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2015 ; 21
(6
): 1297-305
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Monocyte and M1 Macrophage-induced Barrier Defect Contributes to Chronic
Intestinal Inflammation in IBD
#MMPMID25901973
Lissner D
; Schumann M
; Batra A
; Kredel LI
; Kühl AA
; Erben U
; May C
; Schulzke JD
; Siegmund B
Inflamm Bowel Dis
2015[Jun]; 21
(6
): 1297-305
PMID25901973
show ga
BACKGROUND: Macrophages are key players in inflammatory bowel diseases (IBD).
This study aimed to determine site-specific effects of defined macrophage
subtypes on the integrity of the intestinal epithelial barrier. METHODS:
Macrophage subtypes in situ in intestinal specimens of patients with IBD were
visualized by immunohistochemistry. In vitro polarization of human peripheral
CD14 cells yielded M1 or M2 macrophages. The influence of primary monocytes or
macrophage subtypes on epithelial barrier integrity was analyzed by
transepithelial resistance measurements, Western blot analysis, confocal laser
scanning microscopy, and cytometric bead array in a coculture model of primary
human macrophages and layers of intestinal epithelial cell lines. RESULTS: The
lamina propria of the inflamed intestine in patients with IBD, predominantly in
Crohn's disease, is massively infiltrated by CD68 cells also positive for
inducible nitric oxide synthase and tumor necrosis factor (TNF) ?. The presence
of M1 macrophage shifted the balance in the local macrophage compartment towards
a proinflammatory state. In the coculture model, monocytes and M1 macrophages
reduced transepithelial resistance as a marker for epithelial barrier integrity.
The mechanisms for paracellular leakage included intracellular relocalization of
tight junction proteins like claudin-2 and epithelial cell apoptosis. Determined
by specific cytokine blockade, M1 macrophages exerted their deleterious effect
mainly through TNF-?, whereas monocyte-mediated damage was driven by the
inflammasome effector cytokines, interleukin-1? and interleukin-18. CONCLUSIONS:
Lamina propria monocytes and M1 macrophages invading intestinal tissues directly
contribute to disrupting the epithelial barrier through deregulation of tight
junction proteins and induction of epithelial cell apoptosis, thus driving
intestinal inflammation in IBD.