TY - JOUR
T1 - Leukocyte TLR5 deficiency inhibits atherosclerosis by reduced macrophage recruitment and defective T-cell responsiveness
AU - Ellenbroek, Guilielmus H. J. M.
AU - van Puijvelde, Gijs H. M.
AU - Anas, Adam A.
AU - Bot, Martine
AU - Asbach, Miriam
AU - Schoneveld, Arjan
AU - van Santbrink, Peter J.
AU - Foks, Amanda C.
AU - Timmers, Leo
AU - Doevendans, Pieter A.
AU - Pasterkamp, Gerard
AU - Hoefer, Imo E.
AU - van der Poll, Tom
AU - Kuiper, Johan
AU - de Jager, Saskia C. A.
PY - 2017
Y1 - 2017
N2 - 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 approximate to 25% (1030*10(3) +/- 63*10(3) vs. 792*10(3) +/- 61*10(3) mu m(2); p = 0.013) and decreased macrophage area (81.3 +/- 12.0 vs. 44.2 +/- 6.6 mu m(2); 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
AB - 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 approximate to 25% (1030*10(3) +/- 63*10(3) vs. 792*10(3) +/- 61*10(3) mu m(2); p = 0.013) and decreased macrophage area (81.3 +/- 12.0 vs. 44.2 +/- 6.6 mu m(2); 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
U2 - https://doi.org/10.1038/srep42688
DO - https://doi.org/10.1038/srep42688
M3 - Article
C2 - 28202909
SN - 2045-2322
VL - 7
SP - 42688
JO - Scientific reports
JF - Scientific reports
ER -