Phagocytotic Activation of Muscularis Resident Macrophages Inhibits Smooth Muscle Contraction in Rat Ileum

Sato, Koichi; Torihashi, Shigeko; Hori, Masaru; Nasu, Tetsuyuki; Ozaki, Hiroshi

doi:10.1292/jvms.69.1053

Cited by 11 publications

(14 citation statements)

References 27 publications

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“…These three age-related disturbances are thought to be candidate mechanisms for some of the age-related declines in function evidenced in the elderly (Phillips and Powley, 2007, 2010), specifically the increased incidence with advancing age of motility- or transit-related problems, including delays in gastric emptying and longer intestinal transit time with associated fecal stasis (Bouras and Tangalos, 2009; Salles, 2009; Thompson, 2009; Wiskur et al, 2010). A hypothesis that incorporates the idea that macrophages located in the GI tract interact with the aging autonomic nervous system to produce disturbances in smooth muscle function is particularly parsimonious and consistent with the observation(s) in young-adult rats that these same macrophages play a key role in disturbances in GI motility under pathological conditions (Eskandari et al, 1997; Won et al, 2006; Sato et al, 2007). …”

Section: Discussionsupporting

confidence: 55%

Macrophages Associated with the Intrinsic and Extrinsic Autonomic Innervation of the Rat Gastrointestinal Tract

Phillips¹,

Powley²

2012

Autonomic Neuroscience

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Interactions between macrophages and the autonomic innervation of gastrointestinal (GI) tract smooth muscle have received little experimental attention. To better understand this relationship, immunohistochemistry was performed on GI whole mounts from rats at three ages. The phenotypes, morphologies, and distributions of gut macrophages are consistent with the cells performing extensive housekeeping functions in the smooth muscle layers. Specifically, a dense population of macrophages was located throughout the muscle wall where they were distributed among the muscle fibers and along the vasculature. Macrophages were also associated with ganglia and connectives of the myenteric plexus and with the sympathetic innervation. Additionally, these cells were in tight registration with the dendrites and axons of the myenteric neurons as well as the varicosities along the length of the sympathetic axons, suggestive of a contribution by the macrophages to the homeostasis of both synapses and contacts between the various elements of the enteric circuitry. Similarly, macrophages were involved in the presumed elimination of neuropathies as indicated by their association with dystrophic neurons and neurites which are located throughout the myenteric plexus and smooth muscle wall of aged rats. Importantly, the patterns of macrophage-neuron interactions in the gut paralleled the much more extensively characterized interactions of macrophages (i.e., microglia) and neurons in the CNS. The present observations in the PNS as well as extrapolations from homologous microglia in the CNS suggest that GI macrophages play significant roles in maintaining the nervous system of the gut in the face of wear and tear, disease, and aging.

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Section: Discussionsupporting

confidence: 55%

Macrophages Associated with the Intrinsic and Extrinsic Autonomic Innervation of the Rat Gastrointestinal Tract

Phillips¹,

Powley²

2012

Autonomic Neuroscience

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“…This response appears to be a limited housekeeping response of alternatively activated macrophages responding to the local neuropathy. Though macrophages can also, by the cytokine and chemokine signaling that is associated with classical activation, elaborate inflammatory responses and provoke degenerative changes (Bain and Mowat, 2011; Liddiard et al, 2011), α-SYNC aggregates in the ENS do not appear to stimulate an aggressive infiltration of macrophages or monocytes to the site, nor do they appear to produce a classical activation of macrophages (Mikkelsen, 1995; Sato et al, 2007). In this regard, the alternative activational response pattern of macrophages in the wall of the gut to α-SYNC accumulation is much like the partial activation response pattern expressed by macrophages in the gut lamina propria to local disturbances (Bain and Mowatt, 2011).…”

Section: Discussionmentioning

confidence: 99%

“…The accumulation of aggregated α-SYNC in the aging gut emphasizes the need to understand the mechanisms that normally dispose of deposits of insoluble α-SYNC and other cellular debris in the gut (Sato et al, 2007). One key candidate mechanism is phagocytosis by macrophages (Bain and Mowat, 2011; Liddiard et al, 2011; Smith et al, 2011).…”

Section: Introductionmentioning

confidence: 99%

Macrophages are unsuccessful in clearing aggregated alpha‐synuclein from the gastrointestinal tract of healthy aged Fischer 344 rats

