OBJECTIVE: The enteric nervous system (ENS) undergoes @entity528 and degenerative changes with age. The cause of this neurodegeneration is poorly understood. Muscularis macrophages residing in close proximity to enteric @entity4094 via direct crosstalk with enteric neurons and have been implicated in the pathogenesis of @entity1319 like @entity7623 and @entity86 . The aim of this study was to assess whether ageing causes alterations in macrophage phenotype that contributes to age-related degeneration of the ENS. DESIGN: Longitudinal muscle and myenteric plexus from small intestine of young, mid-aged and old @entity19 were dissected and prepared for whole mount immunostaining, flow cytometry, Luminex immunoassays, western blot analysis, enteric neural stem cell (ENSC) isolation or conditioned media. Bone marrow derived macrophages were prepared and polarised to classic (M1) or alternative (M2) activation states. Markers for macrophage phenotype were measured using quantitative RT-PCR. RESULTS: Ageing causes a shift in macrophage polarisation from anti-inflammatory 'M2' to proinflammatory 'M1' that is associated with a rise in cytokines and immune cells in the ENS. This phenotypic shift is associated with a neural response to inflammatory signals, increase in apoptosis and loss of enteric neurons and ENSCs, and delayed intestinal transit. An age-dependent decrease in expression of the transcription factor @entity3114 , a known longevity gene, contributes to the loss of anti-inflammatory behaviour in macrophages of old @entity19 , and @entity3114 -deficient @entity19 demonstrate signs of premature ageing of the ENS. CONCLUSIONS: A shift by macrophages towards a proinflammatory phenotype with ageing causes @entity32 -mediated degeneration of the ENS.

Age-dependent shift in macrophage polarisation causes XXXX -mediated degeneration of enteric nervous system.

@entity4094 :: ('MESH:D009468', 'Disease') :: ['ganglia maintain neuromuscular function'] @entity32 :: ('MESH:D007249', 'Disease') :: ['inflammation'] @entity19 :: ('10090', 'Species') :: ['mice'] @entity3114 :: ('56484(Tax:10090)', 'Gene') :: ['FoxO3'] @entity86 :: ('MESH:D019106', 'Disease') :: ['postoperative ileus'] @entity7623 :: ('MESH:D018589', 'Disease') :: ['gastroparesis'] @entity528 :: ('MESH:D009410', 'Disease') :: ['neuronal loss'] @entity1319 :: ('MESH:D015835', 'Disease') :: ['GI motility disorders']
@entity32 :: (MESH:D007249,Disease) :: ['inflammation']
