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Monocyte-Astrocyte Networks Regulate Matrix Metalloproteinase Gene Expression and Secretion in Central Nervous System Tuberculosis In Vitro and In Vivo¹

James E. Harris^*, Robert K. Nuttall, Paul T. Elkington^*, Justin A. Green^*, Donna E. Horncastle, Manuel B. Graeber, Dylan R. Edwards and Jon S. Friedland^2,*

^* Department of Infectious Diseases and Immunity, Imperial College, London, United Kingdom; School of Biological Sciences, University of East Anglia, Norwich, United Kingdom; and Department of Histopathology and Department of Neuropathology, Imperial College, London, United Kingdom

CNS tuberculosis (CNS-TB) is the most deadly form of tuberculous disease accounting for 10% of clinical cases. CNS-TB is characterized by extensive tissue destruction, in which matrix metalloproteinases (MMPs) may play a critical role. We investigated the hypothesis that Mycobacterium tuberculosis activates monocyte-astrocyte networks increasing the activity of key MMPs. We examined the expression of all human MMPs and the tissue inhibitors of metalloproteinases (TIMPs) in human astrocytes stimulated by conditioned medium from M. tuberculosis-infected monocytes (CoMTB). Real-time RT-PCR showed that gene expression of MMP-1, -2, -3, -7, and -9 was increased (p < 0.05). MMP-9 secretion was significantly up-regulated at 24 h and increased over 120 h (p < 0.01). MMP-1, -3, and -7 secretion was not detected. Secretion of MMP-2 was constitutive and unaffected by CoMTB. Astrocyte gene expression and secretion of TIMP-1 was not affected by CoMTB although TIMP-2 secretion increased 3-fold at 120 h. Immunohistochemical analysis of human brain biopsies confirmed that astrocyte MMP-9 secretion is a predominant feature in CNS-TB in vivo. Dexamethasone inhibited astrocyte MMP-9, but not TIMP-1/2 secretion in response to CoMTB. CoMTB stimulated the nuclear translocation of NF-B, inducing a 6-fold increase in nuclear p65 and a 2-fold increase in nuclear p50. This was associated with degradation of IB and within 30 min, persisting for 24 h. In summary, networks active between monocytes and astrocytes regulate MMP-9 activity in tuberculosis and astrocytes are a major source of MMP-9 in CNS-TB. Astrocytes may contribute to a matrix degrading environment within the CNS and subsequent morbidity and mortality.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ J.E.H. was supported by a Medical Research Council (U.K.) PhD studentship.

² Address correspondence and reprint requests to Prof. Jon S. Friedland, Department of Infectious Diseases and Immunity, Hammersmith Campus, Imperial College, Du Cane Road, London, W12 0NN, U.K. E-mail address: j.friedland{at}imperial.ac.uk

³ Abbreviations used in this paper: CNS-TB, tuberculosis of the CNS; MMP, matrix metalloproteinase; TIMP, tissue inhibitor of metalloproteinase; BBB, blood-brain barrier; CSF, cerebrospinal fluid; C_T, cycle threshold; GFAP, glial fibrillary acid protein; CoMTB, conditioned medium from infected monocytes; CoMCon, control medium from uninfected monocytes; MOI, multiplicity of infection; ref, relative centrifugal force.