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EMMPRIN Promotes the Expression of MMP-9 and Exacerbates Neurological Dysfunction in a Mouse Model of Intracerebral Hemorrhage

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Abstract

Extracellular matrix metalloproteinase inducer (EMMPRIN) has been shown to be a vital inflammatory mediator in several neurological and neurodegenerative diseases. However, the role of EMMPRIN in intracerebral hemorrhage (ICH) remains unexplored. In this study, we aimed to exploit a highly selective monoclonal anti-EMMPRIN antibody to functionally inhibit EMMPRIN activity and thus that of MMPs as the downstream effector. To induce ICH pathology, adult C57BL/6 male mice were injected with collagenase type VII or saline as control into the right basal ganglia and were euthanized at different time points. The anti-EMMPRIN monoclonal antibody was intravenously injected once daily for 3 days to block the expression of EMMPRIN initiating at 4 h post-ICH. Western blot and immunofluorescence analysis results revealed that EMMPRIN expression was significantly increased surrounding the hematoma at 3 and 7 d time points after ICH when compared to the saline treated control group. EMMPRIN expression was co-localized with GFAP (astrocytes) and Iba1 (microglia) at 3 d time point post-ICH, but not in the control group mice. The co-localization of EMMPRIN with CD31 in endothelial cells occurred in both groups and was higher in the ICH brain. However, EMMPRIN expression was not detected in neurons from either group. The inhibition of EMMPRIN reduced the expression of MMP-9, the number of infiltrated neutrophils, the degree of brain injury and promoted neurological recovery after ICH. In conclusion, EMMPRIN could mediate the upregulation of MMP-9 and exacerbate neurological dysfunction in a mouse model of experimental ICH. Furthermore, blocking EMMPRIN reduced brain injury and subsequently promoted neurological recovery in ICH mice brains. These outcomes highlight that inhibition of EMMPRIN can be a potential therapeutic intervention strategy to regulate MMP-9’s pathological roles during ICH.

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Acknowledgements

The authors acknowledge operating grant support from the National Natural Science Foundation of China (Grant Nos: 82071331, 82001191, 81870942, and 81520108011), National Key Research and Development Program of China (Grant No: 2018YFC1312200) and Innovation Scientists and Technicians Troop Constructions Projects of Henan Province of China (for MX and QB); The Henan Medical Science and Technology Research Youth Project Co-Sponsored by the Province and Ministry in China (Grant No: SB201902020), Top Talent Fund of the Second Affiliated Hospital of Zhengzhou University (Grant No: 2020BJRCA03) for (QB); and from the Canadian Institutes of Health Sciences (VWY).

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Authors and Affiliations

  1. Departments of Cerebrovascular Diseases and Anesthesiology, The Second Affiliated Hospital of Zhengzhou University, 2 Jingba Road, Zhengzhou, 450001, Henan, China

    Yang Liu, Qian Bai & Mengzhou Xue

  2. Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, China

    Yang Liu

  3. Henan Medical Key Laboratory of Translational Cerebrovascular Diseases, Zhengzhou, Henan, China

    Yang Liu, Qian Bai & Mengzhou Xue

  4. Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary, AB, Canada

    V. Wee Yong

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YL and QB wrote the first manuscript; YL and QB drew the images; YL did the experiments; VWY edited the manuscript; MX supervised the project.

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Correspondence to V. Wee Yong or Mengzhou Xue.

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11064_2022_3630_MOESM1_ESM.tif

Supplementary file1 Supplement Figure 1 Co-localization of MMP-9 with cellular markers at 3 d post-ICH. Representative images of the co-expression of MMP-9 with GFAP (A), Iba1 (B), and CD31(C) in mouse brain tissue sections at 3 d post-ICH. Images were acquired from the perihematoma region. Scale bar = 20 μm. (TIF 6707 kb)

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Liu, Y., Bai, Q., Yong, V.W. et al. EMMPRIN Promotes the Expression of MMP-9 and Exacerbates Neurological Dysfunction in a Mouse Model of Intracerebral Hemorrhage. Neurochem Res 47, 2383–2395 (2022). https://doi.org/10.1007/s11064-022-03630-z

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  • DOI: https://doi.org/10.1007/s11064-022-03630-z

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