title: Blocking TLR2 activity diminishes and stabilizes advanced atherosclerotic lesions in apolipoprotein E-deficient mice.
abstract: OBJECTIVE
  Toll-like receptor 2 (TLR2) signaling plays a critical role in the initiation of atherosclerosis. The aim of this study was to investigate whether blocking TLR2 activity could produce therapeutic effects on advanced atherosclerosis.
  
  
  METHODS
  Forty-week old apolipoprotein E-deficient (ApoE(-/-)) mice fed on a normal diet were intravenously injected with a TLR2-neutralizing antibody or with an isotype-matched IgG for 18 weeks. Double-knockout ApoE(-/-)Tlr2(-/-) mice were taken as a positive control. At the end of the treatments, the plasma lipid levels were measured, and the plaque morphology, pro-inflammatory cytokines expression and apoptosis in arteries were analyzed. In the second part of this study, 6-week old ApoE(-/-) and ApoE(-/-)Tlr2(-/-) mice fed on a high-cholesterol diet for 12 to 24 weeks, the expression levels of TLR2 and apoptotic markers in arteries were examined.
  
  
  RESULTS
  Blockade of TLR2 activity with TLR2-neutralizing antibody or knockout of Tlr2 gene did not alter the plasma lipid levels in ApoE(-/-) mice. However, the pharmacologic and genetic manipulations significantly reduced the plaque size and vessel stenosis, and increased plaque stability in the brachiocephalic arteries. The protective effects of TLR2 antagonism were associated with the suppressed expression of pro-inflammatory cytokines IL-6 and TNF-α and the inactivation of transcription factors NF-κB and Stat3. In addition, blocking TLR2 activity attenuated ER stress-induced macrophage apoptosis in the brachiocephalic arteries, which could promote the resolution of necrotic cores in advanced atherosclerosis. Moreover, high-cholesterol diet more prominently accelerated atherosclerotic formation and increased the expression of pro-apoptotic protein CHOP and apoptosis in ApoE(-/-) mice than in ApoE(-/-)Tlr2(-/-) mice.
  
  
  CONCLUSIONS
  The pharmacologic or genetic blockade of TLR2 activity diminishes and stabilizes advanced atherosclerotic lesions in ApoE(-/-) mice. Thus, targeting TLR2 signaling may be a promising therapeutic strategy against advanced atherosclerosis.
authors.affiliation: Molecular Immunology and Pharmacology Group, State Key Laboratory of Bioactive Substance and Function of Natural Medicines, Institute of Meteria Medica, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing 100050, China.
authors.forename: Xiao-xing
authors.initials: XX
authors.lastname: Wang
authors.forename: Xiao-xi
authors.initials: XX
authors.lastname: Lv
authors.forename: Jia-ping
authors.initials: JP
authors.lastname: Wang
authors.forename: Hui-min
authors.initials: HM
authors.lastname: Yan
authors.forename: Zi-yan
authors.initials: ZY
authors.lastname: Wang
authors.forename: Han-zhi
authors.initials: HZ
authors.lastname: Liu
authors.forename: Xiao-ming
authors.initials: XM
authors.lastname: Fu
authors.forename: Zhuo-wei
authors.initials: ZW
authors.lastname: Hu
mesh_terms: D000818:Animals; D057134:Antibodies, Neutralizing / Q000494:pharmacology / Q000627:therapeutic use; D001057:Apolipoproteins E / Q000172:deficiency*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D058226:Plaque, Atherosclerotic / Q000188:drug therapy* / Q000378:metabolism* / Q000473:pathology; D011897:Random Allocation; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism*
chemical_list: D057134:Antibodies, Neutralizing; D001057:Apolipoproteins E; C493486:Tlr2 protein, mouse; D051195:Toll-Like Receptor 2