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

Gut ◽  
2017 ◽  
Vol 67 (5) ◽  
pp. 827-836 ◽  
Author(s):  
Laren Becker ◽  
Linh Nguyen ◽  
Jaspreet Gill ◽  
Subhash Kulkarni ◽  
Pankaj Jay Pasricha ◽  
...  
Keyword(s):  
Nervous System ◽  
Enteric Nervous System ◽  
Enteric Neurons ◽  
Macrophage Phenotype ◽  
Macrophage Polarisation ◽  
Enteric Ganglia ◽  
Age Related ◽  
Age Dependent ◽  
Anti Inflammatory ◽  
Old Mice

ObjectiveThe 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.DesignLongitudinal 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.ResultsAgeing 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.ConclusionsA shift by macrophages towards a proinflammatory phenotype with ageing causes inflammation-mediated degeneration of the ENS.

In ovo transplantation of enteric nervous system precursors from vagal to sacral neural crest results in extensive hindgut colonisation

Development ◽  
2002 ◽  
Vol 129 (12) ◽  
pp. 2785-2796 ◽  
Author(s):  
Alan J. Burns ◽  
Jean-Marie M. Delalande ◽  
Nicole M. Le Douarin
Keyword(s):  
Nervous System ◽  
Neural Crest ◽  
Enteric Nervous System ◽  
Enteric Neurons ◽  
In Ovo ◽  
Neuronal Marker ◽  
Sacral Region ◽  
Enteric Ganglia ◽  
Migration Front ◽  
Sacral Neural Crest

The enteric nervous system (ENS) is derived from vagal and sacral neural crest cells (NCC). Within the embryonic avian gut, vagal NCC migrate in a rostrocaudal direction to form the majority of neurons and glia along the entire length of the gastrointestinal tract, whereas sacral NCC migrate in an opposing caudorostral direction, initially forming the nerve of Remak, and contribute a smaller number of ENS cells primarily to the distal hindgut. In this study, we have investigated the ability of vagal NCC, transplanted to the sacral region of the neuraxis, to colonise the chick hindgut and form the ENS in an experimentally generated hypoganglionic hindgut in ovo model. Results showed that when the vagal NC was transplanted into the sacral region of the neuraxis, vagal-derived ENS precursors immediately migrated away from the neural tube along characteristic pathways, with numerous cells colonising the gut mesenchyme by embryonic day (E) 4. By E7, the colorectum was extensively colonised by transplanted vagal NCC and the migration front had advanced caudorostrally to the level of the umbilicus. By E10, the stage at which sacral NCC begin to colonise the hindgut in large numbers, myenteric and submucosal plexuses in the hindgut almost entirely composed of transplanted vagal NCC, while the migration front had progressed into the pre-umbilical intestine, midway between the stomach and umbilicus. Immunohistochemical staining with the pan-neuronal marker, ANNA-1, revealed that the transplanted vagal NCC differentiated into enteric neurons, and whole-mount staining with NADPH-diaphorase showed that myenteric and submucosal ganglia formed interconnecting plexuses, similar to control animals. Furthermore, using an anti-RET antibody, widespread immunostaining was observed throughout the ENS, within a subpopulation of sacral NC-derived ENS precursors, and in the majority of transplanted vagal-to-sacral NCC. Our results demonstrate that: (1) a cell autonomous difference exists between the migration/signalling mechanisms used by sacral and vagal NCC, as transplanted vagal cells migrated along pathways normally followed by sacral cells, but did so in much larger numbers, earlier in development; (2) vagal NCC transplanted into the sacral neuraxis extensively colonised the hindgut, migrated in a caudorostral direction, differentiated into neuronal phenotypes, and formed enteric plexuses; (3) RET immunostaining occurred in vagal crest-derived ENS cells, the nerve of Remak and a subpopulation of sacral NCC within hindgut enteric ganglia.

scholarly journals New Insights into c-Ret Signalling Pathway in the Enteric Nervous System and Its Relationship with ALS

2014 ◽  
Vol 2014 ◽  
pp. 1-7 ◽  
Author(s):  
M. J. Luesma ◽  
I. Cantarero ◽  
J. M. Álvarez-Dotu ◽  
S. Santander ◽  
C. Junquera
Keyword(s):  
Nervous System ◽  
Enteric Nervous System ◽  
Motor Neurons ◽  
Cellular Localization ◽  
Neurological Diseases ◽  
Enteric Neurons ◽  
Human Gut ◽  
Tyrosine Residues ◽  
Enteric Ganglia ◽  
Lateral Sclerosis

