CD14 Plays a Protective Role in Experimental Inflammatory Bowel Disease by Enhancing Intestinal Barrier Function

Abstract

Intestinal homeostasis disturbance through intestinal barrier disruption presumably plays a key role in inflammatory bowel disease (IBD) development. Genetic and candidate gene analyses in an Il10-deficient IBD mouse model system identified Cd14 as a potentially protective candidate gene. The role of Cd14 in colitis development was determined using dextran sulfate sodium (DSS)-induced acute and an Il10-deficiency-induced chronic model of intestinal inflammation. Intestinal permeability was investigated by fluorescein isothiocyanate-dextran uptake assay, quantitative RT-PCR analysis of tight junction proteins, myosin light chain kinase, and proinflammatory cytokine expression. Immunohistological staining of occludin, Ki-67, NF-κB-p65, and terminal deoxynucleotidyl transferase-mediated dUTP nick-end labeling assay was performed, and intestinal inflammation severity was evaluated histologically. Untreated B6-Cd14 mice and wild-type controls did not differ in intestinal barrier function. However, DSS-treated Cd14-deficient and B6-Il10Cd14 mice exhibited more severe intestinal barrier disruption, with increased histological scores and proinflammatory cytokine expression, compared to controls. Therefore, Cd14 deficiency did not influence epithelial integrity under steady-state conditions but caused intestinal barrier dysfunction under inflammation. As expected, CD14 overexpression increased barrier integrity. No difference in intestinal epithelial NF-κB translocation was observed between the investigated groups. Intestinal myosin light chain kinase expression decreased in Cd14-deficient mice under steady-state conditions and in the chronic model, whereas no difference was detected in the DSS models. Thus, CD14 plays a protective role in IBD development by enhancing intestinal barrier function.

Dietary Chitin Particles Called Mimetic Fungi Ameliorate Colitis in Toll-Like Receptor 2/CD14- and Sex-Dependent Manners

“…Previously, we identified that TLR2 and CD14 are essential for CMP-induced classical macrophage (M1) activation of peritoneal macrophages (29). TLR2 KO and CD14 KO mice are known to develop more severe colitis than wild-type (WT) mice in response to DSS treatments, indicating that both TLR2 and CD14 play protective roles (41,42). Therefore, we used 3%, instead of 4%, DSS and explored whether these chitin-binding proteins were responsible for anti-inflammatory effects of LCBs using male mice deficient in TLR2 and male mice deficient in CD14.…”

“…It is unclear why dietary LCBs worsened CD14 KO colitis. In this regard, Buchheister et al (42) demonstrated that the intestinal barrier function is not affected by CD14 deficiency but is reduced in CD14 KO colitis. Alternatively, Wang et al (43) demonstrated that increased inflammatory cytokines, including IFN-␥, induce intestinal epithelial barrier dysfunction by upregulating myosin light-chain kinase expression.…”

“…Provocative findings are that host chitin-binding TLR2 and CD14, protective in mouse colitis elicited by DSS (41,42), are both responsible for anti-inflammatory effects of LCBs. In general, these receptors are expressed by mucosal epithelial cells as well as myeloid cell populations; host immune responses mediated through TLR2 and/or CD14 signals seem to be regulated at least in part under sex chromosomes and be influenced by sex hormones (55)(56)(57)(58).…”

Tight junctions in the development of asthma, chronic rhinosinusitis, atopic dermatitis, eosinophilic esophagitis, and inflammatory bowel diseases

“…CD14 is mainly expressed on the surfaces of monocytes, macrophages, neutrophils, and DCs with a protective function in a dextran sodium sulfate induced colitis model 196,197 . Lack of CD14 results in increased proinflammatory cytokine expression and decreased expression of TJs in an IBD mouse model 198 . The proportion of monocytes is increased in the blood in patients with Crohn's disease and the proportion of CD14 high macrophages are strongly infiltrated in inflamed intestinal mucosa 199 …”

CD14 and ALPK1 Affect Expression of Tight Junction Components and Proinflammatory Mediators upon Bacterial Stimulation in a Colonic 3D Organoid Model

“…CD14 acts as a coreceptor of Toll-like receptor (TLR) 4 and is directly involved in the detection of lipopolysaccharide (LPS) and activation of NF-κB [10]. In previous studies, our group demonstrated that CD14 has a protective function on barrier integrity in a dextran sodium sulfate-(DSS-) induced acute colitis mouse model [11]. We also showed that in wild-type (WT) but not in Cd14 -/mice, monoassociation with Escherichia coli Nissle 1917 (EcN) leads to increased expression of tight junction (TJ) components, associated with protection against bacterial translocation [12].…”