Macrophages in diabetic gastroparesis – the missing link?

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BackgroundDiabetic gastroparesis results in significant morbidity for patients and major economic burden for society. Treatment options for diabetic gastroparesis are currently directed at symptom control rather than the underlying disease and are limited. The pathophysiology of diabetic gastroparesis includes damage to intrinsic and extrinsic neurons, smooth muscle, and interstitial cells of Cajal (ICC). Oxidative damage in diabetes appears to be one of the primary insults involved in the pathogenesis of several complications of diabetes, including gastroparesis. Recent studies have highlighted the potential role of macrophages as key cellular elements in the pathogenesis of diabetic gastroparesis. Macrophages are important for both homeostasis and defense against a variety of pathogens. Heme oxygenase 1 (HO1), an enzyme expressed in a subset of macrophages has emerged as a major protective mechanism against oxidative stress. Activation of macrophages with high levels of HO1 expression protects against development of delayed gastric emptying in animal models of diabetes, while activation of macrophages that do not express HO1 are linked to neuromuscular cell injury. Targeting macrophages and HO1 may therefore be a therapeutic option in diabetic gastroparesis.PurposeThis report briefly reviews the pathophysiology of diabetic gastroparesis with a focus on oxidative damage and how activation and polarization of different subtypes of macrophages in the muscularis propria determines development of delay in gastric emptying or protects against its development.Activation and polarization of macrophages may underlie the diverse cellular changes seen in diabetic gastroparesis including loss of interstitial cells of Cajal (ICC) and nNOS in enteric neurons. We review current knowledge on the role of macrophages in pathogenesis of diabetic gastroparesis. A review of the literature suggests that oxidative stress associated with diabetes activates macrophages. Activation of CD206+, anti-inflammatory M2 macrophages expressing heme oxygenase 1 (HO1) is protective while activation of pro-inflammatory M1 macrophages which lack HO1 is injurious and leads to the development of delay in gastric emptying.

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