Galectin-3 causes enteric neuronal loss in mice after left sided permanent middle cerebral artery occlusion, a model of stroke.

Xiaowen Cheng,Michelle Foldschak Turesson,Ulrikke Voss,Eva Ekblad,Antonio Boza-Serrano,Tomas Deierborg

doi:10.1038/srep32893

Xiaowen Cheng, Michelle Foldschak Turesson + Show 4 more

Open Access

https://doi.org/10.1038/srep32893

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Journal: Scientific Reports	Publication Date: Sep 9, 2016
Citations: 29	License type: CC BY 4.0

Affiliation: Lund University

Abstract

In addition to brain injury stroke patients often suffer gastrointestinal complications. Neuroimmune interactions involving galectin-3, released from microglia in the brain, mediates the post-stroke pro-inflammatory response. We investigated possible consequences of stroke on the enteric nervous system and the involvement of galectin-3. We show that permanent middle cerebral artery occlusion (pMCAO) induces loss of enteric neurons in ileum and colon in galectin-3+/+, but not in galectin-3−/−, mice. In vitro we show that serum from galectin-3+/+, but not from galectin-3−/−, mice subjected to pMCAO, caused loss of C57BL/6J myenteric neurons, while myenteric neurons derived from TLR4−/− mice were unaffected. Further purified galectin-3 (10−6 M) caused loss of cultured C57BL/6J myenteric neurons. Inhibitors of transforming growth factor β-activated kinase 1 (TAK1) or AMP activated kinase (AMPK) counteracted both the purified galectin-3 and the galectin-3+/+ pMCAO serum-induced loss in vitro. Combined we show that stroke (pMCAO) triggers central and peripheral galectin-3 release causing enteric neuronal loss through a TLR4 mediated mechanism involving TAK1 and AMPK. Galectin-3 is suggested a target for treatment of post-stroke complications.

Highlights

In addition to brain injury stroke patients often suffer gastrointestinal complications
In colon no significant differences in numbers of submucous neurons were detected in gal-3−/− mice, regardless of treatment, but significant losses of submucous neurons were detected in gal-3+/+ mice 3 (P < 0.05) and 7 (P < 0.05) days, but not 6 hours, post permanent middle cerebral artery occlusion (pMCAO) compared to the gal+/+ sham group (Fig. 1C)
In colonic myenteric ganglia no significant losses were found in pMCAO gal-3−/− mice, but significant losses of myenteric neurons were observed in gal-3+/+ mice 3 (P < 0.001) and 7 (P < 0.001) days, but not 6 hours, post pMCAO (Fig. 1D)

Summary

Introduction

In addition to brain injury stroke patients often suffer gastrointestinal complications. Neuroimmune interactions involving galectin-3, released from microglia in the brain, mediates the post-stroke proinflammatory response. We show that permanent middle cerebral artery occlusion (pMCAO) induces loss of enteric neurons in ileum and colon in galectin-3+/+, but not in galectin-3−/−, mice. Combined we show that stroke (pMCAO) triggers central and peripheral galectin-3 release causing enteric neuronal loss through a TLR4 mediated mechanism involving TAK1 and AMPK. Post stroke neuroimmune interactions involving microglia and recruited peripheral macrophages determine neurological outcome in the CNS6. It was shown that gal-3 secreted from IBA-1- (marker of microglia and recruited peripheral macrophages) positive cells is an endogenous toll-like receptor 4 (TLR4) agonist leading to a sustained pro-inflammatory response[8]. This study aims to investigate possible consequences of pMCAO on the ENS and the possible role of gal-3 in enteric neuropathy

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