| First Author | Waddell A | Year | 2013 |
| Journal | J Immunol | Volume | 190 |
| Issue | 9 | Pages | 4773-85 |
| PubMed ID | 23562811 | Mgi Jnum | J:195493 |
| Mgi Id | MGI:5484686 | Doi | 10.4049/jimmunol.1200057 |
| Citation | Waddell A, et al. (2013) Intestinal CCL11 and Eosinophilic Inflammation Is Regulated by Myeloid Cell-Specific RelA/p65 in Mice. J Immunol 190(9):4773-85 |
| abstractText | In inflammatory bowel diseases (IBDs), particularly ulcerative colitis, intestinal macrophages (MPhis), eosinophils, and the eosinophil-selective chemokine CCL11, have been associated with disease pathogenesis. MPhis, a source of CCL11, have been reported to be of a mixed classical (NF-kappaB-mediated) and alternatively activated (STAT-6-mediated) phenotype. The importance of NF-kappaB and STAT-6 pathways to the intestinal MPhi/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-kappaB-dependent genes in pediatric ulcerative colitis colonic biopsies. Dextran sodium sulfate (DSS) exposure induced STAT-6 and NF-kappaB activation in mouse intestinal F4/80(+)CD11b(+)Ly6C(hi) (inflammatory) MPhis. DSS-induced CCL11 expression, eosinophilic inflammation, and histopathology were attenuated in RelA/p65(Deltamye) mice, but not in the absence of STAT-6. Deletion of p65 in myeloid cells did not affect inflammatory MPhi recruitment or alter apoptosis, but did attenuate LPS-induced cytokine production (IL-6) and Ccl11 expression in purified F4/80(+)CD11b(+)Ly6C(hi) inflammatory MPhis. 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 MPhis showed calprotectin-induced CCL11 production via a p65-dependent mechanism. Our results indicate that myeloid cell-specific NF-kappaB-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-kappaB-dependent pathways may be of therapeutic benefit for the treatment of eosinophilic inflammation and histopathology in IBD. |
