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

Laren Becker, Linh Nguyen, Jaspreet Gill, Subhash Kulkarni, Pankaj Jay Pasricha, Aida Habtezion

Research output: Contribution to journalArticle

Abstract

Objective The enteric nervous system (ENS) undergoes neuronal loss and degenerative changes with age. The cause of this neurodegeneration is poorly understood. Muscularis macrophages residing in close proximity to enteric ganglia maintain neuromuscular function via direct crosstalk with enteric neurons and have been implicated in the pathogenesis of GI motility disorders like gastroparesis and postoperative ileus. 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 mice 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 FoxO3, a known longevity gene, contributes to the loss of anti-inflammatory behaviour in macrophages of old mice, and FoxO3-deficient mice demonstrate signs of premature ageing of the ENS. Conclusions A shift by macrophages towards a proinflammatory phenotype with ageing causes inflammation-mediated degeneration of the ENS.

Original languageEnglish (US)
Pages (from-to)827-836
Number of pages10
JournalGut
Volume67
Issue number5
DOIs
StatePublished - May 1 2018

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Enteric Nervous System
Macrophages
Inflammation
Phenotype
Anti-Inflammatory Agents
Gastroparesis
Premature Aging
Neurons
Myenteric Plexus
Neural Stem Cells
Ileus
Cell Separation
Conditioned Culture Medium
Immunoassay
Ganglia
Small Intestine
Flow Cytometry
Transcription Factors
Western Blotting
Apoptosis

Keywords

  • AGEING
  • ENTERIC NERVOUS SYSTEM
  • INFLAMMATION
  • MACROPHAGES

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Age-dependent shift in macrophage polarisation causes inflammation-mediated degeneration of enteric nervous system. / Becker, Laren; Nguyen, Linh; Gill, Jaspreet; Kulkarni, Subhash; Pasricha, Pankaj Jay; Habtezion, Aida.

In: Gut, Vol. 67, No. 5, 01.05.2018, p. 827-836.

Research output: Contribution to journalArticle

Becker, Laren ; Nguyen, Linh ; Gill, Jaspreet ; Kulkarni, Subhash ; Pasricha, Pankaj Jay ; Habtezion, Aida. / Age-dependent shift in macrophage polarisation causes inflammation-mediated degeneration of enteric nervous system. In: Gut. 2018 ; Vol. 67, No. 5. pp. 827-836.
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N2 - Objective The enteric nervous system (ENS) undergoes neuronal loss and degenerative changes with age. The cause of this neurodegeneration is poorly understood. Muscularis macrophages residing in close proximity to enteric ganglia maintain neuromuscular function via direct crosstalk with enteric neurons and have been implicated in the pathogenesis of GI motility disorders like gastroparesis and postoperative ileus. 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 mice 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 FoxO3, a known longevity gene, contributes to the loss of anti-inflammatory behaviour in macrophages of old mice, and FoxO3-deficient mice demonstrate signs of premature ageing of the ENS. Conclusions A shift by macrophages towards a proinflammatory phenotype with ageing causes inflammation-mediated degeneration of the ENS.

AB - Objective The enteric nervous system (ENS) undergoes neuronal loss and degenerative changes with age. The cause of this neurodegeneration is poorly understood. Muscularis macrophages residing in close proximity to enteric ganglia maintain neuromuscular function via direct crosstalk with enteric neurons and have been implicated in the pathogenesis of GI motility disorders like gastroparesis and postoperative ileus. 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 mice 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 FoxO3, a known longevity gene, contributes to the loss of anti-inflammatory behaviour in macrophages of old mice, and FoxO3-deficient mice demonstrate signs of premature ageing of the ENS. Conclusions A shift by macrophages towards a proinflammatory phenotype with ageing causes inflammation-mediated degeneration of the ENS.

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