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

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.

Focal, but not global, cerebral ischaemia causes loss of myenteric neurons and upregulation of vasoactive intestinal peptide in mouse ileum

“…) and enteric neuronal loss (Cheng et al . ) have been observed in experimental stroke models. In this study, we investigated enteric neuronal survival and plasticity in mouse ileum after three different types of cerebral ischaemia.…”

“…The pMCAO‐induced enteric neuronal loss has previously been shown to involve the beta‐galactoside binding protein galectin‐3 (gal‐3) (Cheng et al . ). Gal‐3 has immune modulatory capabilities acting as an endogenous Toll‐like receptor 4 (TLR4) agonist (Burguillos et al .…”

“…This is because both models, like pMCAO (Cheng et al . ), are reported to cause loss of central neurons and induction of a pro‐inflammatory response, including elevated gal‐3 and TLR‐4 levels in brain and retina (Hua et al . ; Lee et al .…”

“…; Cheng et al . ). Mice (sham n = 5, pMCAO n = 7) had an incision made between the left lateral part of the orbit and the left ear, and the parotid gland and the temporal muscle were dislocated in distal direction.…”

“…We have recently described significant enteric neuronal losses in myenteric ganglia from mouse ileum 3 and 7 days after permanent middle cerebral artery occlusion (pMCAO), a model of focal cerebral ischaemia (Cheng et al . ). Here, we expand on previous study focusing on neuronal survival and relative numbers of VIP and nNOS expressing neurons in mouse ileum, including not only pMCAO but also global cerebral ischaemia with reperfusion (GCIR), and chronic cerebral hypoperfusion (CCH).…”