Roles of Endothelial Toll-like Receptor (TLR) 4 in Neutrophil Recruitment During Experimental Colitis
Abstract
The innate immune system uses pattern recognition receptors (PRRs) encoded by germline genes of the host to detect danger signals from damaged tissues as well as conserved microbial “molecular patterns” called damage- or pathogen-associated molecular patterns (DAMPs or PAMPs). PRRs are essential for the initiation of immune responses. Among PRRs, Toll-like Receptor (TLR) 4 has gained a great deal of attention, as it is the first discovered PRR, and it is the receptor for lipopolysaccharide (LPS, a major cell wall component of Gram-negative bacteria). It has been demonstrated that TLR4 has many roles in the pathogenesis of inflammatory bowel diseases (IBD) and experimental colitis. However, the functions of endothelial TLR4 remain unclear. In this thesis, we hypothesized that endothelial TLR4 provokes neutrophil recruitment in the colon during experimental colitis. Endothelial TLR4 is upregulated during dextran sulfate sodium (DSS)-induced colitis, in part by tumor necrosis factor (TNF)-α. The upregulation of endothelial TLR4 occurs prior to neutrophil recruitment in DSS colitis. Loss of endothelial TLR4 attenuates the histological damage in DSS-induced colitis. Mice lacking endothelial TLR4 have fewer colonic neutrophils during DSS colitis. Mice with a specific deletion of endothelial TLR4 have a decreased number of adherent neutrophils in the microcirculation of their colon upon DSS challenge. NanoString nCounter CodeSet analysis showed endothelial intercellular adhesion molecule (ICAM) 2 has lower expression in mice lacking endothelial TLR4, measured by immunofluorescence and flow cytometry. In vitro cultured endothelial cells respond to LPS challenge to increase the expression of ICAM2. Blocking of ICAM2 also inhibits neutrophil adhesion in DSS colitis. In conclusion, endothelial TLR4 is an active player in experimental colitis and mediates neutrophil recruitment.
Description
Keywords
Immunology
Citation
Wang, T. (2017). Roles of Endothelial Toll-like Receptor (TLR) 4 in Neutrophil Recruitment During Experimental Colitis (Doctoral thesis, University of Calgary, Calgary, Canada). Retrieved from https://prism.ucalgary.ca. doi:10.11575/PRISM/27690