Stroke-Induced Subventricular Zone Proliferation is Promoted by Tumor Necrosis Factor-α-Converting Enzyme Protease Activity

Abstract

Cerebral stroke induces proliferation of subventricular zone (SVZ) neural progenitor cells in adult rodent brain. Tumor necrosis factor-a-converting enzyme (TACE) proteolysis sheds the nonamyloidogenic soluble ectodomain of the amyloid precursor protein (APP) and is a convertase for tumor necrosis factor-a (TNFa). The resulting soluble peptides of APP and TNFa are mitogenic for neural progenitor cells of the SVZ. Therefore, we hypothesized a role for TACE proteolysis in strokeinduced neurogenesis. Using laser-capture microdissection, we found TACE transcription was increased in SVZ cells of ischemic brain. Immunohistochemistry revealed TACE protein was upregulated in SVZ neuroblasts. Intraventricular infusion of tumor necrosis factor-a protease inhibitor-2 (TAPI-2) decreased bromodeoxyuridine incorporation in SVZ cells of rats subjected to middle cerebral artery occlusion. Furthermore, primary culture SVZ neurospheres from ischemic brain overexpress TACE and its substrates APP and TNF-a. These cells proliferated more rapidly, possessed increased TACE protease-dependent a-secretase activity, and released more soluble APP and TNFa compared with nonischemic control. In addition, TAPI-2 reduced SVZ neuroblast migration out of SVZ explants in vitro. These findings indicate TACE proteolysis as a promoter of stroke-induced SVZ progenitor cell neurogenesis, and suggest this protease activity may represent an attractive therapeutic target for stroke recovery.

Mobilization of Neural Stem Cells and Generation of New Neurons in 6-OHDA–lesioned Rats by Intracerebroventricular Infusion of Liver Growth Factor

“…Interestingly, activated microglia are able to synthesize and release TNF-a (Wang et al 2003;Suzuki et al 2004), a cytokine involved in the proliferation, migration, and differentiation of neural precursors (Wu et al 2000;Ben-Hur et al 2003;Katakowski et al 2007). Because microglia originate from the invasion of monocytes in early development (Ling and Wong 1993) and LGF induces TNF-a release in cultured human monocytes (Díaz-Gil JJ, unpublished data), we can argue that this cytokine could be the molecular effector that mediates LGF-induced neurogenesis in our experimental model of PD.…”

ADAM-17/Tumor Necrosis Factor-α-Converting Enzyme Inhibits Neurogenesis and Promotes Gliogenesis from Neural Stem Cells

“…In other pathological or experimental conditions, such as focal ischemic preconditioning [54], cerebral stroke [44], or photodynamic therapy [55], ADAM-17, but not ADAM-10, is also upregulated either locally or in the SVZ. ADAM-17 upregulation is probably critical in the response of neural tissues to injury, not only because it initiates the sequence of events that lead to EGFR activation, but also because once EGFR is activated, several positive feed-back mechanisms, such as the increased expression of TGF-a, accelerate the transition from physiological to brain-injury conditions [56].…”

Upregulation of Mer Receptor Tyrosine Kinase Signaling Attenuated Lipopolysaccharide-Induced Lung Inflammation

“…because TAPI-0 is extensively used to block ADAM17 activity in vivo and in vitro (Katakowski et al, 2007;Sather et al, 2007). Moreover, its effect on the prevention of cleavage of Mer has been demonstrated in macrophages after in vitro exposure to LPS or phorbol 12-myristate 13-acetate (Sather et al, 2007).…”

“…ADAMs, including ADAM17, also known as tumor necrosis factor-a (TNF-a)-converting enzyme, and ADAM10, are involved in normal processes such as wound repair and tissue remodeling. They are associated with disease states, including renal inflammation and fibrosis (Melenhorst et al, 2009), stroke (Katakowski et al, 2007), and multiple sclerosis (Comabella et al, 2006). Although both of these proteases have been shown to cleave Axl and Mer (Weinger et al, 2009), ADAM17 is the key protease required for sMer shedding (Thorp et al, 2011).…”