GDNF requires HIF-1α and RET activation for suppression of programmed cell death of enteric neurons by metabolic challenge.

Abstract

Intestinal inflammation challenges both function and structure of the enteric nervous system (ENS). In the animal model of TNBS-induced colitis, an influx of immune cells causes early neuron death in the neuromuscular layers, followed by axonal outgrowth from surviving neurons associated with upregulation of the neurotrophin GDNF (glial cell line-derived neurotrophic factor). Inflammation could involve ischemia and metabolic inhibition leading to neuronal damage, which might be countered by a protective action of GDNF. This was examined in a primary co-culture model of rat myenteric neurons and smooth muscle, where metabolic challenge was caused by dinitrophenol (DNP), O-methyl glucose (OMG) or hypoxia. These caused the specific loss of 50% of neurons by 24 h that was blocked by GDNF both in vitro and in whole mounts. Neuroprotection was lost with RET inhibition by vandetanib or GSK3179106, which also caused neuron loss in untreated controls. Thus, both basal and upregulated GDNF levels signal via RET for neuronal survival. This includes a key role for upregulation of HIF-1α, which was detected in neurons in colitis, since the inhibitor chetomin blocked rescue by GDNF or ischemic pre-conditioning in vitro. In DNP-treated co-cultures, neuron death was not inhibited by zVAD, necrosulfonamide or GSK872, and cleaved caspase-3 or - 8 were undetectable. However, combinations of inhibitors or the RIP1kinase inhibitor Nec-1 prevented neuronal death, evidence for RIPK1-dependent necroptosis. Therefore, inflammation challenges enteric neurons via ischemia, while GDNF is neuroprotective, activating RET and HIF-1α to limit programmed cell death. This may support novel strategies to address recurrent inflammation in IBD.

• Authors: Joanne E Kearon, S C Kocherry, D Zoumboulakis, D Rivera, S R Lourenssen, M G Blennerhassett
• Journal: Molecular and cellular neurosciences (Mol Cell Neurosci) Vol. 115 Pg. 103655 (09 2021) ISSN: 1095-9327 [Electronic] United States
• PMID: 34273501 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2021 Elsevier Inc. All rights reserved.

Chemical References

• Gdnf protein, rat
• Glial Cell Line-Derived Neurotrophic Factor
• Glial Cell Line-Derived Neurotrophic Factor Receptors
• Hif1a protein, rat
• Hypoxia-Inducible Factor 1, alpha Subunit
• Proto-Oncogene Proteins c-ret
• Ret protein, rat

Topics

• Animals
• Apoptosis
• Cell Survival
• Enteric Nervous System
• Glial Cell Line-Derived Neurotrophic Factor (metabolism)
• Glial Cell Line-Derived Neurotrophic Factor Receptors
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• Neurons
• Proto-Oncogene Proteins c-ret
• Rats