Variations on brain microglial gene expression of MMPs, RECK, and TIMPs in inflammatory and non-inflammatory diseases
Veronika M Stein1, Christina Puff, Sem Genini
1Department of Small Animal Medicine and Surgery, University of Veterinary Medicine, Bünteweg 9, D-30559 Hannover, Germany. veronika.stein@tiho-hannover.de
Abstract:
Matrix metalloproteinases (MMPs), MMP inhibitors (TIMPs, tissue inhibitors of matrix metalloproteinases), and the membrane-anchored glycoprotein RECK (reversion-inducing cysteine-rich protein with Kazal motifs) contribute to the pathogenesis of many CNS diseases. To assess the potential pathogenetic roles of microglial MMP, TIMP, and RECK generation in extracellular matrix breakdown, opening of the blood brain barrier (BBB) and subsequent recruitment of leukocytes in the CNS, twenty-four dogs suffering from spontaneously occurring different intracranial and extracranial (control group) diseases were examined. Microglia cells were isolated ex vivo by density gradient centrifugation and their expressions of MMP-2, MMP-9, MMP-12, MMP-13, MMP-14, TIMP-1, TIMP-2, and RECK were examined via quantitative real-time polymerase chain reaction (qPCR). Zymography on CNS tissues in selected cases was performed to assess differences at the protein level. Dogs were grouped in different disease categories according to histopathological examinations, in groups with or without inflammatory reactions, and in groups with/without contrast enhancement in advanced diagnostic imaging as a function of BBB breakdown. The results showed a significant up-regulation of MMP-9 in dogs with inflammation in the nervous system compared to dogs with non-inflammatory diseases. An increased expression of MMP-9 might lead to a facilitated invasion of white blood cells. Furthermore, down-regulation of MMP-13 was found in dogs with contrast enhancement. Zymographical data reflected MMP-2 qPCR data. In conclusion, differential expression of MMPs and their inhibitors, but not of RECK, which might crucially influence the pathogenesis of a given disease, could be demonstrated in canine microglia. This reflects a further pathway in the microglial repertoire to respond to various disease conditions in the CNS, a characteristic that might be of particular relevance as a target for specific treatments.
Insights
Matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) are differentially expressed in canine microglia, influencing central nervous system (CNS) diseases. MMP-9 upregulation correlates with inflammation, suggesting a role in leukocyte invasion and potential therapeutic targeting.
Area of Science:
- Neuroscience
- Immunology
- Biochemistry
Background:
- Matrix metalloproteinases (MMPs), tissue inhibitors of matrix metalloproteinases (TIMPs), and RECK are implicated in CNS disease pathogenesis.
- Microglia play a crucial role in the central nervous system's response to injury and disease.
Purpose of the Study:
- To investigate the role of microglial MMPs, TIMPs, and RECK in CNS diseases.
- To assess their involvement in extracellular matrix breakdown and blood-brain barrier (BBB) integrity.
Main Methods:
- Analysis of microglial gene expression (MMP-2, -9, -12, -13, -14, TIMP-1, -2, RECK) using qPCR in 24 dogs with various CNS diseases.
- Zymography performed on CNS tissues to evaluate protein levels.
- Grouping based on histopathology, inflammation, and BBB breakdown (contrast enhancement).
Main Results:
- Significant upregulation of MMP-9 in dogs with CNS inflammation compared to non-inflammatory diseases.
- Downregulation of MMP-13 observed in dogs with contrast enhancement, indicating BBB breakdown.
- Zymography results correlated with MMP-2 qPCR data.
Conclusions:
- Differential expression of MMPs and TIMPs, but not RECK, in canine microglia influences CNS disease pathogenesis.
- Microglial MMPs represent a potential therapeutic target for CNS disorders.
- This study highlights a novel microglial response pathway in CNS disease conditions.
