MMPs and ADAMs in neurological infectious diseases and multiple sclerosis

Abstract

Metalloproteinases-such as matrix metalloproteinases (MMPs) and a disintegrin and metalloproteinases (ADAMs)-are involved in various diseases of the nervous system but also contribute to nervous system development, synaptic plasticity and neuroregeneration upon injury. MMPs and ADAMs proteolytically cleave many substrates including extracellular matrix components but also signaling molecules and receptors. During neuroinfectious disease with associated neuroinflammation, MMPs and ADAMs regulate blood-brain barrier breakdown, bacterial invasion, neutrophil infiltration and cytokine signaling. Specific and broad-spectrum inhibitors for MMPs and ADAMs have experimentally been shown to decrease neuroinflammation and brain damage in diseases with excessive neuroinflammation as a common denominator, such as pneumococcal meningitis and multiple sclerosis, thereby improving the disease outcome. Timing of metalloproteinase inhibition appears to be critical to effectively target the cascade of pathophysiological processes leading to brain damage without inhibiting the neuroregenerative effects of metalloproteinases. As the critical role of metalloproteinases in neuronal repair mechanisms and regeneration was only lately recognized, the original idea of chronic MMP inhibition needs to be conceptually revised. Recently accumulated research urges for a second chance of metalloproteinase inhibitors, which-when correctly applied and dosed-harbor the potential to improve the outcome of different neuroinflammatory diseases.Publisher's Note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Evaluation of neurofilament light chain in the cerebrospinal fluid and blood as a biomarker for neuronal damage in experimental pneumococcal meningitis

“…In ePM, TNF-α, IL-6, and IL-1β appear early, prior to neutrophil recruitment, indicating that they are released by brain-resident cells [40,41]. TNF-α was shown to appear already 4 h after infection, reaching the peak at 12 h and persisting until 20 h after infection [26].…”

“…While the surge of cytokines released at this stage seems to directly lead to later neuronal damage, the induction of MMP-9 by these stimuli may be a further enhancing factor. MMP-9 induces degradation of the BBB and therefore facilitates leukocyte extravasation [12,40]. Additionally, MMP-9 activates and regulates cytokine signaling in a positive feedback loop, enhancing the excessive inflammation [42,43] and is suggested to play a role in glial and neuronal cell death [44] and development of neurological sequelae after PM [14].…”

PBMC of Multiple Sclerosis Patients Show Deregulation of OPA1 Processing Associated with Increased ROS and PHB2 Protein Levels

“…Although YME1L and OMA1 constitutively control OPA1, the proteolytic processing of OPA1 is more complex, in fact, other proteases can act on OPA1 under particular stress condition or metabolic demands [33,34], thus, the involvement of other mitochondrial proteases cannot be ruled out. In this contest, should be noted that, in MS, several proteases are involved [35,36] and that mitochondrial proteases are often involved in the pathogenesis of neurological diseases [37].…”

Neutrophils: Underestimated Players in the Pathogenesis of Multiple Sclerosis (MS)

“…Altogether, this results in persistent inflammation, further injury to myelin and oligodendrocytes as well as axonal loss. The observed damage is probably caused in a direct manner via T cells, microglia, macrophages, complement and antibodies, as well as indirectly through the release of proinflammatory factors such as nitric oxide, matrix metalloproteinases (MMPs), tumor necrosis factor α (TNF-α) and IL-1β, [ 29 , 45 , 46 , 47 ], many of which are produced by neutrophils.…”