CD206-positive M2 macrophages that express heme oxygenase-1 protect against diabetic gastroparesis in mice.
OBJECTIVE
Gastroparesis is a well-recognized complication of diabetes. In diabetics, up-regulation of heme oxygenase-1 (HO1) in gastric macrophages protects against oxidative stress-induced damage. Loss of up-regulation of HO1, the subsequent increase in oxidative stress, and loss of Kit delays gastric emptying; this effect is reversed by induction of HO1. Macrophages have pro- and anti-inflammatory activities, depending on their phenotype. We investigated the number and phenotype of gastric macrophages in NOD/ShiLtJ (nonobese diabetic [NOD]) mice after onset of diabetes, when delayed gastric emptying develops, and after induction of HO1 to reverse delay.


METHODS
Four groups of NOD and db/db mice were studied: nondiabetic, diabetic with normal emptying, diabetic with delayed gastric emptying, and diabetic with delayed gastric emptying reversed by the HO1 inducer hemin. Whole mount samples from stomach were labeled in triplicate with antisera against F4/80, HO1, and CD206, and macrophages were quantified in stacked confocal images. Markers for macrophage subtypes were measured by quantitative polymerase chain reaction.


RESULTS
Development of diabetes was associated with an increased number of macrophages and up-regulation of HO1 in CD206(+) M2 macrophages. Onset of delayed gastric emptying did not alter the total number of macrophages, but there was a selective loss of CD206(+)/HO1(+) M2 macrophages. Normalization of gastric emptying was associated with repopulation of CD206(+)/HO1(+) M2 macrophages.


CONCLUSIONS
CD206(+) M2 macrophages that express HO1 appear to be required for prevention of diabetes-induced delayed gastric emptying. Induction of HO1 in macrophages might be a therapeutic option for patients with diabetic gastroparesis.
Choi
Kyoung Moo
KM
Enteric Neuroscience Program and Department of Physiology, Mayo Clinic, Rochester, Minnesota, USA.
Kashyap
Purna C
PC
Dutta
Nirjhar
N
Stoltz
Gary J
GJ
Ordog
Tamas
T
Shea Donohue
Terez
T
Bauer
Anthony J
AJ
Linden
David R
DR
Szurszewski
Joseph H
JH
Gibbons
Simon J
SJ
Farrugia
Gianrico
G
D000818:Animals; D001119:Arginase / Q000235:genetics; D001786:Blood Glucose / Q000032:analysis; D048909:Diabetes Complications / Q000517:prevention & control*; D005260:Female; D005746:Gastric Emptying; D018589:Gastroparesis / Q000517:prevention & control*; D051547:Heme Oxygenase-1 / Q000032:analysis / Q000502:physiology*; D016753:Interleukin-10 / Q000235:genetics; D037181:Lectins, C-Type / Q000032:analysis*; D008264:Macrophages / Q000201:enzymology / Q000502:physiology*; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins / Q000032:analysis*; D008565:Membrane Proteins / Q000032:analysis / Q000502:physiology*; D051379:Mice; D016688:Mice, Inbred NOD; D011956:Receptors, Cell Surface / Q000032:analysis*
D001786:Blood Glucose; D037181:Lectins, C-Type; D000090323:Mannose Receptor; D037241:Mannose-Binding Lectins; D008565:Membrane Proteins; D011956:Receptors, Cell Surface; D016753:Interleukin-10; D051547:Heme Oxygenase-1; C496542:Hmox1 protein, mouse; C544448:Arg1 protein, mouse; D001119:Arginase