The receptor tyrosine kinase Ret (c-Ret) transduces the glial cell line-derived neurotrophic factor (GDNF) signal, one of the neurotrophic factors related to the degeneration process or the regeneration activity of motor neurons in amyotrophic lateral sclerosis (ALS). The phosphorylation of several tyrosine residues of c-Ret seems to be altered in ALS. c-Ret is expressed in motor neurons and in the enteric nervous system (ENS) during the embryonic period. The characteristics of the ENS allow using it as model for central nervous system (CNS) study and being potentially useful for the research of human neurological diseases such as ALS. The aim of the present study was to investigate the cellular localization and quantitative evaluation of marker c-Ret in the adult human gut. To assess the nature of c-Ret positive cells, we performed colocalization with specific markers of cells that typically are located in the enteric ganglia. The colocalization of PGP9.5 and c-Ret was preferentially intense in enteric neurons with oval morphology and mostly peripherally localized in the ganglion, so we concluded that the c-Ret receptor is expressed by a specific subtype of enteric neurons in the mature human ENS of the gut. The functional significance of these c-Ret positive neurons is discussed.

Origins, migration and differentiation of glial cells in the insect enteric nervous system from a discrete set of glial precursors

Development ◽  
1993 ◽  
Vol 117 (1) ◽  
pp. 59-74 ◽  
Author(s):  
P. F. Copenhaver
Keyword(s):  
Nervous System ◽  
Enteric Nervous System ◽  
Glial Cells ◽  
Neuronal Migration ◽  
Extended Period ◽  
Enteric Neurons ◽  
Distinct Population ◽  
Enteric Ganglia ◽  
Enteric Glial Cells ◽  
Enteric Plexus

The enteric nervous system (ENS) of the moth, Manduca sexta, consists of two primary cellular domains and their associated nerves. The neurons of the anterior domain occupy two small peripheral ganglia (the frontal and hypocerebral ganglia), while a second population of neurons occupies a branching nerve plexus (the enteric plexus) that spans the foregut-midgut boundary. Previously, we have shown these two regions arise by separate programs of neurogenesis: cells that form the anterior enteric ganglia are generated from three discrete proliferative zones that differentiate within the foregut epithelium. In contrast, the cells of the enteric plexus (the EP cells) emerge from a neurogenic placode within the posterior lip of the foregut. Both sets of neurons subsequently undergo an extended period of migration and reorganization to achieve their mature distributions. We now show that prior to the completion of neurogenesis, an additional class of precursor cells is generated from the three proliferative zones of the foregut. Coincident with the onset of neuronal migration, this precursor class enters a phase of enhanced mitotic activity, giving rise to a population of cells that continue to divide as the ENS matures. Using clonal analyses of individual precursors, we demonstrate that the progeny of these cells become distributed along the same pathways taken by the migratory neurons; subsequently, they contribute to an ensheathing layer around the branches of the enteric plexus and the enteric ganglia. We conclude that this additional precursor class, which shares a common developmental origin with the enteric neurons, gives rise to a distinct population of peripheral glial cells. Moreover, the distribution of enteric glial cells is achieved by their migration and differentiation along the same pathways that are formed during the preceding phases of neuronal migration.

scholarly journals Age-Dependent Resistance to Lethal Alphavirus Encephalitis in Mice: Analysis of Gene Expression in the Central Nervous System and Identification of a Novel Interferon-Inducible Protective Gene, Mouse ISG12

2002 ◽  
Vol 76 (22) ◽  
pp. 11688-11703 ◽  
Author(s):  
Lucia Labrada ◽  
Xiao Huan Liang ◽  
Wei Zheng ◽  
Christine Johnston ◽  
Beth Levine
Keyword(s):  
Gene Expression ◽  
Central Nervous System ◽  
Nervous System ◽  
Virus Infection ◽  
Sindbis Virus ◽  
Expressed Sequence Tag ◽  
Severe Disease ◽  
Altered Expression ◽  
Age Dependent ◽  
Old Mice

