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

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.

Automated summary

EMMPRIN plays a vital role as an inflammatory mediator in intracerebral hemorrhage (ICH) and contributes to the upregulation of MMP-9. Inhibiting EMMPRIN expression can reduce brain injury and promote neurological recovery.