Blocking TLR2 in vivo protects against accumulation of inflammatory cells and neuronal injury in experimental stroke.
Reduced infarct volume in TLR2-knockout mice compared with C57Bl/6 wild-type mice has recently been shown in experimental stroke and confirmed in this study. We now also show a significant decrease of CD11b-positive cell counts and decreased neuronal death in the ischemic hemispheres of TLR2-deficient mice compared with C57Bl/6wt mice 2 days after transient focal cerebral ischemia. To examine the potential benefit of intravascular TLR2 inhibition, C57Bl/6wt mice were treated intraarterially with TLR2-blocking anti-TLR2 antibody (clone T2.5) after 45 minutes of cerebral ischemia and compared with control antibody (isotype) treated wild-type mice. Whereas T2.5-treated mice had no reduction in infarct volumes at 48 hours after reperfusion, they did have decreased numbers of CD11b-positive inflammatory cells and decreased neuronal death compared with isotype-treated control mice. Comparison of the isotype antibody treatment to control (saline) treatment showed no effects on infarct volumes or neuronal survival. However, mice treated with the control isotype antibody had increased numbers of CD11b-positive inflammatory cells compared with saline-treated animals. Thus, antibody treatment itself (i.e., control isotype antibody, but potentially of any antibody) may have adverse effects and limit therapeutic benefit of anti-TLR2-antibody therapy. We conclude that TLR2 mediates leukocyte and microglial infiltration and neuronal death, which can be attenuated by TLR2 inhibition. The TLR2 inhibition in vivo improves neuronal survival and may represent a future stroke therapy.
Ziegler
Gina
G
Max-Planck-Institute for Molecular Genetics, Berlin, Germany.
Freyer
Dorette
D
Harhausen
Denise
D
Khojasteh
Uldus
U
Nietfeld
Wilfried
W
Trendelenburg
George
G
D000818:Animals; D019138:Antibodies, Blocking / Q000494:pharmacology; D001929:Brain Edema / Q000473:pathology / Q000517:prevention & control; D039481:CD11b Antigen / Q000378:metabolism; D002452:Cell Count; D016923:Cell Death / Q000187:drug effects; D002544:Cerebral Infarction / Q000473:pathology / Q000517:prevention & control; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000473:pathology / Q000517:prevention & control; D007249:Inflammation / Q000473:pathology*; D002546:Ischemic Attack, Transient / Q000188:drug therapy / Q000473:pathology; D008264:Macrophages / Q000187:drug effects / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000473:pathology*; D015398:Signal Transduction / Q000187:drug effects / Q000235:genetics; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology*; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000502:physiology*
D019138:Antibodies, Blocking; D039481:CD11b Antigen; D051195:Toll-Like Receptor 2