F. Zaguia, M.C. Guiot, A. Bar-Or, and J.P. Antel. 2012. Comparison of polarization properties of human adult microglia and blood-derived macrophages. Glia 60: 717–727.
Perry, V.H., and J. Teeling. 2013. Microglia and macrophages of the central nervous system: the contribution of microglia priming and systemic inflammation to chronic neurodegeneration. Seminars in Immunopathology 35: 601–612.
Tobin, D.M., and L. Ramakrishnan. 2008. Comparative pathogenesis of mycobacterium marinum and mycobacterium tuberculosis. Cellular Microbiology 10: 1027–1039.
Mishra, B.B., V.A. Rathinam, G.W. Martens, A.J. Martinot, H. Kornfeld, K.A. Fitzgerald, and C.M. Sassetti. 2013. Nitric oxide controls the immunopathology of tuberculosis by inhibiting NLRP3 inflammasome-dependent processing of IL-1beta. Nature Immunology 14: 52–60.
Saura, J., J.M. Tusell, and J. Serratosa. 2003. High-yield isolation of murine microglia by mild trypsinization. Glia 44: 183–189.
Dong, D., D. Wang, M. Li, H. Wang, J. Yu, C. Wang, J. Liu, and Q. Gao. 2012. PPE38 modulates the innate immune response and is required for mycobacterium marinum virulence. Infection and Immunity 80: 43–54.
Green, J.A., P.T. Elkington, C.J. Pennington, F. Roncaroli, S. Dholakia, R.C. Moores, A. Bullen, J.C. Porter, D. Agranoff, D.R. Edwards, and J.S. Friedland. 2010. Mycobacterium tuberculosis upregulates microglial matrix metalloproteinase-1 and -3 expression and secretion via NF-kappaB- and activator protein-1-dependent monocyte networks. Journal of Immunology 184: 6492–6503.
Lee, H.M., J. Kang, S.J. Lee, and E.K. Jo. 2013. Microglial activation of the NLRP3 inflammasome by the priming signals derived from macrophages infected with mycobacteria. Glia 61: 441–452.
Hickey, W.F. 2001. Basic principles of immunological surveillance of the normal central nervous system. Glia 36: 118–124.
Isabel, B.E., and H.P. Rogelio. 2014. Pathogenesis and immune response in tuberculous meningitis. Malays Journal of Medical Sciences 21: 4–10.
Moens, L., G. Wuyts, L. Boon, M.T. den Hartog, J.L. Ceuppens, and X. Bossuyt. 2008. The human polysaccharide- and protein-specific immune response to Streptococcus pneumoniae is dependent on CD4 (+) T lymphocytes, CD14 (+) monocytes, and the CD40-CD40 ligand interaction. The Journal of Allergy and Clinical Immunology 122: 1231–1233.
Colton, C., and D.M. Wilcock. 2010. Assessing activation states in microglia. CNS & Neurological Disorders Drug Targets 9: 174–191.
Bogdan, C. 2001. Nitric oxide and the immune response. Nature Immunology 2: 907–916.
Chan, J., Y. Xing, R.S. Magliozzo, and B.R. Bloom. 1992. Killing of virulent mycobacterium tuberculosis by reactive nitrogen intermediates produced by activated murine macrophages. The Journal of Experimental Medicine 175: 1111–1122.
Chacon-Salinas, R., J. Serafin-Lopez, R. Ramos-Payan, P. Mendez-Aragon, R. Hernandez-Pando, D. Van Soolingen, L. Flores-Romo, S. Estrada-Parra, and I. Estrada-Garcia. 2005. Differential pattern of cytokine expression by macrophages infected in vitro with different Mycobacterium tuberculosis genotypes. Clinical and Experimental Immunology 140: 443–449.
Raju, B., Y. Hoshino, I. Belitskaya-Levy, R. Dawson, S. Ress, J.A. Gold, R. Condos, R. Pine, S. Brown, A. Nolan, W.N. Rom, and M.D. Weiden. 2008. Gene expression profiles of bronchoalveolar cells in pulmonary TB. Tuberculosis (Edinburgh, Scotland) 88: 39–51.
Kiszewski, A.E., E. Becerril, L.D. Aguilar, I.T. Kader, W. Myers, F. Portaels, and P.R. Hernandez. 2006. The local immune response in ulcerative lesions of Buruli disease. Clinical and Experimental Immunology 143: 445–451.
Murphy, J.T., S. Sommer, E.A. Kabara, N. Verman, M.A. Kuelbs, P. Saama, R. Halgren, and P.M. Coussens. 2006. Gene expression profiling of monocyte-derived macrophages following infection with mycobacterium avium subspecies avium and mycobacterium avium subspecies paratuberculosis. Physiological Genomics 28: 67–75.
Gordon, S. 2003. Alternative activation of macrophages. Nature Reviews Immunology 3: 23–35.
Lugo-Villarino, G., D. Hudrisier, A. Benard, and O. Neyrolles. 2012. Emerging trends in the formation and function of tuberculosis granulomas. Frontiers in Immunology 3: 405.
Acknowledgments
This work was supported by the National Natural Science Foundation of China (Grant numbers: 81201252, 81373223, 31100112), a project funded by the Priority Academic Program Development of Jiangsu Higher Education Institutions (PAPD), a project funded by the Scientific Research Programme of Nantong (HS2012059, BK2014033); and a project funded by the Natural Scientific Research Programme of Jiangsu Province (14KJD180002).
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Yongwei Qin and Xiaolei Sun contributed equally to this work.
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Qin, Y., Sun, X., Shao, X. et al. Macrophage-Microglia Networks Drive M1 Microglia Polarization After Mycobacterium Infection. Inflammation 38, 1609–1616 (2015). https://doi.org/10.1007/s10753-015-0136-y
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DOI: https://doi.org/10.1007/s10753-015-0136-y