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Background & Aims: Muscularis propria macrophages lie close to cells that regulate gastrointestinal motor function, including interstitial cells of Cajal (ICC) and myenteric neurons. In animal models of diabetic gastroparesis, development of delayed gastric emptying has been associated with loss of macrophages that express cytoprotective markers and reduced networks of ICC. Mice with long-term diabetes and normal gastric emptying have macrophages that express anti-inflammatory markers and have normal gastric ICC. Mice homozygous for the osteopetrosis spontaneous mutation in the colony-stimulating factor 1 gene (Csf1op/op) do not have macrophages; when they are given streptozotocin to induce diabetes, they do not develop delayed gastric emptying. We investigated whether population of the gastric muscularis propria of diabetic Csf1op/op mice with macrophages is necessary to change gastric emptying, ICC, and myenteric neurons and investigated the macrophage-derived factors that determine whether diabetic mice do or do not develop delayed gastric emptying.

Methods: Wild-type and Csf1op/op mice were given streptozotocin to induce diabetes. Some Csf1op/op mice were given daily intraperitoneal injections of CSF1 for 7 weeks; gastric tissues were collected and cellular distributions were analyzed by immunohistochemistry. CD45 + , CD11b + , F4/80 + macrophages were dissociated from gastric muscularis propria, isolated by flow cytometry and analyzed by quantitative real-time polymerase chain reaction. Cultured gastric muscularis propria from Csf1op/op mice was exposed to medium that was conditioned by culture with bone marrow-derived macrophages from wild-type mice.

Results: Gastric muscularis propria from Csf1op/op mice given CSF1 contained macrophages; 11 of 15 diabetic mice given CSF1 developed delayed gastric emptying and had damaged ICC. In non-diabetic Csf1op/op mice, administration of CSF1 reduced numbers of gastric myenteric neurons but did not affect the proportion of nitrergic neurons or ICC. In diabetic Csf1op/op mice given CSF1 that developed delayed gastric emptying, the proportion of nitrergic neurons was the same as in non-diabetic wild-type controls. Medium conditioned by macrophages previously exposed to oxidative injury caused damage to ICC in cultured gastric muscularis propria from Csf1op/op mice; neutralizing antibodies against IL6R or TNF prevented this damage to ICC. CD45 + , CD11b + , and F4/80 + macrophages isolated from diabetic wild-type mice with delayed gastric emptying expressed higher levels of messenger RNAs encoding inflammatory markers (IL6 and inducible nitric oxide synthase) and lower levels of messenger RNAs encoding markers of anti-inflammatory cells (heme oxygenase 1, arginase 1, and FIZZ1) than macrophages isolated from diabetic mice with normal gastric emptying.

Conclusions: In studies of Csf1op/op and wild-type mice with diabetes, we found delayed gastric emptying to be associated with increased production of inflammatory factors, and reduced production of anti-inflammatory factors, by macrophages, leading to loss of ICC.

