The Role Of Peritoneal CD169~+ Macrophages In DSS-Induced Colitis

Background:Crohn’s disease (CD) and ulcerative colitis (UC) are the most widely known types of IBD and have been the focus of attention due to their increasing incidence. The correlation between inflammation and the development of cancer has been confirmed by many studies, and IBD is also related to a substantial increase in the risk of colorectal cancer (CRC). At present, although the factors that contribute to the development of IBD and the pathogenesis have not been fully elucidated, an interaction between genetic, immune and environmental risk factors is thought to play a role in the pathogenesis of IBD.Macrophages, known for their role as immune sentinels, play a critical role in inflammation disease. Macrophages are highly heterogeneous cells that many tissues and serous cavities contain multiple types of macrophages with distinct phenotypes and functions. CD 169 (also known as sialoadhesin, Siglec-1) is a cell surface sialic-acid-binding receptor, which is expressed by specific macrophage subsets. In lymph node, CD169+ macrophages dominate antitumor immunity by phagocytosing dead tumor cells transported via lymphatic flow and crosspresenting tumor antigens to CD8+ T cells subsequently. In spleen, CD169+ macrophages that located in the marginal zone (MZ) have a role in inducing immune tolerance. It has been reported a LP-resident macrophage subset expressing CD169 links mucosal damage and inflammatory monocyte recruitment. Peritoneal macrophages also play important roles in the control of inflammatory pathologies, as well as in the defense against infection of the abdominal cavity. However, whether a peritoneal macrophage expressing CD 169 plays important role in mucosal inflammation has not been reported yet.Research purpose:To study the role of a peritoneal CD169-expressing macrophages subset during the development of inflammation by using Dextran sulphate sodium (DSS) induced colitis and CD169-DTR (diphtheria toxin receptor) transgenic mice, and try to investigate the cellular and molecular mechanism of IBD mediated by CD 169 expressing cells in peritoneal cavity.Methods:Firstly, the role of CD11b+CD169+ macrophages from peritoneal cavity was examined by FACS and immunofluorescence histochemistry during the inflammatory of DSS-induced colitis. Next, the role of peritonealCD169+ macrophages in DSS induced colitis was studied by using the CD169-human diphtheria toxin receptor (DTR) transgenic mice in which CD169+ macrophages could be deleted by diphtheria toxin (DT) injection. Wild type (WT) mice and CD169-DTR mice were administrated orally with 3.5% DSS in drinking water for 7 days to induce colitis. The severity of colitis was assessed by body weight, colon length and histological examination. And the expression levels of inflammatory cytokines and chemokines in the peritoneal macrophages were also detected by Q-PCR and ELISA both in WT mice and DT-injected CD169-DTR mice. At last, the potential effect of CCL22 for therapy of IBD was explored by using DSS-induced colitis.Results:Both the results of FACS and histological analysis showed that the numbers of CD11b+CD169+ macrophages increased significantly during the DSS-induced colitis and these results strongly indicated that peritoneal macrophages expressing CD 169 were exactly involved in the UC. Moreover, DSS-induced colitis was alleviated in CD169-DTR mice at least partially due to the deletion CD169+ macrophages. The symptoms of colitis such as diarrhea, rectal bleeding and weight loss were not significant in CD169-DTR mice than those in WT mice and the expression levels of inflammatory cytokines such as IL-1β、IL-6、IL-12、IL-23 and TNFa decreased significantly in CD169-DTR mice than those in WT mice. Histological examination of the colons from CD169-DTR mice showed a lower degree of mucosal injury and greatly reduced numbers of infiltrating inflammatory cells. Furthermore, the CCL22 expression level in peritoneal macrophages from CD169-DTR mice was much higher than that from WT mice in DSS-induced colitis. And, a total of six daily subcutaneous injections of rmCCL22 during the DSS-induced colitis ameliorated clinical symptoms of colitis.Conclusions:The present study demonstrated peritoneal CD169+ macrophages play critical role in DSS-induced colitis. CD169+ macrophages transiently deleted by DT injection caused higher expression of CCL22 in DSS-induced colitis. The in vivo treatment with rmCCL22 ameliorated the clinical symptoms of DSS-induced colitis. CD169+ macrophages may influence the DSS-induced colitis by dominantly the secreting of CCL22. CCL22 could be potentially used as a preventive agent or as an adjuvant in anti-inflammatory therapy.