Role of macrophages and eosinophils in inflammatory bowel diseases
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University of Cincinnati / OhioLINK
2012
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ndltd-OhioLink-oai-etd.ohiolink.edu-ucin13279496082021-08-03T06:15:19Z Role of macrophages and eosinophils in inflammatory bowel diseases Waddell, Amanda B. Immunology eotaxin-1 ulcerative colitis inflammatory bowel diseases NF-kappa B STAT-6 macrophages The inflammatory bowel diseases (IBD) are chronic, relapsing and remitting gastrointestinal diseases of unknown etiology. It is postulated that in genetically susceptible hosts, epithelial barrier function is disrupted and intestinal microbes activate microbial sensing systems in macrophages (MΦs)/dendritic cells, which initiate an adaptive immune response, characterized by both CD4<sup>+</sup> T helper (TH)1 and TH17 cells in Crohn’s disease (CD) and by a TH17/TH2 response in ulcerative colitis (UC). These activated T cells release an array of pro-inflammatory cytokines, which promotes the recruitment of other immune cells, including monocytes/MΦs, neutrophils and eosinophils, all of which cause extensive damage to the local tissues. The involvement of cell-cell interactions between eosinophils and MΦs and the importance of these interactions to the pathophysiology of IBD remain poorly defined. In this dissertation, we employ a mouse model of experimental colitis to further understand the interactions between eosinophils and MΦs in the pathogenesis of the chronic inflammatory response in IBD. We demonstrate increased eosinophil numbers and degranulation in rectosigmoid pediatric UC colonic biopsies compared to healthy control biopsies and that eosinophil levels correlate with disease severity. In preclinical studies employing eosinophil-deficient mice, we demonstrate that eosinophils play a pathogenic role in the histopathology of DSS-induced colitis. Furthermore, we demonstrate increased levels of the eosinophil-specific chemokines, eotaxin-1/CCL11 and eotaxin-2/CCL24 in the colon during DSS-induced colitis, and we identify that CCL11 and not CCL24 is required for DSS-induced eosinophilia. Furthermore, we identify F4/80<sup>+</sup> MΦs as a cellular source of CCL11 and demonstrate a role for a subset of pro-inflammatory colonic MΦs (F4/80<sup>+</sup>CD11b<sup>+</sup>Ly6C<sup>hi</sup>) in CCL11 expression and eosinophil recruitment in DSS-induced colitis. Consistent with this preclinical observation, we show that CCL11 mRNA is increased and correlates with eosinophil levels and that CD68<sup>+</sup> MΦs express CCL11 in pediatric UC biopsies. Using a novel mouse, RelA/p65<sup>Δmye</sup>, which lacks expression of NF-κB RelA/p65 in myeloid cells, we demonstrate that colonic CCL11 expression, eosinophilia and DSS-induced histopathology are dependent on myeloid expressed RelA/p65. These studies demonstrate a role for RelA/p65 activation in MΦs in the regulation of MΦ-derived CCL11, DSS-induced eosinophilia and disease pathology. These data provide important insights into the role of both eosinophils and MΦs in IBD and indicate that targeting myeloid cells and NF-κB-dependent pathways may be of therapeutic benefit for the treatment of eosinophilic inflammation in IBD. 2012-04-20 English text University of Cincinnati / OhioLINK http://rave.ohiolink.edu/etdc/view?acc_num=ucin1327949608 http://rave.ohiolink.edu/etdc/view?acc_num=ucin1327949608 unrestricted This thesis or dissertation is protected by copyright: all rights reserved. It may not be copied or redistributed beyond the terms of applicable copyright laws. |
| collection |
NDLTD |
| language |
English |
| sources |
NDLTD |
| topic |
Immunology eotaxin-1 ulcerative colitis inflammatory bowel diseases NF-kappa B STAT-6 macrophages |
| spellingShingle |
Immunology eotaxin-1 ulcerative colitis inflammatory bowel diseases NF-kappa B STAT-6 macrophages Waddell, Amanda B. Role of macrophages and eosinophils in inflammatory bowel diseases |
| author |
Waddell, Amanda B. |
| author_facet |
Waddell, Amanda B. |
| author_sort |
Waddell, Amanda B. |
| title |
Role of macrophages and eosinophils in inflammatory bowel diseases |
| title_short |
Role of macrophages and eosinophils in inflammatory bowel diseases |
| title_full |
Role of macrophages and eosinophils in inflammatory bowel diseases |
| title_fullStr |
Role of macrophages and eosinophils in inflammatory bowel diseases |
| title_full_unstemmed |
Role of macrophages and eosinophils in inflammatory bowel diseases |
| title_sort |
role of macrophages and eosinophils in inflammatory bowel diseases |
| publisher |
University of Cincinnati / OhioLINK |
| publishDate |
2012 |
| url |
http://rave.ohiolink.edu/etdc/view?acc_num=ucin1327949608 |
| work_keys_str_mv |
AT waddellamandab roleofmacrophagesandeosinophilsininflammatoryboweldiseases |
| _version_ |
1719433514363912192 |