Intestinal CCL11 and eosinophilic inflammation is regulated by myeloid cell-specific RelA/p65 in mice.
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ABSTRACT: In inflammatory bowel diseases (IBDs), particularly ulcerative colitis, intestinal macrophages (M?s), eosinophils, and the eosinophil-selective chemokine CCL11, have been associated with disease pathogenesis. M?s, a source of CCL11, have been reported to be of a mixed classical (NF-?B-mediated) and alternatively activated (STAT-6-mediated) phenotype. The importance of NF-?B and STAT-6 pathways to the intestinal M?/CCL11 response and eosinophilic inflammation in the histopathology of experimental colitis is not yet understood. Our gene array analyses demonstrated elevated STAT-6- and NF-?B-dependent genes in pediatric ulcerative colitis colonic biopsies. Dextran sodium sulfate (DSS) exposure induced STAT-6 and NF-?B activation in mouse intestinal F4/80(+)CD11b(+)Ly6C(hi) (inflammatory) M?s. DSS-induced CCL11 expression, eosinophilic inflammation, and histopathology were attenuated in RelA/p65(?mye) mice, but not in the absence of STAT-6. Deletion of p65 in myeloid cells did not affect inflammatory M? recruitment or alter apoptosis, but did attenuate LPS-induced cytokine production (IL-6) and Ccl11 expression in purified F4/80(+)CD11b(+)Ly6C(hi) inflammatory M?s. Molecular and cellular analyses revealed a link between expression of calprotectin (S100a8/S100a9), Ccl11 expression, and eosinophil numbers in the DSS-treated colon. In vitro studies of bone marrow-derived M?s showed calprotectin-induced CCL11 production via a p65-dependent mechanism. Our results indicate that myeloid cell-specific NF-?B-dependent pathways play an unexpected role in CCL11 expression and maintenance of eosinophilic inflammation in experimental colitis. These data indicate that targeting myeloid cells and NF-?B-dependent pathways may be of therapeutic benefit for the treatment of eosinophilic inflammation and histopathology in IBD.
SUBMITTER: Waddell A
PROVIDER: S-EPMC3969817 | biostudies-literature | 2013 May
REPOSITORIES: biostudies-literature
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