Advertisement

Macrophages: The Missing Link in Diabetic Gastroparesis?

  • Shanthi Srinivasan
    Correspondence
    Correspondence Address correspondence to: Shanthi Srinivasan, MD, Department of Digestive Diseases, Emory University School of Medicine, RM 1C-174, Atlanta VA Medical Center, 1670 Clairmont Road, Decatur, Georgia 30033.
    Affiliations
    Department of Digestive Diseases, Emory University School of Medicine, Atlanta, Georgia
    Search for articles by this author
Open AccessPublished:November 25, 2015DOI:https://doi.org/10.1016/j.jcmgh.2015.11.003
      Gastroparesis is a clinical condition associated with delayed gastric emptying in the absence of mechanical obstruction. Patients present with nausea, vomiting, bloating, and early satiety. The underlying cause may be related to diabetes but also can be caused by upper gastrointestinal surgery, neurologic disease, collagen vascular disease, viral infections, and drugs.
      • Tack J.
      • Carbone F.
      • Rotondo A.
      Gastroparesis.
      In approximately 35% of patients there is no underlying cause. The pathogenesis and underlying cellular changes in diabetic gastroparesis are largely unknown. Changes in neurons, the interstitial cells of Cajal (ICC), and intestinal smooth muscle have been believed to have shown in diabetic gastroparesis. Macrophages have been believed to play some role in the development of diabetic gastroparesis but the mechanisms are not known.
      In the article by Cipriani et al,
      • Cipriani G.
      • Gibbons S.J.
      • Verhulst P.-J.
      • et al.
      Diabetic Csf1op/op mice lacking macrophages are protected against the development of delayed gastric emptying.
      data are presented to support the role of macrophages in the development of delayed gastric emptying. Cipriani et al show the concept that macrophages are necessary for the pathogenesis of delayed gastric emptying. To do this, they used the Csf1op/op mice that lack biologically active macrophage-colony stimulating factor Csf1, resulting in the absence of Csf1-dependent tissue macrophages. Absence of macrophages in the muscle layer of the small intestine of these mice has been shown previously. Mice were injected with streptozotocin to make them diabetic and gastric emptying was assessed weekly. In addition, macrophages were identified by immunostaining and oxidative stress and messenger RNA levels were measured. The study showed that Csf1op/op mice have normal ICCs. When diabetes is induced there is increased oxidative stress in both the wild-type Csf1+/+ mice and the Csf1op/op mice. Interestingly, despite this increased oxidative stress, the Csf1op/op mice did not develop loss of ICCs and the consequent delayed gastric emptying, however, the wild-type mice did. This led to the conclusion that the presence of muscle layer macrophages is required for the development of diabetic gastroparesis.
      This work helps us to further understand the pathophysiology of diabetic gastroparesis with a focus on the muscle layer macrophages. It strengthens the role of ICC injury in diabetic gastroparesis and thereby highlights targets for the prevention and treatment of gastroparesis.
      Macrophages present in the muscle layer can be polarized in response to changes in the microenvironment and are classified as M1 (proinflammatory macrophages) and M2 (anti-inflammatory macrophages). A previous study by Choi et al
      • Choi K.M.
      • Kashyap P.C.
      • Dutta N.
      • et al.
      CD206-positive M2 macrophages that express heme oxygenase-1 protect against diabetic gastroparesis in mice.
      showed that CD206-positive M2 macrophages are very important in preventing diabetic gastroparesis and this appears to be owing due to a heme oxygenase–dependent mechanism. Interestingly, in human beings, the number of CD206-positive M2 macrophages correlates with the number of ICCs, and this in turn correlates with gastric emptying.
      • Bernard C.E.
      • Gibbons S.J.
      • Mann I.S.
      • et al.
      Association of low numbers of CD206-positive cells with loss of ICC in the gastric body of patients with diabetic gastroparesis.
      In the Csf1op/op mice the baseline gastric emptying time was less that of the wild-type mice. It was noted that with the induction of diabetes in the Csf1op/op mice there was no reduction in gastric emptying. This was despite evidence for increased oxidative stress in these mice to the levels seen in the wild-type (WT) mice with delayed gastric emptying. The WT mice without delayed gastric emptying had lower oxidative stress levels, indicating that oxidative stress does play a role in diabetes-related delayed gastric emptying. The findings in this study suggest that the M1 macrophages may be releasing proinflammatory cytokines, which are required for the streptozotocin-induced damage to the ICCs noted in the wild-type but not Csf1op/op mice. This protection was seen despite the mice being equally hyperglycemic and having similar levels of oxidative stress. The lack of macrophages could protect against the loss of ICCs induced by streptozotocin. One point to be noted is that the Csf1op/op mice had developmental abnormalities including failure to develop teeth and some skeletal abnormalities. The investigators did ensure that the mice completed at least 50% of the meal to ensure comparable gastric emptying data between WT and Csf1op/op mice.
      In summary, the study showed a role for macrophages in regulating the changes in the ICCs in diabetic gastroparesis, suggesting the role of M1 macrophages. Resident macrophages also could have a role in regulating gastrointestinal muscle contraction.
      • Schaefer N.
      • Tahara K.
      • Schmidt J.
      • et al.
      Resident macrophages are involved in intestinal transplantation-associated inflammation and motoric dysfunction of the graft muscularis.
      Future studies will need to examine the role of macrophages in other models of type 1 and type 2 diabetes. The current study advances the understanding of the complex pathophysiology of diabetic gastroparesis, focusing on the role of macrophages, and opens up a new area of research and potential therapeutic targets.

      References

        • Tack J.
        • Carbone F.
        • Rotondo A.
        Gastroparesis.
        Curr Opin Gastroenterol. 2015; 31: 499-505
        • Cipriani G.
        • Gibbons S.J.
        • Verhulst P.-J.
        • et al.
        Diabetic Csf1op/op mice lacking macrophages are protected against the development of delayed gastric emptying.
        Cell Mol Gastroenterol Hepatol. 2016; 2: 40-47
        • Choi K.M.
        • Kashyap P.C.
        • Dutta N.
        • et al.
        CD206-positive M2 macrophages that express heme oxygenase-1 protect against diabetic gastroparesis in mice.
        Gastroenterology. 2010; 138 (2409 e1): 2399-2409
        • Bernard C.E.
        • Gibbons S.J.
        • Mann I.S.
        • et al.
        Association of low numbers of CD206-positive cells with loss of ICC in the gastric body of patients with diabetic gastroparesis.
        Neurogastroenterol Motil. 2014; 26: 1275-1284
        • Schaefer N.
        • Tahara K.
        • Schmidt J.
        • et al.
        Resident macrophages are involved in intestinal transplantation-associated inflammation and motoric dysfunction of the graft muscularis.
        Am J Transplant. 2007; 7: 1062-1070

      Linked Article

      • Diabetic Csf1op/op Mice Lacking Macrophages Are Protected Against the Development of Delayed Gastric Emptying
        Cellular and Molecular Gastroenterology and HepatologyVol. 2Issue 1
        • Preview
          Diabetic 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.
        • Full-Text
        • PDF
        Open Access