Matrix metalloproteinase activity stimulates N-cadherin shedding and the soluble N-cadherin ectodomain promotes classical microglial activation

Abstract

BackgroundMatrix metalloproteinases (MMPs) are a family of enzymes that are typically released from intracellular stores to act on specific extracellular substrates. MMP expression and activity can be increased in a neuronal activity-dependent manner, and further increased in response to tissue injury. MMP substrates include cell adhesion molecules (CAMs) that are abundantly expressed in the brain and well positioned for membrane proximal cleavage. Importantly, CAM integrity is important to synaptic structure and axon-myelin interactions, and shed ectodomains may themselves influence cellular function.MethodsIn the present study, we have examined proteolysis of N-cadherin (N-cdh) by MMP-7, a family member that has been implicated in disorders including HIV dementia, multiple sclerosis, and major depression. With in vitro digest assays, we tested N-cdh cleavage by increasing concentrations of recombinant enzyme. We also tested MMP-7 for its potential to stimulate N-cdh shedding from cultured neural cells. Since select CAM ectodomains may interact with cell surface receptors that are expressed on microglial cells, we subsequently tested the N-cdh ectodomain for its ability to stimulate activation of this cell type as determined by nuclear translocation of NF-κB, Iba-1 expression, and TNF-α release.ResultsWe observed that soluble N-cdh increased Iba-1 levels in microglial lysates, and also increased microglial release of the cytokine TNF-α. Effects were associated with increased NF-κB immunoreactivity in microglial nuclei and diminished by an inhibitor of the toll-like receptor adaptor protein, MyD88.ConclusionsTogether, these in vitro results suggest that soluble N-cdh may represent a novel effector of microglial activation, and that disorders with increased MMP levels may stimulate a cycle in which the products of excess proteolysis further exacerbate microglial-mediated tissue injury. Additional in vivo studies are warranted to address this issue.

The inhibition of invasion of human melanoma cells through N-cadherin knock-down

“…The FGF-1 may interact with the fourth extracellular domain (EC4) of N-cadherin based on the fact that transfer of EC4 domain from N-cadherin onto E-cadherin reconstituted the invasive function of N-cadherin [ 21 ]. Other authors suggest the role of the cytoplasmic domain of N-cadherin [ 35 , 36 ] and soluble N-cadherin domain in regulating cell migration [ 37 ].…”

Protocadherins at the Crossroad of Signaling Pathways

“…Proteolytic processing is an important transduction mechanism for type I classical cadherins, such as N-cad and epithelial cadherin (Marambaud et al, 2002;Maretzky et al, 2005;Reiss et al, 2005;Symowicz et al, 2007;Jang et al, 2011;Conant et al, 2017). ICD cleavage and subsequent nuclear translocation might also be a general characteristic of Pcdh-dependent signaling, as multiple studies have shown nuclear ICD localization for several Pcdhs (e.g., PcdhγC3, PcdhγC5, Pcdhα4, and Pcdh1α).…”

HIV‐1 Tat promotes astrocytic release of CCL2 through MMP/PAR‐1 signaling

“…The increased levels of MMP substrate cleavage fragments provide evidence for a role of aberrant MMP activity in the context of impaired cognition. We have previously shown that the MMP-cleaved ectodomain of the adhesion molecule N-cadherin promotes microglial activation (Conant et al, 2017) which may reflect an alternate pathway whereby HIV promotes MMPdependent gliosis.…”