title: Leukocyte TLR5 deficiency inhibits atherosclerosis by reduced macrophage recruitment and defective T-cell responsiveness.
abstract: Toll-like receptors (TLR) provide a critical link between innate and adaptive immunity, both important players in atherosclerosis. Since evidence for the role of TLR5 is lacking, we aimed to establish this in the immune axis of atherosclerosis. We assessed the effect of the TLR5-specific ligand Flagellin on macrophage maturation and T-cell polarisation. Next, we generated TLR5-/-LDLr-/-chimeras to study the effect of hematopoietic TLR5 deficiency on atherosclerosis formation. Flagellin stimulation did not influence wildtype or TLR5-/-macrophage maturation. Only in wildtype macrophages, Flagellin exposure increased MCP-1 and IL6 expression. Flagellin alone reduced T-helper 1 proliferation, which was completely overruled in the presence of T-cell receptor activation. In vivo, hematopoietic TLR5 deficiency attenuated atherosclerotic lesion formation by ≈25% (1030*103± 63*103vs. 792*103± 61*103μm2; p = 0.013) and decreased macrophage area (81.3 ± 12.0 vs. 44.2 ± 6.6 μm2; p = 0.011). In TLR5-/-chimeric mice, we observed lower IL6 plasma levels (36.4 ± 5.6 vs. 15.1 ± 2.2 pg/mL; p = 0.003), lower (activated) splenic CD4+T-cell content (32.3 ± 2.1 vs. 21.0 ± 1.2%; p = 0.0018), accompanied by impaired T-cell proliferative responses. In conclusion, hematopoietic TLR5 deficiency inhibits atherosclerotic lesion formation by attenuated macrophage accumulation and defective T-cell responsiveness.
authors.affiliation: Laboratory of Experimental Cardiology, University Medical Center Utrecht, The Netherlands.
authors.forename: Guilielmus H J M
authors.initials: GH
authors.lastname: Ellenbroek
authors.affiliation: Division of Biopharmaceutics, Leiden Academic Center for Drug Research, The Netherlands.
authors.forename: Gijs H M
authors.initials: GH
authors.lastname: van Puijvelde
authors.affiliation: Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, The Netherlands.
authors.forename: Adam A
authors.initials: AA
authors.lastname: Anas
authors.affiliation: Division of Biopharmaceutics, Leiden Academic Center for Drug Research, The Netherlands.
authors.forename: Martine
authors.initials: M
authors.lastname: Bot
authors.affiliation: Division of Biopharmaceutics, Leiden Academic Center for Drug Research, The Netherlands.
authors.forename: Miriam
authors.initials: M
authors.lastname: Asbach
authors.affiliation: Laboratory of Experimental Cardiology, University Medical Center Utrecht, The Netherlands.
authors.forename: Arjan
authors.initials: A
authors.lastname: Schoneveld
authors.affiliation: Division of Biopharmaceutics, Leiden Academic Center for Drug Research, The Netherlands.
authors.forename: Peter J
authors.initials: PJ
authors.lastname: van Santbrink
authors.affiliation: Division of Biopharmaceutics, Leiden Academic Center for Drug Research, The Netherlands.
authors.forename: Amanda C
authors.initials: AC
authors.lastname: Foks
authors.affiliation: Department of Cardiology, University Medical Center Utrecht, The Netherlands.
authors.forename: Leo
authors.initials: L
authors.lastname: Timmers
authors.affiliation: Department of Cardiology, University Medical Center Utrecht, The Netherlands.
authors.forename: Pieter A
authors.initials: PA
authors.lastname: Doevendans
authors.affiliation: Laboratory of Experimental Cardiology, University Medical Center Utrecht, The Netherlands.|Laboratory of Clinical Chemistry and Hematology, University Medical Center Utrecht, The Netherlands.
authors.forename: Gerard
authors.initials: G
authors.lastname: Pasterkamp
authors.affiliation: Laboratory of Experimental Cardiology, University Medical Center Utrecht, The Netherlands.|Laboratory of Clinical Chemistry and Hematology, University Medical Center Utrecht, The Netherlands.
authors.forename: Imo E
authors.initials: IE
authors.lastname: Hoefer
authors.affiliation: Division of Infectious Diseases, Academic Medical Center, University of Amsterdam, the Netherlands.|Center for Experimental and Molecular Medicine, Academic Medical Center, University of Amsterdam, The Netherlands.
authors.forename: Tom
authors.initials: T
authors.lastname: van der Poll
authors.affiliation: Division of Biopharmaceutics, Leiden Academic Center for Drug Research, The Netherlands.
authors.forename: Johan
authors.initials: J
authors.lastname: Kuiper
authors.affiliation: Laboratory of Experimental Cardiology, University Medical Center Utrecht, The Netherlands.|Division of Biopharmaceutics, Leiden Academic Center for Drug Research, The Netherlands.
authors.forename: Saskia C A
authors.initials: SC
authors.lastname: de Jager
mesh_terms: D000818:Animals; D050197:Atherosclerosis / Q000097:blood / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D002454:Cell Differentiation / Q000235:genetics / Q000276:immunology; D002465:Cell Movement / Q000235:genetics / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D004195:Disease Models, Animal; D018836:Inflammation Mediators / Q000378:metabolism; D007958:Leukocyte Count; D007962:Leukocytes / Q000276:immunology* / Q000378:metabolism*; D008264:Macrophages / Q000276:immunology* / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009000:Monocytes / Q000276:immunology / Q000378:metabolism; D058226:Plaque, Atherosclerotic / Q000235:genetics / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D016176:T-Lymphocyte Subsets / Q000166:cytology / Q000276:immunology* / Q000378:metabolism*; D051198:Toll-Like Receptor 5 / Q000172:deficiency*
chemical_list: D016207:Cytokines; D018836:Inflammation Mediators; D051198:Toll-Like Receptor 5