Diabetic Csf1op/op Mice Lacking Macrophages Are Protected Against the Development of Delayed Gastric Emptying

Abstract

Background & AimsDiabetic gastroparesis is associated with changes in interstitial cells of Cajal (ICC), neurons, and smooth muscle cells in both animal models and humans. Macrophages appear to be critical to the development of cellular damage that leads to delayed gastric emptying (GE), but the mechanisms involved are not well understood. Csf1op/op (Op/Op) mice lack biologically active Csf1 (macrophage colony stimulating factor), resulting in the absence of Csf1-dependent tissue macrophages. We used Csf1op/op mice to determine the role of macrophages in the development of delayed GE.MethodsAnimals were injected with streptozotocin to make them diabetic. GE was determined weekly. Immunohistochemistry was used to identify macrophages and ICC networks in the gastric muscular layers. Oxidative stress was measured by serum malondialdehyde (MDA) levels. Quantitative reverse-transcription polymerase chain reaction was used to measure levels of mRNA.ResultsCsf1op/op mice had normal ICC. With onset of diabetes both Csf1op/op and wild-type Csf1+/+ mice developed increased levels of oxidative stress (75.8 ± 9.1 and 41.2 ± 13.6 nmol/mL MDA, respectively). Wild-type Csf1+/+ mice developed delayed GE after the onset of diabetes (4 of 13) whereas no diabetic Csf1op/op mouse developed delayed GE (0 of 15, P = .035). The ICC were disrupted in diabetic wild-type Csf1+/+ mice with delayed GE but remained normal in diabetic Csf1op/op mice.ConclusionsCellular injury and development of delayed GE in diabetes requires the presence of muscle layer macrophages. Targeting macrophages may be an effective therapeutic option to prevent cellular damage and development of delayed GE in diabetes.

Tumor necrosis factor alpha derived from classically activated “M1” macrophages reduces interstitial cell of Cajal numbers

“…16, 18 Furthermore, we recently reported that diabetic CSF1 op/op mice, which lack macrophages, never develop delayed gastric emptying and have normal ICC networks. 17 Based on these previous observations, we hypothesized that activated M1 macrophages secrete injurious pro-inflammatory mediators that can damage ICC. In this study, we provided evidence supporting the hypothesis that activated M1 macrophages can directly alter ICC survival and contribute to the pathophysiology of motility disorders such as diabetic gastroparesis where damage to ICC networks is observed.…”

“…It is known that CD206-negative macrophages are required for development of delayed gastric emptying in diabetic mice, as diabetic osteopetrotric (CSF1 op/op ) mice, which lack gastric macrophages due to a mutation in the macrophage colony stimulating factor (CSF1), never develop delayed gastric emptying and have normal ICC networks. 17 These data suggest that macrophages are needed to induce damage to ICC networks, resulting in delayed gastric emptying.…”

“…Loss of Kit-positive ICC is associated with the development of delayed gastric emptying in both humans and diabetic mice. 13, 15–17 …”

Diabetic and idiopathic gastroparesis is associated with loss of CD206‐positive macrophages in the gastric antrum

“…However, gastric emptying delay was evident only after M2 macrophages phenotypically switched to pro‐inflammatory (M1 or classically activated) macrophages and ICC were lost. In another study using diabetic, macrophage‐deficient CSF1 op/op mice, absence of muscle layer macrophages was protective against the development of delayed gastric emptying . These data suggest that interactions between the innate immune system, specifically macrophages, and ICC and the neuromuscular apparatus may be central in the pathophysiology of human gastroparesis …”

A Severe Alkaline Gastritis in Type 1 Diabetes Gastroparesis: A Case Report

“…Targeting macrophages may be an effective therapeutic option to prevent cellular damage and development of delayed gastric emptying in diabetes [2].…”