Premium
The 5A apolipoprotein A‐I (apoA‐I) mimetic peptide ameliorates experimental colitis by regulating monocyte infiltration
Author(s) -
Nowacki Tobias M,
Remaley Alan T,
Bettenworth Dominik,
Eisenblätter Michel,
Vowinkel Thorsten,
Becker Felix,
Vogl Thomas,
Roth Johannes,
Tietge Uwe J,
Lügering Andreas,
Heidemann Jan,
Nofer JerzyRoch
Publication year - 2016
Publication title -
british journal of pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.432
H-Index - 211
eISSN - 1476-5381
pISSN - 0007-1188
DOI - 10.1111/bph.13556
Subject(s) - inflammation , monocyte , intravital microscopy , integrin alpha m , colitis , cell adhesion molecule , inflammatory bowel disease , peptide , chemistry , intercellular adhesion molecule 1 , immunology , tumor necrosis factor alpha , pharmacology , biochemistry , medicine , immune system , microcirculation , disease
Background and Purpose New therapies for inflammatory bowel disease (IBD) are highly desirable. As apolipoprotein (apo)A‐I mimetic peptides are beneficial in several animal models of inflammation, we hypothesized that they might be effective at inhibiting murine colitis. Experimental Approach Daily injections of 5A peptide, a synthetic bihelical apoA‐I mimetic dissolved in PBS, or PBS alone were administered to C57BL/6 mice fed 3% (w v ‐1 ) dextran sodium sulfate (DSS) in drinking water or healthy controls. Key Results Daily treatment with 5A peptide potently restricted DSS‐induced inflammation, as indicated by improved disease activity indices and colon histology, as well as decreased intestinal tissue myeloperoxidase levels and plasma TNFα and IL‐6 concentrations. Additionally, plasma levels of monocyte chemoattractant protein‐1 and the monocyte expression of adhesion‐mediating molecule CD11b were down‐regulated, pro‐inflammatory CD11b + /Ly6c high monocytes were decreased, and the number of intestinal monocytes was reduced in 5A peptide‐treated animals as determined by intravital macrophage‐related peptide‐8/14‐directed fluorescence‐mediated tomography and post‐mortem immunhistochemical F4/80 staining. Intravital fluorescence microscopy of colonic microvasculature demonstrated inhibitory effects of 5A peptide on leukocyte adhesion accompanied by reduced plasma levels of the soluble adhesion molecule sICAM‐1. In vitro 5A peptide reduced monocyte adhesion and transmigration in TNFα‐stimulated monolayers of human intestinal microvascular endothelial cells. Increased susceptibility to DSS‐induced inflammation was noted in apoA‐I −/− mice. Conclusions and Implications The 5A peptide is effective at ameliorating murine colitis by preventing intestinal monocyte infiltration and activation. These findings point to apoA‐I mimetics as a potential treatment approach for IBD.