MMP-9 Processing of Intestinal Smooth Muscle-derived GDNF is Required for Neurotrophic Action on Enteric Neurons.

Neuroscience
Demetri ZoumboulakisM G Blennerhassett

Abstract

The neurotrophin GDNF guides development of the enteric nervous system (ENS) in embryogenesis and directs survival and axon outgrowth in postnatal myenteric neurons in vitro. GDNF expression in intestinal smooth muscle cells is dynamic, with upregulation by inflammatory cytokines in vitro or intestinal inflammation in vivo, but the role of post-translational proteolytic cleavage is undefined. In a co-culture model of myenteric neurons, smooth muscle and glia, inhibition of serine or cysteine protease activity was ineffective against the >2-fold increase in axon density caused by TNFα. However, inhibitors of metalloproteinases (MMP) identified an essential role of MMP-9, and qPCR and western blotting showed that pro-inflammatory cytokines increased both mRNA and protein expression for MMP-9, in both cellular lysates and conditioned medium (CM). Inhibition of MMP-9 prevented the cytokine-induced increase in mature GDNF in CM or cellular lysates of co-cultures or cell lines of intestinal smooth muscle cells (ISMC) from adult rat colon. Western blotting showed parallel upregulation of mature GDNF and MMP-9 vs control in ISMC isolated on Day 2 of TNBS-induced colitis. Nonetheless, transfection of GDNF plasmid into HEK-293 cells as a...Continue Reading

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Citations

Feb 6, 2021·Cellular and Molecular Neurobiology·M G Blennerhassett, S R Lourenssen
Mar 19, 2021·Nature Reviews. Gastroenterology & Hepatology·Luisa Seguella, Brian D Gulbransen
Jul 18, 2021·Molecular and Cellular Neurosciences·Joanne E KearonM G Blennerhassett

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