Phillips

Billingsley

Powley

2013

The Anatomical Record

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With age, alpha-synuclein (α-SYNC) misfolds and forms insoluble deposits of protein in the myenteric plexus, leading presumably to dystrophy and degeneration in the circuitry controlling gastrointestinal (GI) function. The present experiment examined aggregates of α-SYNC in the aging small intestine and investigated how macrophages in the wall of the GI tract respond to these aberrant deposits. Groups of adult and aged Fisher 344 rats were studied. Whole mounts of duodenal, jejunal and ileal smooth muscle wall, including the myenteric plexus, were prepared. Double labeling immunohistochemistry was used to stain α-SYNC protein and the phenotypic macrophage antigens CD163 and MHCII. Alpha-synuclein accumulated in dense aggregates in axons of both postganglionic and preganglionic neurons throughout the small intestine. Staining patterns suggested that deposits of protein occur initially in axonal terminals and then spread retrogradely towards the somata. Macrophages that were adjacent to dystrophic terminal processes were swollen and contained vacuoles filled with insoluble α-SYNC, and these macrophages commonly had the phenotype of alternatively activated phagocytes. The present results suggest that macrophages play an active phagocytotic role in removing α-SYNC aggregates that accumulate with age in the neural circuitry of the gut. Our observations further indicate that this housekeeping response does not clear the protein sufficiently to eliminate all synucleinopathies or their precursor aggregates from the healthy aging GI tract. Thus, accumulating deposits of insoluble α-SYNC in the wall of the GI tract may contribute, especially when compounded by disease or inflammation, to the age-associated neuropathies in the gut that compromise GI function.

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“…This method is also convenient combined with macrophage antibodies [36] as well as for identifying cells with activation markers. However, intraperitoneal injection with FITC-D results in COX-2 expression – which suggests innate activation – but also release of prostaglandin E 2 and reduced muscle contractility [45]. …”

Section: Identification Of the Cellsmentioning

confidence: 99%

Interstitial cells of Cajal, macrophages and mast cells in the gut musculature: morphology, distribution, spatial and possible functional interactions

Mikkelsen

2010

J Cellular Molecular Medi

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Interstitial cells of Cajal (ICC) are recognized as pacemaker cells for gastrointestinal movement and are suggested to be mediators of neuromuscular transmission. Intestinal motility disturbances are often associated with a reduced number of ICC and/or ultrastructural damage, sometimes associated with immune cells. Macrophages and mast cells in the intestinal muscularis externa of rodents can be found in close spatial contact with ICC. Macrophages are a constant and regularly distributed cell population in the serosa and at the level of Auerbach’s plexus (AP). In human colon, ICC are in close contact with macrophages at the level of AP, suggesting functional interaction. It has therefore been proposed that ICC and macrophages interact. Macrophages and mast cells are considered to play important roles in the innate immune defence by producing pro-inflammatory mediators during classical activation, which may in itself result in damage to the tissue. They also take part in alternative activation which is associated with anti-inflammatory mediators, tissue remodelling and homeostasis, cancer, helminth infections and immunophenotype switch. ICC become damaged under various circumstances – surgical resection, possibly post-operative ileus in rodents – where innate activation takes place, and in helminth infections – where alternative activation takes place. During alternative activation the muscularis macrophage can switch phenotype resulting in up-regulation of F4/80 and the mannose receptor. In more chronic conditions such as Crohn’s disease and achalasia, ICC and mast cells develop close spatial contacts and piecemeal degranulation is possibly triggered.

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Phagocytotic Activation of Muscularis Resident Macrophages Inhibits Smooth Muscle Contraction in Rat Ileum

Cited by 11 publications

References 27 publications

Macrophages Associated with the Intrinsic and Extrinsic Autonomic Innervation of the Rat Gastrointestinal Tract

Macrophages Associated with the Intrinsic and Extrinsic Autonomic Innervation of the Rat Gastrointestinal Tract

Macrophages are unsuccessful in clearing aggregated alpha‐synuclein from the gastrointestinal tract of healthy aged Fischer 344 rats

Interstitial cells of Cajal, macrophages and mast cells in the gut musculature: morphology, distribution, spatial and possible functional interactions

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