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MMPs and ADAMs in neurological infectious diseases and multiple sclerosis - PubMed

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MMPs and ADAMs in neurological infectious diseases and multiple sclerosis

Lukas Muri et al. Cell Mol Life Sci. 2019 Aug.

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.

Keywords: Bacterial meningitis; MMP; Metalloproteinase; Multiple sclerosis; Neuroinfection; Neuroinflammation.

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Figures

Fig. 1
Fig. 1

Pro-inflammatory roles of metalloproteinases during neuroinflammation. MMPs directly and indirectly contribute to chemotactic gradients in the bloodstream and neutrophil (orange cells) recruitment at site of infection. ADAMs and MMPs contribute to adherens junction protein (AJP) and tight junction protein (TJP) degradation. MMPs further show specific cleavage of basal lamina components. Upon destruction of the BBB, neutrophils enter the central nervous system and further generate chemotactic gradients with secreted MMP-9 being able to cleave and activate IL-8. Collagenases further contribute to BBB leakage by degradation of the extracellular matrix (ECM). ADAMs and MMPs directly contribute to neuroinflammation by activating pro-inflammatory cytokines like IL-1β and TNF-α from microglia/macrophage (green cell). This illustration only summarizes the most important roles of ADAMs and MMPs in induction of neuroinflammation, a more thorough picture is found in Table 1. For simplicity, the BBB is depicted without pericytes and astrocytes. Illustration design inspired by Khokha et al. [15]

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