title: A Critical Role for Monocytes/Macrophages During Intestinal Inflammation-associated Lymphangiogenesis.
abstract: 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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
authors.affiliation: *Department of Molecular & Cellular Physiology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana; †Department of General and Visceral Surgery, University Hospital Muenster, Germany; ‡Department of Medicine, Center of Excellence for Arthritis and Rheumatology, Louisiana State University Health Sciences Center-Shreveport, Louisiana; Departments of §Neurology, ‖Microbiology and Immunology, ¶Cellular Biology and Anatomy; and **Pathology, Louisiana State University Health Sciences Center-Shreveport, Shreveport, Louisiana.
authors.forename: Felix
authors.initials: F
authors.lastname: Becker
authors.forename: Elvira
authors.initials: E
authors.lastname: Kurmaeva
authors.forename: Felicity N E
authors.initials: FN
authors.lastname: Gavins
authors.forename: Emily V
authors.initials: EV
authors.lastname: Stevenson
authors.forename: Aaron R
authors.initials: AR
authors.lastname: Navratil
authors.forename: Long
authors.initials: L
authors.lastname: Jin
authors.forename: Ikuo
authors.initials: I
authors.lastname: Tsunoda
authors.forename: A Wayne
authors.initials: AW
authors.lastname: Orr
authors.forename: Jonathan S
authors.initials: JS
authors.lastname: Alexander
authors.forename: Dmitry V
authors.initials: DV
authors.lastname: Ostanin
mesh_terms: D000208:Acute Disease; D019264:Adoptive Transfer; D000818:Animals; D002908:Chronic Disease; D003092:Colitis / Q000139:chemically induced / Q000276:immunology* / Q000473:pathology*; D016264:Dextran Sulfate; D005260:Female; D007958:Leukocyte Count; D042583:Lymphangiogenesis; D042601:Lymphatic Vessels / Q000473:pathology*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D009000:Monocytes / Q000276:immunology* / Q000378:metabolism; D054390:Receptors, CCR2 / Q000235:genetics; D042582:Vascular Endothelial Growth Factor C / Q000378:metabolism
chemical_list: C515335:Ccr2 protein, mouse; D054390:Receptors, CCR2; D042582:Vascular Endothelial Growth Factor C; C467483:vascular endothelial growth factor C, mouse; D016264:Dextran Sulfate