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

BACKGROUND: Animal studies have increasingly highlighted the role of macrophages in the development of delayed gastric emptying. However, their role in the pathophysiology of human gastroparesis is unclear. Our aim was to determine changes in macrophages and other cell types in the gastric antrum muscularis propria of patients with diabetic and idiopathic gastroparesis. METHODS: Full thickness gastric antrum biopsies were obtained from patients enrolled in the Gastroparesis Clinical Research Consortium (11 diabetic, 6 idiopathic) and 5 controls. Immunolabeling and quantitative assessment was done for interstitial cells of Cajal (ICC) (Kit), enteric nerves protein gene product 9.5, neuronal nitric oxide synthase, vasoactive intestinal peptide, substance P, tyrosine hydroxylase), overall immune cells (CD45) and anti-inflammatory macrophages (CD206). Gastric emptying was assessed using nuclear medicine scintigraphy and symptom severity using the Gastroparesis Cardinal Symptom Index. RESULTS: Both diabetic and idiopathic gastroparesis patients showed loss of ICC as compared to controls (Mean [standard error of mean]/hpf: diabetic, 2.28 [0.16]; idiopathic, 2.53 [0.47]; controls, 6.05 [0.62]; P=.004). Overall immune cell population (CD45) was unchanged but there was a loss of anti-inflammatory macrophages (CD206) in circular muscle (diabetic, 3.87 [0.32]; idiopathic, 4.16 [0.52]; controls, 6.59 [1.09]; P=.04) and myenteric plexus (diabetic, 3.83 [0.27]; idiopathic, 3.59 [0.68]; controls, 7.46 [0.51]; P=.004). There was correlation between the number of ICC and CD206-positive cells (r=.55, P=.008). Enteric nerves (PGP9.5) were unchanged: diabetic, 33.64 (3.45); idiopathic, 41.26 (6.40); controls, 46.80 (6.04). CONCLUSION: Loss of antral CD206-positive anti-inflammatory macrophages is a key feature in human gastroparesis and it is associates with ICC loss.

Association of low numbers of CD206-positive cells with loss of ICC in the gastric body of patients with diabetic gastroparesis.

BACKGROUND: There is increasing evidence for specific cellular changes in the stomach of patients with diabetic (DG) and idiopathic (IG) gastroparesis. The most significant findings are loss of interstitial cells of Cajal (ICC), neuronal abnormalities, and an immune cellular infiltrate. Studies done in diabetic mice have shown a cytoprotective effect of CD206+ M2 macrophages. To quantify overall immune cellular infiltrate, identify macrophage populations, and quantify CD206+ and iNOS+ cells. To investigate associations between cellular phenotypes and ICC. METHODS: Full thickness gastric body biopsies were obtained from non-diabetic controls (C), diabetic controls (DC), DG, and IG patients. Sections were labeled for CD45, CD206, Kit, iNOS, and putative human macrophage markers (HAM56, CD68, and EMR1). Immunoreactive cells were quantified from the circular muscle layer. KEY RESULTS: Significantly fewer ICC were detected in DG and IG tissues, but there were no differences in the numbers of cells immunoreactive for other markers between patient groups. There was a significant correlation between the number of CD206+ cells and ICC in DG and DC patients, but not in C and IG and a significant correlation between iNOS+ cells and ICC in the DC group, but not the other groups. CD68 and HAM56 reliably labeled the same cell populations, but EMR1 labeled other cell types. CONCLUSIONS & INFERENCES: Depletion of ICC and correlation with changes in CD206+ cell numbers in DC and DG patients suggests that in humans, like mice, CD206+ macrophages may play a cytoprotective role in diabetes. These findings may lead to novel therapeutic options, targeting alternatively activated macrophages.