Toll-like receptor 5 (TLR5) is the receptor of bacterial Flagellin. Reportedly, TLR5 engagement helps to combat infections, especially at mucosal sites, by evoking responses from epithelial cells... Show moreToll-like receptor 5 (TLR5) is the receptor of bacterial Flagellin. Reportedly, TLR5 engagement helps to combat infections, especially at mucosal sites, by evoking responses from epithelial cells and immune cells. Here we report that TLR5 is expressed on a previously defined bipotent progenitor of macrophages (M phi s) and osteoclasts (OCs) that resides in the mouse bone marrow (BM) and circulates at low frequency in the blood. In vitro, Flagellin promoted the generation of M phi s, but not OCs from this progenitor. In vivo, M phi/OC progenitors were recruited from the blood into the lung upon intranasal inoculation of Flagellin, where they rapidly differentiated into M phi s. Recruitment of the M phi/OC progenitors into the lung was likely promoted by the CCL2/CCR2 axis, since the progenitors expressed CCR2 and type 2 alveolar epithelial cells (AECs) produced CCL2 upon stimulation by Flagellin. Moreover, CCR2 blockade reduced migration of the M phi/OC progenitors toward lung lavage fluid (LLF) from Flagellin-inoculated mice. Our study points to a novel role of the Flagellin/TLR5 axis in recruiting circulating M phi/OC progenitors into infected tissue and stimulating these progenitors to locally differentiate into M phi s. The progenitor pathway to produce M phi s may act, next to monocyte recruitment, to fortify host protection against bacterial infection at mucosal sites. Show less
Herein we report the design and synthesis of a series of highly selective CCR2 antagonists as18F‐labeled PET tracers. The derivatives were evaluated extensively for their off-target profile at 48... Show moreHerein we report the design and synthesis of a series of highly selective CCR2 antagonists as18F‐labeled PET tracers. The derivatives were evaluated extensively for their off-target profile at 48 different targets. The most potent and selective candidate was applied in vivo in a biodistribution study, demonstrating a promising profile for further preclinical development. This compound represents the first potential nonpeptidic PET tracer for the imaging of CCR2 receptors. Show less
This thesis focuses on the role of chemokine receptors CXCR3 and CCR2 in the inflammatory process and infection control using the zebrafish model. It describes the regulatory interplay between an... Show moreThis thesis focuses on the role of chemokine receptors CXCR3 and CCR2 in the inflammatory process and infection control using the zebrafish model. It describes the regulatory interplay between an atypical and a conventional chemokine receptor during chemotaxis in macrophages, the role of chemotactic signaling in cell polarization and explores an in vivo screening workflow for human anti-inflammatory drugs using zebrafish. Show less
Wezel, A.; Velden, D. van der; Maassen, J.M.; Lagraauw, H.M.; Vries, M.R. de; Karper, J.C.; ... ; Quax, P.H.A. 2015
