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A Critical Role for Monocytes/Macrophages During Intestinal Inflammation-associated Lymphangiogenesis.

Abstract：

BACKGROUND:Inflammation-associated lymphangiogenesis (IAL) is frequently observed in inflammatory bowel diseases. IAL is believed to limit inflammation by enhancing fluid and immune cell clearance. Although monocytes/macrophages (MΦ) are known to contribute to intestinal pathology in inflammatory bowel disease, their role in intestinal IAL has never been studied mechanistically. We investigated contributions of monocytes/MΦ to the development of intestinal inflammation and IAL. METHODS:Because inflammatory monocytes express CC chemokine receptor 2 (CCR2), we used CCR2 diphtheria toxin receptor transgenic (CCR2.DTR) mice, in which monocytes can be depleted by diphtheria toxin injection, and CCR2 mice, which have reduced circulating monocytes. Acute or chronic colitis was induced by dextran sodium sulfate or adoptive transfer of CD4CD45RB T cells, respectively. Intestinal inflammation was assessed by flow cytometry, immunofluorescence, disease activity, and histopathology, whereas IAL was assessed by lymphatic vessel morphology and density. RESULTS:We demonstrated that intestinal MΦ expressed vascular endothelial growth factor-C/D. In acute colitis, monocyte-depleted mice were protected from intestinal injury and showed reduced IAL, which was reversed after transfer of wild-type monocytes into CCR2 mice. In chronic colitis, CCR2 deficiency did not attenuate inflammation but reduced IAL. CONCLUSIONS:We propose a dual role of MΦ in (1) promoting acute inflammation and (2) contributing to IAL. Our data suggest that intestinal inflammation and IAL could occur independently, because IAL was reduced in the absence of monocytes/MΦ, even when inflammation was present. Future inflammatory bowel disease therapies might exploit promotion of IAL and suppression of MΦ independently, to restore lymphatic clearance and reduce inflammation.

journal_name

Inflamm Bowel Dis

journal_title

Inflammatory bowel diseases

authors

Becker F,Kurmaeva E,Gavins FN,Stevenson EV,Navratil AR,Jin L,Tsunoda I,Orr AW,Alexander JS,Ostanin DV

doi

10.1097/MIB.0000000000000731

subject

Has Abstract

pub_date

2016-06-01 00:00:00

pages

1326-45

issue

eissn

1078-0998

issn

1536-4844

journal_volume

pub_type

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A Critical Role for Monocytes/Macrophages During Intestinal Inflammation-associated Lymphangiogenesis.