ABSTRACT Several different mammalian neurotropic viruses produce an age-dependent encephalitis characterized by more severe disease in younger hosts. To elucidate potential factors that contribute to age-dependent resistance to lethal viral encephalitis, we compared central nervous system (CNS) gene expression in neonatal and weanling mice that were either mock infected or infected intracerebrally with a recombinant strain, dsTE12Q, of the prototype alphavirus Sindbis virus. In 1-day-old mice, infection with dsTE12Q resulted in rapidly fatal disease associated with high CNS viral titers and extensive CNS apoptosis, whereas in 4-week-old mice, dsTE12Q infection resulted in asymptomatic infection with lower CNS virus titers and undetectable CNS apoptosis. GeneChip expression comparisons of mock-infected neonatal and weanling mouse brains revealed developmental regulation of the mRNA expression of numerous genes, including some apoptosis regulatory genes, such as the proapoptotic molecules caspase-3 and TRAF4, which are downregulated during development, and the neuroprotective chemokine, fractalkine, which is upregulated during postnatal development. In parallel with increased neurovirulence and increased viral replication, Sindbis virus infection in 1-day-old mice resulted in both a greater number of host inflammatory genes with altered expression and greater changes in levels of host inflammatory gene expression than infection in 4-week-old mice. Only one inflammatory response gene, an expressed sequence tag similar to human ISG12, increased by a greater magnitude in infected 4-week-old mouse brains than in infected 1-day-old mouse brains. Furthermore, we found that enforced neuronal ISG12 expression results in a significant delay in Sindbis virus-induced death in neonatal mice. Together, our data identify genes that are developmentally regulated in the CNS and genes that are differentially regulated in the brains of different aged mice in response to Sindbis virus infection.

scholarly journals Abnormalities of the intestinal pacemaker cells, enteric neurons, and smooth muscle in intestinal atresia

2019 ◽  
Vol 11 (03) ◽  
pp. 180-185 ◽  
Author(s):  
Radhika krishna OH ◽  
Mohammed Abdul Aleem ◽  
Geetha Kayla
Keyword(s):  
Nervous System ◽  
Small Bowel ◽  
Enteric Nervous System ◽  
Gastrointestinal Motility ◽  
Interstitial Cells Of Cajal ◽  
Interstitial Cells ◽  
Enteric Neurons ◽  
Small Bowel Atresia ◽  
Bowel Atresia ◽  
Cells Of Cajal

Abstract BACKGROUND: Small bowel atresia is a congenital disorder that carves a substantial morbidity. Numerous postoperative gastrointestinal motility problems occur. The underlying cause of this motility disorder is still unclear. Interstitial cells of Cajal (ICC) play a major role in gastrointestinal motility. AIMS AND OBJECTIVES: To investigate the morphological changes of enteric nervous system and ICC in small bowel atresia. MATERIAL AND METHODS: Resected small bowel specimen from affected patients (n=15) were divided into three parts (proximal, distal, atretic). Standard histology and immunohistochemistry with anti C-KIT receptor antibody (CD117), calretinin and α-SMA was carried out. The density of myenteric ICCs in the proximal, atretic and distal parts was demonstrated by CD 117 while Calretinin was used for ganglion cells and nerve bundles, α-SMA highlighted muscle hypertrophy. RESULT AND CONCLUSION: The proximal and distal bowel revealed clear changes in the morphology and density of enteric nervous system and interstitial cells of Cajal..

scholarly journals G protein-coupled receptor trafficking and signaling: new insights into the enteric nervous system

2019 ◽  
Vol 316 (4) ◽  
pp. G446-G452 ◽  
Author(s):  
Simona E. Carbone ◽  
Nicholas A. Veldhuis ◽  
Arisbel B. Gondin ◽  
Daniel P. Poole
Keyword(s):  
Nervous System ◽  
Enteric Nervous System ◽  
G Protein ◽  
Molecular Mechanisms ◽  
Intestinal Inflammation ◽  
Receptor Expression ◽  
Enteric Neurons ◽  
Future Research ◽  
Detailed Knowledge ◽  
G Protein Coupled

G protein-coupled receptors (GPCRs) are essential for the neurogenic control of gastrointestinal (GI) function and are important and emerging therapeutic targets in the gut. Detailed knowledge of both the distribution and functional expression of GPCRs in the enteric nervous system (ENS) is critical toward advancing our understanding of how these receptors contribute to GI function during physiological and pathophysiological states. Equally important, but less well defined, is the complex relationship between receptor expression, ligand binding, signaling, and trafficking within enteric neurons. Neuronal GPCRs are internalized following exposure to agonists and under pathological conditions, such as intestinal inflammation. However, the relationship between the intracellular distribution of GPCRs and their signaling outputs in this setting remains a “black box”. This review will briefly summarize current knowledge of agonist-evoked GPCR trafficking and location-specific signaling in the ENS and identifies key areas where future research could be focused. Greater understanding of the cellular and molecular mechanisms involved in regulating GPCR signaling in the ENS will provide new insights into GI function and may open novel avenues for therapeutic targeting of GPCRs for the treatment of digestive disorders.

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