Titel:	Change in Populations of Macrophages Promotes Development of Delayed Gastric Emptying in Mice.
Autor/in / Beteiligte Person:	Cipriani, G ; Gibbons, SJ ; Miller, KE ; Yang, DS ; Terhaar, ML ; Eisenman, ST ; Ördög, T ; Linden, DR ; Gajdos, GB ; Szurszewski, JH ; Farrugia, G
Link:	Full Text Finder (Volltext)
Zeitschrift:	Gastroenterology, Jg. 154 (2018-06-01), Heft 8, S. 2122-2136.e12
Veröffentlichung:	Philadelphia, PA : W.B. Saunders ; <i>Original Publication</i>: Baltimore., 2018
Medientyp:	academicJournal
ISSN:	1528-0012 (electronic)
DOI:	10.1053/j.gastro.2018.02.027
Schlagwort:	Animals Diabetes Mellitus, Experimental chemically induced Diabetes Mellitus, Experimental genetics Gastroparesis etiology Humans Immunohistochemistry Interstitial Cells of Cajal physiology Macrophage Colony-Stimulating Factor genetics Mice Muscle, Smooth cytology Muscle, Smooth pathology Muscle, Smooth physiopathology Mutation Stomach cytology Stomach pathology Streptozocin toxicity Diabetes Mellitus, Experimental complications Gastric Emptying physiology Gastroparesis physiopathology Macrophages physiology Stomach physiopathology
Sonstiges:	Nachgewiesen in: MEDLINE Sprachen: English Publication Type: Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't Language: English [Gastroenterology] 2018 Jun; Vol. 154 (8), pp. 2122-2136.e12. <i>Date of Electronic Publication: </i>2018 Mar 06. MeSH Terms: Diabetes Mellitus, Experimental / complications ; Gastric Emptying / physiology ; Gastroparesis / physiopathology ; Macrophages / physiology ; Stomach / *physiopathology ; Animals ; Diabetes Mellitus, Experimental / chemically induced ; Diabetes Mellitus, Experimental / genetics ; Gastroparesis / etiology ; Humans ; Immunohistochemistry ; Interstitial Cells of Cajal / physiology ; Macrophage Colony-Stimulating Factor / genetics ; Mice ; Muscle, Smooth / cytology ; Muscle, Smooth / pathology ; Muscle, Smooth / physiopathology ; Mutation ; Stomach / cytology ; Stomach / pathology ; Streptozocin / toxicity References: Neurogastroenterol Motil. 2014 Sep;26(9):1275-84. (PMID: 25041465) ; Gastroenterology. 2011 May;140(5):1575-85.e8. (PMID: 21300066) ; Mol Reprod Dev. 1997 Jan;46(1):4-10. (PMID: 8981357) ; Nat Immunol. 2014 Oct;15(10 ):929-937. (PMID: 25151491) ; Gastroenterology. 2008 Dec;135(6):2055-64, 2064.e1-2. (PMID: 18926825) ; Sci Rep. 2016 Jan 13;6:19396. (PMID: 26759189) ; J Clin Invest. 2000 Sep;106(6):803. (PMID: 10995791) ; Dig Dis. 1995 Sep-Oct;13(5):291-300. (PMID: 8542664) ; Cell. 2014 Jul 17;158(2):300-313. (PMID: 25036630) ; Gastroenterology. 2010 Sep;139(3):942-52. (PMID: 20621681) ; Am J Gastroenterol. 2001 May;96(5):1422-8. (PMID: 11374677) ; Histol Histopathol. 1995 Jul;10(3):719-36. (PMID: 7579823) ; Nature. 1990 May 31;345(6274):442-4. (PMID: 2188141) ; Proc Natl Acad Sci U S A. 2017 May 2;114(18):E3709-E3718. (PMID: 28420791) ; Cell Mol Gastroenterol Hepatol. 2016 Jan 1;2(1):40-47. (PMID: 26771000) ; Kidney Int Suppl. 2000 Sep;77:S26-30. (PMID: 10997687) ; Auton Neurosci. 2012 Jul 2;169(1):12-27. (PMID: 22436622) ; Nat Clin Pract Gastroenterol Hepatol. 2007 Jun;4(6):336-46. (PMID: 17541447) ; Proc Natl Acad Sci U S A. 1990 Jun;87(12):4828-32. (PMID: 2191302) ; Cell Mol Gastroenterol Hepatol. 2016 Mar 1;2(2):120-130.e1. (PMID: 27047989) ; Gastroenterology. 2010 Jun;138(7):2399-409, 2409.e1. (PMID: 20178793) ; Cell Mol Gastroenterol Hepatol. 2016 Apr 23;2(4):454-467. (PMID: 27795979) ; Curr Top Med Chem. 2009;9(7):599-610. (PMID: 19689368) ; Cell. 2016 Jan 28;164(3):378-91. (PMID: 26777404) ; Gastroenterology. 2017 Aug;153(2):521-535.e20. (PMID: 28438610) ; Development. 1994 Jun;120(6):1357-72. (PMID: 8050349) ; Gastroenterology. 2002 Dec;123(6):2028-40. (PMID: 12454859) ; Nat Rev Immunol. 2008 Dec;8(12):958-69. (PMID: 19029990) ; Annu Rev Immunol. 2015;33:643-75. (PMID: 25861979) ; Diabetes. 2000 Oct;49(10):1731-9. (PMID: 11016458) ; Neurogastroenterol Motil. 2004 Feb;16(1):39-51. (PMID: 14764204) ; Gut. 2018 May;67(5):827-836. (PMID: 28228489) ; Neurogastroenterol Motil. 2017 Apr;29(4):. (PMID: 27781339) ; PLoS One. 2015 Feb 06;10(2):e0115563. (PMID: 25659123) ; Life Sci. 2013 Jun 21;92(23):1110-7. (PMID: 23643634) Grant Information: P01 DK068055 United States DK NIDDK NIH HHS; P30 DK084567 United States DK NIDDK NIH HHS; R01 DK058185 United States DK NIDDK NIH HHS Contributed Indexing: Keywords: Cytokine; Gastroparesis; ICC; Immune Response Substance Nomenclature: 5W494URQ81 (Streptozocin) ; 81627-83-0 (Macrophage Colony-Stimulating Factor) Entry Date(s): Date Created: 20180305 Date Completed: 20180718 Latest Revision: 20221013 Update Code: 20240513 PubMed Central ID: PMC5985210

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Change in Populations of Macrophages Promotes Development of Delayed Gastric Emptying in Mice.