Gelatinase B [matrix metalloproteinase (MMP)‐9] and collagenases (MMP‐8/‐13) are upregulated in cerebrospinal fluid during aseptic and bacterial meningitis in children

Abstract

We investigated the protein expression of gelatinases [matrix metalloproteinase (MMP)-2 and -9] and collagenases (MMP-8 and -13) in cerebrospinal fluid (CSF) from patients with bacterial (BM, n = 17) and aseptic (AM, n = 14) meningitis. In both, MMP-8 and -9 were increased in 100% of patients, whereas MMP-13 was detectable in 53% and 82% respectively. Three patients with clinical signs of meningitis, without CSF pleocytosis, scored positive for all three MMPs. MMP-8 appeared in two isoforms, granulocyte-type [polymorphonuclear cell (PMN)] and fibroblast/macrophage (F/M) MMP-8. Analysis of kinetic changes from serial lumbar punctures showed that these MMPs are independently regulated, and correlate only partly with CSF cytosis or levels of the endogenous inhibitor, tissue inhibitor of matrix metalloproteinase-1. In vitro, T cells, peripheral blood mononuclear cells (PBMCs) and granulocytes (PMN) release MMP-8 and -9, whereas MMP-13 could be found only in the former two cell types. Using models of exogenous (n-formyl-Met-Leu-Phe, T cell receptor cross-linking) and host-derived stimuli (interleukin-2), the kinetics and the release of the MMP-8, -9 and -13 showed strong variation between these immune cells and suggest release from preformed stocks. In addition, MMP-9 is also synthesized de novo in PBMCs and T cells. In conclusion, invading immune cells contribute only partially to MMPs in CSF during meningitis, and parenchymal cells are an equally relevant source. In this context, in patients with clinical signs of meningitis, but without CSF pleocytosis, MMPs seem to be a highly sensitive marker for intrathecal inflammation. The present data support the concept that broad-spectrum enzyme inhibition targeting gelatinases and collagenases is a potential strategy for adjunctive therapy in infectious meningitis.

Bacterial Meningitis: Insights Into Pathogenesis and Evaluation of New Treatment Options: A Perspective from Experimental Studies

“…The observation that inflammatory parameters, including cyto-/chemokine concentrations and MMP activity in the CSF, were reduced in animals treated with MMP inhibitors compared with control littermates is in agreement with the assumption that an overshooting inflammatory response contributes to the development of brain injury in BM [16,41,70]. During acute neuroinflammation, pharmacological inhibition of the released active forms of MMPs is a more targetspecific intervention compared with other adjuvant therapies, in other words, corticosteroids, which act by modulating the transcriptional regulation of multiple target genes [28,131].…”

Immunohistochemical analysis of MMP-9, MMP-2 and TIMP-1, TIMP-2 expression in the central nervous system following infection with viral and bacterial meningitis.

“…Analysis from serial lumbar punctures [7] revealed that the concentration of MMPs in the cerebrospinal fluid are only partially correlated with the CSF leukocyte count. This suggests that invading immune cells are only partially responsible for the activity of MMPs in the CSF during meningitis; therefore, parenchymal cells may be another relevant source.…”

“…Numerous studies have provided converging evidence that MMPs play a key role in the pathogenesis of meningitis through their contribution to the breakdown of the BBB and the accumulation of blood-derived immune cells. Gelatinases (MMP-2 and MMP-9) are probably the most extensively studied MMPs in the context of the pathogenesis of meningitis [6][7][8]. However, the cellular sources of MMP activity in the CNS are not yet clear.…”

Matrix metalloproteinases in neuromuscular disease

“…MMP activity is not restricted to the ECM, but extends to mechanisms of cellular signaling by activation and inactivation of cytokines, growth factors, and hormones, among others. 76 In the context of neurologic diseases, MMPs mediate blood-brain and blood-nerve barrier breakdown and parenchymal invasion of neural tissue by blood-derived immune cells, 39,40 which has been extensively studied in multiple sclerosis, 41,46 infectious meningitis, 36,37,43,47 and stroke. 48,57,66 -68 The broad coverage of the role of MMPs in diseases of the central nervous system (CNS) is contrasted by a relative paucity of publications dealing with their role in the pathology of the peripheral nervous system (PNS), such as in neuropathy and myopathy.…”