Focal MMP-2 and MMP-9 Activity at the Blood-Brain Barrier Promotes Chemokine-Induced Leukocyte Migration

Abstract

Although chemokines are sufficient for chemotaxis of various cells, increasing evidence exists for their fine-tuning by selective proteolytic processing. Using a model of immune cell chemotaxis into the CNS (experimental autoimmune encephalomyelitis [EAE]) that permits precise localization of immigrating leukocytes at the blood-brain barrier, we show that, whereas chemokines are required for leukocyte migration into the CNS, additional MMP-2/9 activities specifically at the border of the CNS parenchyma strongly enhance this transmigration process. Cytokines derived from infiltrating leukocytes regulate MMP-2/9 activity at the parenchymal border, which in turn promotes astrocyte secretion of chemokines and differentially modulates the activity of different chemokines at the CNS border, thereby promoting leukocyte migration out of the cuff. Hence, cytokines, chemokines, and cytokine-induced MMP-2/9 activity specifically at the inflammatory border collectively act to accelerate leukocyte chemotaxis across the parenchymal border.

Metformin Inhibited Growth, Invasion and Metastasis of Esophageal Squamous Cell Carcinoma in Vitro and in Vivo

“…3). As modulators of the tumor microenvironment [23], the matrix metalloproteinases (MMPs) such as MMP-2 and MMP-9 catalyze the proteolysis of epithelial basement membrane, extracellular matrix and components of vascular, thus facilitating cancer invasion, intravasation and extravasation [23,[29][30][31]. Our study showed that metformin treatment down-regulated the expression levels of MMP-2 and MMP-9 in a time-dependent manner (Fig.…”

Astrocytic tight junctions control inflammatory CNS lesion pathogenesis

“…Interestingly, accumulation of degradation products was blocked by pretreatment of cocultures with the serine protease inhibitor aprotinin, and by MMP inhibitor-2, which blocks the activity of MMP-1, -3, -7, and -9 ( Figure 7, C and D). Notably, MMPs have been implicated in EAE pathogenesis, are secreted by astrocytes, T lymphocytes, and myeloid cells within the PVS, and facilitate leukocyte entry past the GL into the CNS (39). In contrast, degradation product accumulation was not blocked by the cysteine protease inhibitor E-64, or the aspartic protease inhibitor pepstatin.…”

“…Influences on this process could include presentation of CNS antigen in the context of MHC class II within the PVS (8), and dynamic expression of astrocytic cell adhesion molecules and signaling factors (59), as well as induction of local proteases (60)(61)(62). While previous work has revealed a critical role for local proteases, MMP-2 and MMP-9, in activating chemokine pathways within the PVS and inducing immune cells to cross the GL (39,63), our data suggest that local proteases also facilitate immune cell entry by simply digesting the astrocytic TJ barrier. Furthermore, we found that unique patterns of astrocytic and lymphocytic proteases are Collectively, these studies suggest that integral structural components of reactive astrocyte TJs are susceptible to serine protease-and MMP-mediated degradation within the PVS, notably in the presence of activated T lymphocytes.…”

Local Matrix Metalloproteinase 9 Level Determines Early Clinical Presentation of ST-Segment–Elevation Myocardial Infarction

“…Correlation coefficient between systemic and local MMP-9 is modest (r=0.572; P<0.01). Systemic MMP-9 might be compromised by systemic atherosclerosis and various pathological conditions, [25][26][27] even though systemic assessment is convenient for clinicians. Therefore, we think that local MMP-9 is more suitable for assessment of coronary-specific inflammatory activity in coronary artery disease.…”