The function of TLRs in innate immunity has aroused worldwide attention soon after its discovery. Because of the broad functions of TLR2 in innate immunity, the drive for the development of TLR2... Show moreThe function of TLRs in innate immunity has aroused worldwide attention soon after its discovery. Because of the broad functions of TLR2 in innate immunity, the drive for the development of TLR2-targeted vaccines or therapeutic treatments has accelerated in the last decades. However, its dual role in both activation and suppression of innate immune responses makes it very difficult to use the available results from basic research for the development of clinical trials. In addition, it is still not clear what is the function of TLR2 in regulating phagocytic cell migration. Therefore, we aimed to determine the function of TLR2 in mycobacterial infection and explore its role in regulating phagocytic cell migration in inflammatory tissue by using a zebrafish larval model in this thesis. We showed that infection of a tlr2 mutant in zebrafish larvae leads to a higher mycobacterial burden, accompanied by a lower number of granulomas and increased extracellular bacterial growth. Through a tail fin wounding and tail fin infection zebrafish model, we demonstrated that tlr2 is involved in modulating leukocyte migration. This thesis provides a better understanding of the functions of TLR2 in innate immune responses to infection and tissue wounding. Show less
Glucocorticoids (GCs) are widely prescribed as anti-inflammatory drugs due to their well-established immunosuppressive effects. However, their utilization is severely limited by the occurrence of... Show moreGlucocorticoids (GCs) are widely prescribed as anti-inflammatory drugs due to their well-established immunosuppressive effects. However, their utilization is severely limited by the occurrence of side effects and drug resistance. Therefore, there is still a major need to investigate the molecular and cellular mechanisms underlying the effects of GCs. Zebrafish are increasingly used as an in vivo model system for studying the immune system, in particular the inflammatory response. In Chapter 2, an overview is provided of the available inflammation models in zebrafish, and how they are used to unravel molecular mechanisms underlying the inflammatory response and for testing of potential novel anti-inflammatory drugs, in particular GCs. In this thesis, we have used zebrafish model system to study molecular and cellular mechanisms of GC action on the immune system and to develop a model for in vivo screening of the anti-inflammatory effects as well as possible adverse effects of novel GC therapies. For this purpose, we have studied the effect of GCs on leukocyte migration and differentiation during an inflammatory response (Chapter 3), how GCs modulate the immune response to a mycobacterial infection (Chapter 4), and we have investigated targeting of GCs to inflamed tissue by liposomal delivery (Chapter 5). Show less
